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10091612 | Variations in the monoamine oxidase B (MAOB) gene are associated with Parkinson's disease. | The monoamine oxidase B gene (MAOB; Xp15.21-4) is a candidate gene for Parkinson's disease (PD) given its role in dopamine metabolism and its possible role in the activation of neurotoxins. The association of MAOB polymorphisms (a [GT] repeat allelic variation in intron 2 and an A-G transition in intron 13) with Parkinson's disease (PD) was studied in an Australian cohort of 204 (male:female ratio 1.60) people with PD and 285 (male:female ratio 1.64) age- and gender-matched control subjects. Genomic DNA was extracted from venous blood and polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis and a DNA fragment analyzer, while the G-A genotype was determined using 2% agarose gel electrophoresis. The G-A polymorphism showed no association with PD (odds ratio [OR] = 0.80; p = 0.51; 95% confidence interval [CI] = 0.42-1.53). There was a significant difference in allele frequencies of the (GT) repeat allelic variation between patients and control subjects (chi2 = 20.09; p<0.01). After statistical adjustment for potential confounders using a logistic regression analysis, the (GT) repeat alleles > or =188 base pairs in the intron 2 marker of the MAOB gene were significantly associated with PD (OR = 4.60; p<0.00005; 95% CI = 1.97-10.77). The 186 base pair allele was also significantly associated with PD (OR = 1.85; p = 0.048; 95% CI = 1.01-3.42). The GT repeat in intron 2 of the MAOB gene is a powerful marker for PD in this large Australian cohort. | Variations in the /"monoamine oxidase B"/ (/"MAOB"/) gene are associated with /"Parkinson's disease"/. | The /"monoamine oxidase B"/ gene (/"MAOB"/; Xp15.21-4) is a candidate gene for /"Parkinson's disease"/ (/"PD"/) given its role in dopamine metabolism and its possible role in the activation of neurotoxins. The association of /"MAOB"/ polymorphisms (a [GT] repeat allelic variation in intron 2 and an A-G transition in intron 13) with /"Parkinson's disease"/ (/"PD"/) was studied in an Australian cohort of 204 (male:female ratio 1.60) people with /"PD"/ and 285 (male:female ratio 1.64) age- and gender-matched control subjects. Genomic DNA was extracted from venous blood and polymerase chain reaction was used to amplify the appropriate regions of the /"MAOB"/ gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis and a DNA fragment analyzer, while the G-A genotype was determined using 2% agarose gel electrophoresis. The G-A polymorphism showed no association with /"PD"/ (odds ratio [OR] = 0.80; p = 0.51; 95% confidence interval [CI] = 0.42-1.53). There was a significant difference in allele frequencies of the (GT) repeat allelic variation between patients and control subjects (chi2 = 20.09; p<0.01). After statistical adjustment for potential confounders using a logistic regression analysis, the (GT) repeat alleles > or =188 base pairs in the intron 2 marker of the /"MAOB"/ gene were significantly associated with /"PD"/ (OR = 4.60; p<0.00005; 95% CI = 1.97-10.77). The 186 base pair allele was also significantly associated with /"PD"/ (OR = 1.85; p = 0.048; 95% CI = 1.01-3.42). The GT repeat in intron 2 of the /"MAOB"/ gene is a powerful marker for /"PD"/ in this large Australian cohort. | [
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10091612 | Variations in the monoamine oxidase B (MAOB) gene are associated with Parkinson's disease. | The monoamine oxidase B gene (MAOB; Xp15.21-4) is a candidate gene for Parkinson's disease (PD) given its role in dopamine metabolism and its possible role in the activation of neurotoxins. The association of MAOB polymorphisms (a [GT] repeat allelic variation in intron 2 and an A-G transition in intron 13) with Parkinson's disease (PD) was studied in an Australian cohort of 204 (male:female ratio 1.60) people with PD and 285 (male:female ratio 1.64) age- and gender-matched control subjects. Genomic DNA was extracted from venous blood and polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis and a DNA fragment analyzer, while the G-A genotype was determined using 2% agarose gel electrophoresis. The G-A polymorphism showed no association with PD (odds ratio [OR] = 0.80; p = 0.51; 95% confidence interval [CI] = 0.42-1.53). There was a significant difference in allele frequencies of the (GT) repeat allelic variation between patients and control subjects (chi2 = 20.09; p<0.01). After statistical adjustment for potential confounders using a logistic regression analysis, the (GT) repeat alleles > or =188 base pairs in the intron 2 marker of the MAOB gene were significantly associated with PD (OR = 4.60; p<0.00005; 95% CI = 1.97-10.77). The 186 base pair allele was also significantly associated with PD (OR = 1.85; p = 0.048; 95% CI = 1.01-3.42). The GT repeat in intron 2 of the MAOB gene is a powerful marker for PD in this large Australian cohort. | Variations in the /"monoamine oxidase B"/ (/"MAOB"/) gene are associated with Parkinson's disease. | The /"monoamine oxidase B"/ gene (/"MAOB"/; Xp15.21-4) is a candidate gene for Parkinson's disease (PD) given its role in dopamine metabolism and its possible role in the activation of neurotoxins. The association of /"MAOB"/ polymorphisms (a [/"GT"/] repeat allelic variation in intron 2 and an A-G transition in intron 13) with Parkinson's disease (PD) was studied in an Australian cohort of 204 (male:female ratio 1.60) people with PD and 285 (male:female ratio 1.64) age- and gender-matched control subjects. Genomic DNA was extracted from venous blood and polymerase chain reaction was used to amplify the appropriate regions of the /"MAOB"/ gene. The length of each (/"GT"/) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis and a DNA fragment analyzer, while the G-A genotype was determined using 2% agarose gel electrophoresis. The G-A polymorphism showed no association with PD (odds ratio [OR] = 0.80; p = 0.51; 95% confidence interval [CI] = 0.42-1.53). There was a significant difference in allele frequencies of the (/"GT"/) repeat allelic variation between patients and control subjects (chi2 = 20.09; p<0.01). After statistical adjustment for potential confounders using a logistic regression analysis, the (/"GT"/) repeat alleles > or =188 base pairs in the intron 2 marker of the /"MAOB"/ gene were significantly associated with PD (OR = 4.60; p<0.00005; 95% CI = 1.97-10.77). The 186 base pair allele was also significantly associated with PD (OR = 1.85; p = 0.048; 95% CI = 1.01-3.42). The /"GT"/ repeat in intron 2 of the /"MAOB"/ gene is a powerful marker for PD in this large Australian cohort. | [
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10094550 | Identification of a 5' splice site mutation in the RPGR gene in a family with X-linked retinitis pigmentosa (RP3). | We have identified a novel RPGR gene mutation in a large Dutch family with X-linked retinitis pigmentosa (RP3). In affected members, a G-->T transversion was found at position +1 of the 5' splice site of intron 5 of the RPGR (retinitis pigmentosa GTPase regulator) gene. Analysis of this mutation at the RNA level showed cryptic splicing upstream of the mutation in exon 5 leading to a frameshift and downstream termination codon. Identification of the causative mutation in this family has facilitated the detection of females at risk of having an affected son. | Identification of a 5' splice site mutation in the /"RPGR"/ gene in a family with X-linked retinitis pigmentosa (/"RP3"/). | We have identified a novel /"RPGR"/ gene mutation in a large Dutch family with X-linked retinitis pigmentosa (/"RP3"/). In affected members, a G-->T transversion was found at position +1 of the 5' splice site of intron 5 of the /"RPGR"/ (/"retinitis pigmentosa"/ GTPase regulator) gene. Analysis of this mutation at the RNA level showed cryptic splicing upstream of the mutation in exon 5 leading to a frameshift and downstream termination codon. Identification of the causative mutation in this family has facilitated the detection of females at risk of having an affected son. | [
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} | Yes |
10094550 | Identification of a 5' splice site mutation in the RPGR gene in a family with X-linked retinitis pigmentosa (RP3). | We have identified a novel RPGR gene mutation in a large Dutch family with X-linked retinitis pigmentosa (RP3). In affected members, a G-->T transversion was found at position +1 of the 5' splice site of intron 5 of the RPGR (retinitis pigmentosa GTPase regulator) gene. Analysis of this mutation at the RNA level showed cryptic splicing upstream of the mutation in exon 5 leading to a frameshift and downstream termination codon. Identification of the causative mutation in this family has facilitated the detection of females at risk of having an affected son. | Identification of a 5' splice site mutation in the /"RPGR"/ gene in a family with /"X-linked retinitis pigmentosa"/ (/"RP3"/). | We have identified a novel /"RPGR"/ gene mutation in a large Dutch family with /"X-linked retinitis pigmentosa"/ (/"RP3"/). In affected members, a G-->T transversion was found at position +1 of the 5' splice site of intron 5 of the /"RPGR"/ (retinitis pigmentosa GTPase regulator) gene. Analysis of this mutation at the RNA level showed cryptic splicing upstream of the mutation in exon 5 leading to a frameshift and downstream termination codon. Identification of the causative mutation in this family has facilitated the detection of females at risk of having an affected son. | [
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} | No |
10200057 | Two novel mutations in exon 11 of the PAH gene (V1163del TG and P362T) associated with classic phenylketonuira and mild phenylketonuria. Mutations in brief no. 143. Online. | PKU is one of the commonest genetic disease in man, affecting 1/10,000 individuals. It presents a wide phenotypical spectrum, from classic PKU to moderate Hyperpheylalaninemia depending on the residual enzymatic activity. Two novel mutations 1163/1164delTG and P362T in exon 11 have been detected during the mutational screening of the PAH gene in 84 families. 1163/1164delTC can be confused with V388M if the mutational screening is performed with BsaAI restriction enzyme, this mutation in heterozigosis presents a moderate phenotype. P362T mutation in heterozigosis with V388M shows a classical PKU phenotype. We report here two new mutations in exon 11 of the PAH gene (GenBank U49897), V1163delTG and P362T (using cDNA sequence), detected during the analysis of 57 PKU and 36 HPA patients belonging to 84 unrelated families detected under a neonatal screening program performed in Catalonia. | Two novel mutations in exon 11 of the /"PAH"/ gene (V1163del TG and P362T) associated with classic phenylketonuira and mild /"phenylketonuria"/. Mutations in brief no. 143. Online. | /"PKU"/ is one of the commonest genetic disease in man, affecting 1/10,000 individuals. It presents a wide phenotypical spectrum, from classic /"PKU"/ to moderate Hyperpheylalaninemia depending on the residual enzymatic activity. Two novel mutations 1163/1164delTG and P362T in exon 11 have been detected during the mutational screening of the /"PAH"/ gene in 84 families. 1163/1164delTC can be confused with V388M if the mutational screening is performed with BsaAI restriction enzyme, this mutation in heterozigosis presents a moderate phenotype. P362T mutation in heterozigosis with V388M shows a classical /"PKU"/ phenotype. We report here two new mutations in exon 11 of the /"PAH"/ gene (GenBank U49897), V1163delTG and P362T (using cDNA sequence), detected during the analysis of 57 /"PKU"/ and 36 /"HPA"/ patients belonging to 84 unrelated families detected under a neonatal screening program performed in Catalonia. | [
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} | Yes |
10200057 | Two novel mutations in exon 11 of the PAH gene (V1163del TG and P362T) associated with classic phenylketonuira and mild phenylketonuria. Mutations in brief no. 143. Online. | PKU is one of the commonest genetic disease in man, affecting 1/10,000 individuals. It presents a wide phenotypical spectrum, from classic PKU to moderate Hyperpheylalaninemia depending on the residual enzymatic activity. Two novel mutations 1163/1164delTG and P362T in exon 11 have been detected during the mutational screening of the PAH gene in 84 families. 1163/1164delTC can be confused with V388M if the mutational screening is performed with BsaAI restriction enzyme, this mutation in heterozigosis presents a moderate phenotype. P362T mutation in heterozigosis with V388M shows a classical PKU phenotype. We report here two new mutations in exon 11 of the PAH gene (GenBank U49897), V1163delTG and P362T (using cDNA sequence), detected during the analysis of 57 PKU and 36 HPA patients belonging to 84 unrelated families detected under a neonatal screening program performed in Catalonia. | Two novel mutations in exon 11 of the /"PAH"/ gene (V1163del TG and P362T) associated with classic phenylketonuira and mild phenylketonuria. Mutations in brief no. 143. Online. | PKU is one of the commonest /"genetic disease"/ in man, affecting 1/10,000 individuals. It presents a wide phenotypical spectrum, from classic PKU to moderate Hyperpheylalaninemia depending on the residual enzymatic activity. Two novel mutations 1163/1164delTG and P362T in exon 11 have been detected during the mutational screening of the /"PAH"/ gene in 84 families. 1163/1164delTC can be confused with V388M if the mutational screening is performed with BsaAI restriction enzyme, this mutation in heterozigosis presents a moderate phenotype. P362T mutation in heterozigosis with V388M shows a classical PKU phenotype. We report here two new mutations in exon 11 of the /"PAH"/ gene (GenBank U49897), V1163delTG and P362T (using cDNA sequence), detected during the analysis of 57 PKU and 36 HPA patients belonging to 84 unrelated families detected under a neonatal screening program performed in Catalonia. | [
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10213916 | Urocortin and inflammation: confounding effects of hypotension on measures of inflammation. | Urocortin, a newly isolated 40-amino-acid mammalian peptide homologous to corticotropin-releasing hormone (CRH), activates both CRH type 1 and 2 receptors, but may be an endogenous ligand for CRH receptor type 2. Urocortin given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of urocortin in the carrageenin-induced subcutaneous inflammation model. Rats were treated with urocortin 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. However, since subcutaneous urocortin has been shown to reduce arterial blood pressure, we tested the hypothesis that its antiedema and antiextravasatory effects were secondary to arterial hypotension. Therefore, we examined the parallel effects of urocortin- and hydralazine-induced hypotension on acute inflammation induced by carrageenin in the rat. Rats were treated with subcutaneous carrageenin and control injections (n = 8), carrageenin and urocortin (20 nmol/kg, n = 9), or carrageenin and intraperitoneal hydralazine (10 mg/kg, n = 8). Mean arterial blood pressure was measured hourly for 7 h in 12 animals, and after 2 h, the nadir of treatment, in a further 13 animals. Rats were then sacrificed, and the inflammatory exudate volume and leukocyte count were measured. Mean exudate volumes were reduced from 4.8 +/- 0.5 ml (controls) to 2.4 +/- 0.3 ml (p = 0.004) and 2.9 +/- 0.6 ml (p = 0.007) in urocortin- and hydralazine-treated animals, respectively. Urocortin and hydralazine both produced a significant fall in blood pressure compared to controls, with mean arterial pressure 2 h after carrageenin injection falling to 51.0 +/- 4.1 (p < 0.001) and 34.6 +/- 4.6 (p < 0.001) vs. 92.9 +/- 3.7 mm Hg in controls, respectively. A significant positive correlation was noted between blood pressure and inflammatory exudate volume (r = 0. 52, p = 0.007). As both hydralazine and urocortin lowered blood pressure and inflammatory exudate volume, we suggest that the anti-inflammatory effects of urocortin and related neuropeptides may be nonspecific, acting through hypotension rather than through direct anti-inflammatory mechanisms. The use of inflammatory models which rely on extravasation may be inappropriate for the study of substances that produce hypotension. | /"Urocortin"/ and /"inflammation"/: confounding effects of hypotension on measures of /"inflammation"/. | /"Urocortin"/, a newly isolated 40-amino-acid mammalian peptide homologous to corticotropin-releasing hormone (CRH), activates both CRH type 1 and 2 receptors, but may be an endogenous ligand for CRH receptor type 2. /"Urocortin"/ given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of /"urocortin"/ in the carrageenin-induced subcutaneous /"inflammation"/ model. Rats were treated with /"urocortin"/ 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. However, since subcutaneous /"urocortin"/ has been shown to reduce arterial blood pressure, we tested the hypothesis that its antiedema and antiextravasatory effects were secondary to arterial hypotension. Therefore, we examined the parallel effects of /"urocortin"/- and hydralazine-induced hypotension on acute /"inflammation"/ induced by carrageenin in the rat. Rats were treated with subcutaneous carrageenin and control injections (n = 8), carrageenin and /"urocortin"/ (20 nmol/kg, n = 9), or carrageenin and intraperitoneal hydralazine (10 mg/kg, n = 8). Mean arterial blood pressure was measured hourly for 7 h in 12 animals, and after 2 h, the nadir of treatment, in a further 13 animals. Rats were then sacrificed, and the inflammatory exudate volume and leukocyte count were measured. Mean exudate volumes were reduced from 4.8 +/- 0.5 ml (controls) to 2.4 +/- 0.3 ml (p = 0.004) and 2.9 +/- 0.6 ml (p = 0.007) in /"urocortin"/- and hydralazine-treated animals, respectively. /"Urocortin"/ and hydralazine both produced a significant fall in blood pressure compared to controls, with mean arterial pressure 2 h after carrageenin injection falling to 51.0 +/- 4.1 (p < 0.001) and 34.6 +/- 4.6 (p < 0.001) vs. 92.9 +/- 3.7 mm Hg in controls, respectively. A significant positive correlation was noted between blood pressure and inflammatory exudate volume (r = 0. 52, p = 0.007). As both hydralazine and /"urocortin"/ lowered blood pressure and inflammatory exudate volume, we suggest that the anti-inflammatory effects of /"urocortin"/ and related neuropeptides may be nonspecific, acting through hypotension rather than through direct anti-inflammatory mechanisms. The use of inflammatory models which rely on extravasation may be inappropriate for the study of substances that produce hypotension. | [
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10213916 | Urocortin and inflammation: confounding effects of hypotension on measures of inflammation. | Urocortin, a newly isolated 40-amino-acid mammalian peptide homologous to corticotropin-releasing hormone (CRH), activates both CRH type 1 and 2 receptors, but may be an endogenous ligand for CRH receptor type 2. Urocortin given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of urocortin in the carrageenin-induced subcutaneous inflammation model. Rats were treated with urocortin 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. However, since subcutaneous urocortin has been shown to reduce arterial blood pressure, we tested the hypothesis that its antiedema and antiextravasatory effects were secondary to arterial hypotension. Therefore, we examined the parallel effects of urocortin- and hydralazine-induced hypotension on acute inflammation induced by carrageenin in the rat. Rats were treated with subcutaneous carrageenin and control injections (n = 8), carrageenin and urocortin (20 nmol/kg, n = 9), or carrageenin and intraperitoneal hydralazine (10 mg/kg, n = 8). Mean arterial blood pressure was measured hourly for 7 h in 12 animals, and after 2 h, the nadir of treatment, in a further 13 animals. Rats were then sacrificed, and the inflammatory exudate volume and leukocyte count were measured. Mean exudate volumes were reduced from 4.8 +/- 0.5 ml (controls) to 2.4 +/- 0.3 ml (p = 0.004) and 2.9 +/- 0.6 ml (p = 0.007) in urocortin- and hydralazine-treated animals, respectively. Urocortin and hydralazine both produced a significant fall in blood pressure compared to controls, with mean arterial pressure 2 h after carrageenin injection falling to 51.0 +/- 4.1 (p < 0.001) and 34.6 +/- 4.6 (p < 0.001) vs. 92.9 +/- 3.7 mm Hg in controls, respectively. A significant positive correlation was noted between blood pressure and inflammatory exudate volume (r = 0. 52, p = 0.007). As both hydralazine and urocortin lowered blood pressure and inflammatory exudate volume, we suggest that the anti-inflammatory effects of urocortin and related neuropeptides may be nonspecific, acting through hypotension rather than through direct anti-inflammatory mechanisms. The use of inflammatory models which rely on extravasation may be inappropriate for the study of substances that produce hypotension. | /"Urocortin"/ and inflammation: confounding effects of /"hypotension"/ on measures of inflammation. | /"Urocortin"/, a newly isolated 40-amino-acid mammalian peptide homologous to corticotropin-releasing hormone (CRH), activates both CRH type 1 and 2 receptors, but may be an endogenous ligand for CRH receptor type 2. /"Urocortin"/ given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of /"urocortin"/ in the carrageenin-induced subcutaneous inflammation model. Rats were treated with /"urocortin"/ 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. However, since subcutaneous /"urocortin"/ has been shown to reduce arterial blood pressure, we tested the hypothesis that its antiedema and antiextravasatory effects were secondary to arterial /"hypotension"/. Therefore, we examined the parallel effects of /"urocortin"/- and hydralazine-induced /"hypotension"/ on acute inflammation induced by carrageenin in the rat. Rats were treated with subcutaneous carrageenin and control injections (n = 8), carrageenin and /"urocortin"/ (20 nmol/kg, n = 9), or carrageenin and intraperitoneal hydralazine (10 mg/kg, n = 8). Mean arterial blood pressure was measured hourly for 7 h in 12 animals, and after 2 h, the nadir of treatment, in a further 13 animals. Rats were then sacrificed, and the inflammatory exudate volume and leukocyte count were measured. Mean exudate volumes were reduced from 4.8 +/- 0.5 ml (controls) to 2.4 +/- 0.3 ml (p = 0.004) and 2.9 +/- 0.6 ml (p = 0.007) in /"urocortin"/- and hydralazine-treated animals, respectively. /"Urocortin"/ and hydralazine both produced a significant /"fall in blood pressure"/ compared to controls, with mean arterial pressure 2 h after carrageenin injection falling to 51.0 +/- 4.1 (p < 0.001) and 34.6 +/- 4.6 (p < 0.001) vs. 92.9 +/- 3.7 mm Hg in controls, respectively. A significant positive correlation was noted between blood pressure and inflammatory exudate volume (r = 0. 52, p = 0.007). As both hydralazine and /"urocortin"/ lowered blood pressure and inflammatory exudate volume, we suggest that the anti-inflammatory effects of /"urocortin"/ and related neuropeptides may be nonspecific, acting through /"hypotension"/ rather than through direct anti-inflammatory mechanisms. The use of inflammatory models which rely on extravasation may be inappropriate for the study of substances that produce /"hypotension"/. | [
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10213916 | Urocortin and inflammation: confounding effects of hypotension on measures of inflammation. | Urocortin, a newly isolated 40-amino-acid mammalian peptide homologous to corticotropin-releasing hormone (CRH), activates both CRH type 1 and 2 receptors, but may be an endogenous ligand for CRH receptor type 2. Urocortin given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of urocortin in the carrageenin-induced subcutaneous inflammation model. Rats were treated with urocortin 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. However, since subcutaneous urocortin has been shown to reduce arterial blood pressure, we tested the hypothesis that its antiedema and antiextravasatory effects were secondary to arterial hypotension. Therefore, we examined the parallel effects of urocortin- and hydralazine-induced hypotension on acute inflammation induced by carrageenin in the rat. Rats were treated with subcutaneous carrageenin and control injections (n = 8), carrageenin and urocortin (20 nmol/kg, n = 9), or carrageenin and intraperitoneal hydralazine (10 mg/kg, n = 8). Mean arterial blood pressure was measured hourly for 7 h in 12 animals, and after 2 h, the nadir of treatment, in a further 13 animals. Rats were then sacrificed, and the inflammatory exudate volume and leukocyte count were measured. Mean exudate volumes were reduced from 4.8 +/- 0.5 ml (controls) to 2.4 +/- 0.3 ml (p = 0.004) and 2.9 +/- 0.6 ml (p = 0.007) in urocortin- and hydralazine-treated animals, respectively. 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The use of inflammatory models which rely on extravasation may be inappropriate for the study of substances that produce hypotension. | Urocortin and /"inflammation"/: confounding effects of hypotension on measures of /"inflammation"/. | Urocortin, a newly isolated 40-amino-acid mammalian peptide homologous to /"corticotropin-releasing hormone"/ (/"CRH"/), activates both /"CRH"/ type 1 and 2 receptors, but may be an endogenous ligand for /"CRH"/ receptor type 2. Urocortin given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of urocortin in the carrageenin-induced subcutaneous /"inflammation"/ model. Rats were treated with urocortin 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. 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Urocortin and hydralazine both produced a significant fall in blood pressure compared to controls, with mean arterial pressure 2 h after carrageenin injection falling to 51.0 +/- 4.1 (p < 0.001) and 34.6 +/- 4.6 (p < 0.001) vs. 92.9 +/- 3.7 mm Hg in controls, respectively. A significant positive correlation was noted between blood pressure and inflammatory exudate volume (r = 0. 52, p = 0.007). As both hydralazine and urocortin lowered blood pressure and inflammatory exudate volume, we suggest that the anti-inflammatory effects of urocortin and related neuropeptides may be nonspecific, acting through hypotension rather than through direct anti-inflammatory mechanisms. The use of inflammatory models which rely on extravasation may be inappropriate for the study of substances that produce hypotension. | [
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10213916 | Urocortin and inflammation: confounding effects of hypotension on measures of inflammation. | Urocortin, a newly isolated 40-amino-acid mammalian peptide homologous to corticotropin-releasing hormone (CRH), activates both CRH type 1 and 2 receptors, but may be an endogenous ligand for CRH receptor type 2. Urocortin given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of urocortin in the carrageenin-induced subcutaneous inflammation model. Rats were treated with urocortin 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. However, since subcutaneous urocortin has been shown to reduce arterial blood pressure, we tested the hypothesis that its antiedema and antiextravasatory effects were secondary to arterial hypotension. 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The use of inflammatory models which rely on extravasation may be inappropriate for the study of substances that produce hypotension. | Urocortin and /"inflammation"/: confounding effects of hypotension on measures of /"inflammation"/. | Urocortin, a newly isolated 40-amino-acid mammalian peptide homologous to /"corticotropin-releasing hormone"/ (/"CRH"/), activates both /"CRH"/ type 1 and 2 receptors, but may be an endogenous ligand for /"CRH"/ receptor type 2. Urocortin given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of urocortin in the carrageenin-induced subcutaneous /"inflammation"/ model. Rats were treated with urocortin 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. However, since subcutaneous urocortin has been shown to reduce arterial blood pressure, we tested the hypothesis that its antiedema and antiextravasatory effects were secondary to arterial hypotension. Therefore, we examined the parallel effects of urocortin- and hydralazine-induced hypotension on acute /"inflammation"/ induced by carrageenin in the rat. Rats were treated with subcutaneous carrageenin and control injections (n = 8), carrageenin and urocortin (20 nmol/kg, n = 9), or carrageenin and intraperitoneal hydralazine (10 mg/kg, n = 8). Mean arterial blood pressure was measured hourly for 7 h in 12 animals, and after 2 h, the nadir of treatment, in a further 13 animals. Rats were then sacrificed, and the inflammatory exudate volume and leukocyte count were measured. Mean exudate volumes were reduced from 4.8 +/- 0.5 ml (controls) to 2.4 +/- 0.3 ml (p = 0.004) and 2.9 +/- 0.6 ml (p = 0.007) in urocortin- and hydralazine-treated animals, respectively. 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10234503 | Mutational analysis of PAX6: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype. | Mutations in the developmental control gene PAX6 have been shown to be the genetic cause of aniridia, which is a severe panocular eye disease characterised by iris hypoplasia. The inheritance is autosomal dominant with high penetrance but variable expressivity. Here we describe a mutational analysis of 27 Danish patients using a dideoxy fingerprinting method, which identified PAX6 mutations in 18 individuals with aniridia. A thorough phenotype description was made for the 18 patients. A total of 19 mutations, of which 16 were novel, are described. Among these were five missense mutations which tended to be associated with a milder aniridia phenotype, and in fact one of them seemed to be non-penetrant. Four of the five missense mutations were located in the paired domain. We also describe a third alternative spliced PAX6 isoform in which two of the four missense mutations would be spliced out. Our observations support the concept of dosage effects of PAX6 mutations as well as presenting evidence for variable expressivity and gonadal mosaicism. | Mutational analysis of /"PAX6"/: 16 novel mutations including 5 missense mutations with a mild /"aniridia"/ phenotype. | Mutations in the developmental control gene /"PAX6"/ have been shown to be the genetic cause of /"aniridia"/, which is a severe panocular eye disease characterised by iris hypoplasia. The inheritance is autosomal dominant with high penetrance but variable expressivity. Here we describe a mutational analysis of 27 Danish patients using a dideoxy fingerprinting method, which identified /"PAX6"/ mutations in 18 individuals with /"aniridia"/. A thorough phenotype description was made for the 18 patients. A total of 19 mutations, of which 16 were novel, are described. Among these were five missense mutations which tended to be associated with a milder /"aniridia"/ phenotype, and in fact one of them seemed to be non-penetrant. Four of the five missense mutations were located in the paired domain. We also describe a third alternative spliced /"PAX6"/ isoform in which two of the four missense mutations would be spliced out. Our observations support the concept of dosage effects of /"PAX6"/ mutations as well as presenting evidence for variable expressivity and gonadal mosaicism. | [
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10234503 | Mutational analysis of PAX6: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype. | Mutations in the developmental control gene PAX6 have been shown to be the genetic cause of aniridia, which is a severe panocular eye disease characterised by iris hypoplasia. The inheritance is autosomal dominant with high penetrance but variable expressivity. Here we describe a mutational analysis of 27 Danish patients using a dideoxy fingerprinting method, which identified PAX6 mutations in 18 individuals with aniridia. A thorough phenotype description was made for the 18 patients. A total of 19 mutations, of which 16 were novel, are described. Among these were five missense mutations which tended to be associated with a milder aniridia phenotype, and in fact one of them seemed to be non-penetrant. Four of the five missense mutations were located in the paired domain. We also describe a third alternative spliced PAX6 isoform in which two of the four missense mutations would be spliced out. Our observations support the concept of dosage effects of PAX6 mutations as well as presenting evidence for variable expressivity and gonadal mosaicism. | Mutational analysis of /"PAX6"/: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype. | Mutations in the developmental control gene /"PAX6"/ have been shown to be the genetic cause of aniridia, which is a severe panocular eye disease characterised by /"iris hypoplasia"/. The inheritance is autosomal dominant with high penetrance but variable expressivity. Here we describe a mutational analysis of 27 Danish patients using a dideoxy fingerprinting method, which identified /"PAX6"/ mutations in 18 individuals with aniridia. A thorough phenotype description was made for the 18 patients. A total of 19 mutations, of which 16 were novel, are described. Among these were five missense mutations which tended to be associated with a milder aniridia phenotype, and in fact one of them seemed to be non-penetrant. Four of the five missense mutations were located in the paired domain. We also describe a third alternative spliced /"PAX6"/ isoform in which two of the four missense mutations would be spliced out. Our observations support the concept of dosage effects of /"PAX6"/ mutations as well as presenting evidence for variable expressivity and gonadal mosaicism. | [
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10318961 | Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. | Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Delta9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the CB1 receptor. | Increased mortality, hypoactivity, and hypoalgesia in cannabinoid /"CB1"/ receptor knockout mice. | Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the /"CB1"/ cannabinoid receptor, we have produced a mouse strain with a disrupted /"CB1"/ gene. /"CB1"/ knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring /"catalepsy"/, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-/"catalepsy"/, hypomobility, and hypothermia were completely absent in /"CB1"/ mutant mice. In contrast, we still found Delta9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the /"CB1"/ receptor. | [
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10318961 | Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. | Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Delta9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the CB1 receptor. | Increased mortality, hypoactivity, and hypoalgesia in cannabinoid /"CB1"/ receptor knockout mice. | Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as /"analgesia"/ suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the /"CB1"/ cannabinoid receptor, we have produced a mouse strain with a disrupted /"CB1"/ gene. /"CB1"/ knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in /"CB1"/ mutant mice. In contrast, we still found Delta9-THC-induced /"analgesia"/ in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the /"CB1"/ receptor. | [
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10433910 | Goosecoid acts cell autonomously in mesenchyme-derived tissues during craniofacial development. | Mice homozygous for a targeted deletion of the homeobox gene Goosecoid (Gsc) have multiple craniofacial defects. To understand the mechanisms responsible for these defects, the behavior of Gsc-null cells was examined in morula aggregation chimeras. In these chimeras, Gsc-null cells were marked with beta-galactosidase (beta-gal) activity using the ROSA26 lacZ allele. In addition, mice with a lacZ gene that had been introduced into the Gsc locus were used as a guide to visualize the location of Gsc-expressing cells. In Gsc-null<->wild-type chimeras, tissues that would normally not express Gsc were composed of both Gsc-null and wild-type cells that were well mixed, reflecting the overall genotypic composition of the chimeras. However, craniofacial tissues that would normally express Gsc were essentially devoid of Gsc-null cells. Furthermore, the nasal capsules and mandibles of the chimeras had defects similar to Gsc-null mice that varied in severity depending upon the proportion of Gsc-null cells. These results combined with the analysis of Gsc-null mice suggest that Gsc functions cell autonomously in mesenchyme-derived tissues of the head. A developmental analysis of the tympanic ring bone, a bone that is always absent in Gsc-null mice because of defects at the cell condensation stage, showed that Gsc-null cells had the capacity to form the tympanic ring condensation in the presence of wild-type cells. However, analysis of the tympanic ring bones of 18.5 d.p.c. chimeras suggests that Gsc-null cells were not maintained. The participation of Gsc-null cells in the tympanic ring condensation of chimeras may be an epigenetic phenomenon that results in a local environment in which more precursor cells are present. Thus, the skeletal defects observed in Gsc-null mice may reflect a regional reduction of precursor cells during embryonic development. | /"Goosecoid"/ acts cell autonomously in mesenchyme-derived tissues during craniofacial development. | Mice homozygous for a targeted deletion of the homeobox gene /"Goosecoid"/ (/"Gsc"/) have multiple /"craniofacial defects"/. To understand the mechanisms responsible for these defects, the behavior of /"Gsc"/-null cells was examined in morula aggregation chimeras. In these chimeras, /"Gsc"/-null cells were marked with beta-galactosidase (beta-gal) activity using the ROSA26 lacZ allele. In addition, mice with a lacZ gene that had been introduced into the /"Gsc"/ locus were used as a guide to visualize the location of /"Gsc"/-expressing cells. In /"Gsc"/-null<->wild-type chimeras, tissues that would normally not express /"Gsc"/ were composed of both /"Gsc"/-null and wild-type cells that were well mixed, reflecting the overall genotypic composition of the chimeras. However, craniofacial tissues that would normally express /"Gsc"/ were essentially devoid of /"Gsc"/-null cells. Furthermore, the nasal capsules and mandibles of the chimeras had defects similar to /"Gsc"/-null mice that varied in severity depending upon the proportion of /"Gsc"/-null cells. These results combined with the analysis of /"Gsc"/-null mice suggest that /"Gsc"/ functions cell autonomously in mesenchyme-derived tissues of the head. A developmental analysis of the tympanic ring bone, a bone that is always absent in /"Gsc"/-null mice because of defects at the cell condensation stage, showed that /"Gsc"/-null cells had the capacity to form the tympanic ring condensation in the presence of wild-type cells. However, analysis of the tympanic ring bones of 18.5 d.p.c. chimeras suggests that /"Gsc"/-null cells were not maintained. The participation of /"Gsc"/-null cells in the tympanic ring condensation of chimeras may be an epigenetic phenomenon that results in a local environment in which more precursor cells are present. Thus, the skeletal defects observed in /"Gsc"/-null mice may reflect a regional reduction of precursor cells during embryonic development. | [
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10433910 | Goosecoid acts cell autonomously in mesenchyme-derived tissues during craniofacial development. | Mice homozygous for a targeted deletion of the homeobox gene Goosecoid (Gsc) have multiple craniofacial defects. To understand the mechanisms responsible for these defects, the behavior of Gsc-null cells was examined in morula aggregation chimeras. In these chimeras, Gsc-null cells were marked with beta-galactosidase (beta-gal) activity using the ROSA26 lacZ allele. In addition, mice with a lacZ gene that had been introduced into the Gsc locus were used as a guide to visualize the location of Gsc-expressing cells. In Gsc-null<->wild-type chimeras, tissues that would normally not express Gsc were composed of both Gsc-null and wild-type cells that were well mixed, reflecting the overall genotypic composition of the chimeras. However, craniofacial tissues that would normally express Gsc were essentially devoid of Gsc-null cells. Furthermore, the nasal capsules and mandibles of the chimeras had defects similar to Gsc-null mice that varied in severity depending upon the proportion of Gsc-null cells. These results combined with the analysis of Gsc-null mice suggest that Gsc functions cell autonomously in mesenchyme-derived tissues of the head. A developmental analysis of the tympanic ring bone, a bone that is always absent in Gsc-null mice because of defects at the cell condensation stage, showed that Gsc-null cells had the capacity to form the tympanic ring condensation in the presence of wild-type cells. However, analysis of the tympanic ring bones of 18.5 d.p.c. chimeras suggests that Gsc-null cells were not maintained. The participation of Gsc-null cells in the tympanic ring condensation of chimeras may be an epigenetic phenomenon that results in a local environment in which more precursor cells are present. Thus, the skeletal defects observed in Gsc-null mice may reflect a regional reduction of precursor cells during embryonic development. | /"Goosecoid"/ acts cell autonomously in mesenchyme-derived tissues during craniofacial development. | Mice homozygous for a targeted deletion of the homeobox gene /"Goosecoid"/ (/"Gsc"/) have multiple craniofacial defects. To understand the mechanisms responsible for these defects, the behavior of /"Gsc"/-null cells was examined in morula aggregation chimeras. In these chimeras, /"Gsc"/-null cells were marked with /"beta-galactosidase"/ (/"beta-gal"/) activity using the ROSA26 lacZ allele. In addition, mice with a lacZ gene that had been introduced into the /"Gsc"/ locus were used as a guide to visualize the location of /"Gsc"/-expressing cells. In /"Gsc"/-null<->wild-type chimeras, tissues that would normally not express /"Gsc"/ were composed of both /"Gsc"/-null and wild-type cells that were well mixed, reflecting the overall genotypic composition of the chimeras. However, craniofacial tissues that would normally express /"Gsc"/ were essentially devoid of /"Gsc"/-null cells. Furthermore, the nasal capsules and mandibles of the chimeras had defects similar to /"Gsc"/-null mice that varied in severity depending upon the proportion of /"Gsc"/-null cells. These results combined with the analysis of /"Gsc"/-null mice suggest that /"Gsc"/ functions cell autonomously in mesenchyme-derived tissues of the head. A developmental analysis of the tympanic ring bone, a bone that is always absent in /"Gsc"/-null mice because of defects at the cell condensation stage, showed that /"Gsc"/-null cells had the capacity to form the tympanic ring condensation in the presence of wild-type cells. However, analysis of the tympanic ring bones of 18.5 d.p.c. chimeras suggests that /"Gsc"/-null cells were not maintained. The participation of /"Gsc"/-null cells in the tympanic ring condensation of chimeras may be an epigenetic phenomenon that results in a local environment in which more precursor cells are present. Thus, the skeletal defects observed in /"Gsc"/-null mice may reflect a regional reduction of precursor cells during embryonic development. | [
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10459349 | Allelic loss of the NF1 gene in NF1-associated plexiform neurofibromas. | Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical symptoms. Genetic alteration of the NF1 gene on 17q11.2 is the disease. Neurofibromas of the peripheral nervous system are one main manifestation. A variant of neurofibroma is the plexiform neurofibroma which can be found in about 30% of NF1-patients, often causing severe clinical symptoms. In this study, we examined 14 such tumors from 10 NF1-patients for allele loss of the NF1 gene (LOH: loss of heterozygosity) using four intragenic polymorphic markers. Loss of heterozygosity was found in eight tumors from five patients, and suspected in one additional tumor from another patient. This finding suggests that loss of the second allele, and thus inactivation of both alleles of the NF1 gene, is associated with the development of plexiform neurofibromas. The 14 plexiform neufibromas were also examined for mutation in the TP53 gene by screening exons 5 through 8 using temperature gradient gel electrophoresis. No mutation was found in any of the tumors. | Allelic loss of the /"NF1"/ gene in /"NF1"/-associated plexiform neurofibromas. | /"Neurofibromatosis 1"/ (/"NF1"/) is an autosomal dominant disorder with a complex variety of clinical symptoms. Genetic alteration of the /"NF1"/ gene on 17q11.2 is the disease. Neurofibromas of the peripheral nervous system are one main manifestation. A variant of /"neurofibroma"/ is the plexiform neurofibroma which can be found in about 30% of /"NF1"/-patients, often causing severe clinical symptoms. In this study, we examined 14 such tumors from 10 /"NF1"/-patients for allele loss of the /"NF1"/ gene (LOH: loss of heterozygosity) using four intragenic polymorphic markers. Loss of heterozygosity was found in eight tumors from five patients, and suspected in one additional tumor from another patient. This finding suggests that loss of the second allele, and thus inactivation of both alleles of the /"NF1"/ gene, is associated with the development of plexiform neurofibromas. The 14 plexiform neufibromas were also examined for mutation in the TP53 gene by screening exons 5 through 8 using temperature gradient gel electrophoresis. No mutation was found in any of the tumors. | [
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10459349 | Allelic loss of the NF1 gene in NF1-associated plexiform neurofibromas. | Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical symptoms. Genetic alteration of the NF1 gene on 17q11.2 is the disease. Neurofibromas of the peripheral nervous system are one main manifestation. A variant of neurofibroma is the plexiform neurofibroma which can be found in about 30% of NF1-patients, often causing severe clinical symptoms. In this study, we examined 14 such tumors from 10 NF1-patients for allele loss of the NF1 gene (LOH: loss of heterozygosity) using four intragenic polymorphic markers. Loss of heterozygosity was found in eight tumors from five patients, and suspected in one additional tumor from another patient. This finding suggests that loss of the second allele, and thus inactivation of both alleles of the NF1 gene, is associated with the development of plexiform neurofibromas. The 14 plexiform neufibromas were also examined for mutation in the TP53 gene by screening exons 5 through 8 using temperature gradient gel electrophoresis. No mutation was found in any of the tumors. | Allelic loss of the /"NF1"/ gene in /"NF1"/-associated plexiform neurofibromas. | /"Neurofibromatosis 1"/ (/"NF1"/) is an autosomal dominant disorder with a complex variety of clinical symptoms. Genetic alteration of the /"NF1"/ gene on 17q11.2 is the disease. Neurofibromas of the peripheral nervous system are one main manifestation. A variant of neurofibroma is the plexiform neurofibroma which can be found in about 30% of /"NF1"/-patients, often causing severe clinical symptoms. In this study, we examined 14 such /"tumors"/ from 10 /"NF1"/-patients for allele loss of the /"NF1"/ gene (LOH: loss of heterozygosity) using four intragenic polymorphic markers. Loss of heterozygosity was found in eight /"tumors"/ from five patients, and suspected in one additional /"tumor"/ from another patient. This finding suggests that loss of the second allele, and thus inactivation of both alleles of the /"NF1"/ gene, is associated with the development of plexiform neurofibromas. The 14 plexiform neufibromas were also examined for mutation in the TP53 gene by screening exons 5 through 8 using temperature gradient gel electrophoresis. No mutation was found in any of the /"tumors"/. | [
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10488956 | The genotype interactions of methylenetetrahydrofolate reductase and renin-angiotensin system genes are associated with myocardial infarction. | We analyzed the evolution with age of the frequencies of the I/D polymorphism of the angiotensin I-converting enzyme (ACE), a1166c of the angiotensin II AT1 receptor (AT1R), M235T of the angiotensinogen (AGT) and A225V of their methylenetetrahydrofolate reductase (MTHFR) gene in a healthy (H) population and the subsequent comparison to age- and sex-matched groups of myocardial infarction (MI) subjects. A total of 472 H subjects were divided into three groups < 30, 30-55 and > 55 years old and 277 individuals with MI into two groups 30-55 and > 55 years old. The evolution with age showed that the AGT M allele (P < 0.001) and the MTHFR V allele (P < 0.05) frequency decreased with age in H men. The comparison between healthy and MI groups showed that the MM genotype frequency increased in MI men > 55 years (OR =4.16; 95% CI; 1.72-10.1) The cc genotype showed a similar behaviour (OR = 3.96; 95% CI; 1.21-12.9). In men, all the combinations with MM genotype presented a high risk, with OR values between 1.10 and 7.22. In women, the cc genotype increased in the MI > 55 group (OR = 6.66; 95% CI; 2.02-21.9). All the combinations with the cc genotype showed OR values between 1.71 and 13.3. The MM genotype in men and cc genotype in men and women, are independent risk factors for MI. We propose that the study of the allele frequency evolution in an H population at different ages is essential to determine risk factors for MI in case-control studies, since data from isolated age-matched groups can be misinterpreted. | The genotype interactions of /"methylenetetrahydrofolate reductase"/ and renin-angiotensin system genes are associated with /"myocardial infarction"/. | We analyzed the evolution with age of the frequencies of the I/D polymorphism of the angiotensin I-converting enzyme (ACE), a1166c of the angiotensin II AT1 receptor (AT1R), M235T of the angiotensinogen (AGT) and A225V of their /"methylenetetrahydrofolate reductase"/ (/"MTHFR"/) gene in a healthy (H) population and the subsequent comparison to age- and sex-matched groups of /"myocardial infarction"/ (/"MI"/) subjects. A total of 472 H subjects were divided into three groups < 30, 30-55 and > 55 years old and 277 individuals with /"MI"/ into two groups 30-55 and > 55 years old. The evolution with age showed that the AGT M allele (P < 0.001) and the /"MTHFR"/ V allele (P < 0.05) frequency decreased with age in H men. The comparison between healthy and /"MI"/ groups showed that the MM genotype frequency increased in /"MI"/ men > 55 years (OR =4.16; 95% CI; 1.72-10.1) The cc genotype showed a similar behaviour (OR = 3.96; 95% CI; 1.21-12.9). In men, all the combinations with MM genotype presented a high risk, with OR values between 1.10 and 7.22. In women, the cc genotype increased in the /"MI"/ > 55 group (OR = 6.66; 95% CI; 2.02-21.9). All the combinations with the cc genotype showed OR values between 1.71 and 13.3. The MM genotype in men and cc genotype in men and women, are independent risk factors for /"MI"/. We propose that the study of the allele frequency evolution in an H population at different ages is essential to determine risk factors for /"MI"/ in case-control studies, since data from isolated age-matched groups can be misinterpreted. | [
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10488956 | The genotype interactions of methylenetetrahydrofolate reductase and renin-angiotensin system genes are associated with myocardial infarction. | We analyzed the evolution with age of the frequencies of the I/D polymorphism of the angiotensin I-converting enzyme (ACE), a1166c of the angiotensin II AT1 receptor (AT1R), M235T of the angiotensinogen (AGT) and A225V of their methylenetetrahydrofolate reductase (MTHFR) gene in a healthy (H) population and the subsequent comparison to age- and sex-matched groups of myocardial infarction (MI) subjects. A total of 472 H subjects were divided into three groups < 30, 30-55 and > 55 years old and 277 individuals with MI into two groups 30-55 and > 55 years old. The evolution with age showed that the AGT M allele (P < 0.001) and the MTHFR V allele (P < 0.05) frequency decreased with age in H men. The comparison between healthy and MI groups showed that the MM genotype frequency increased in MI men > 55 years (OR =4.16; 95% CI; 1.72-10.1) The cc genotype showed a similar behaviour (OR = 3.96; 95% CI; 1.21-12.9). In men, all the combinations with MM genotype presented a high risk, with OR values between 1.10 and 7.22. In women, the cc genotype increased in the MI > 55 group (OR = 6.66; 95% CI; 2.02-21.9). All the combinations with the cc genotype showed OR values between 1.71 and 13.3. The MM genotype in men and cc genotype in men and women, are independent risk factors for MI. We propose that the study of the allele frequency evolution in an H population at different ages is essential to determine risk factors for MI in case-control studies, since data from isolated age-matched groups can be misinterpreted. | The genotype interactions of methylenetetrahydrofolate reductase and renin-angiotensin system genes are associated with /"myocardial infarction"/. | We analyzed the evolution with age of the frequencies of the I/D polymorphism of the angiotensin I-converting enzyme (ACE), a1166c of the angiotensin II AT1 receptor (/"AT1R"/), M235T of the angiotensinogen (AGT) and A225V of their methylenetetrahydrofolate reductase (MTHFR) gene in a healthy (H) population and the subsequent comparison to age- and sex-matched groups of /"myocardial infarction"/ (/"MI"/) subjects. A total of 472 H subjects were divided into three groups < 30, 30-55 and > 55 years old and 277 individuals with /"MI"/ into two groups 30-55 and > 55 years old. The evolution with age showed that the AGT M allele (P < 0.001) and the MTHFR V allele (P < 0.05) frequency decreased with age in H men. The comparison between healthy and /"MI"/ groups showed that the MM genotype frequency increased in /"MI"/ men > 55 years (OR =4.16; 95% CI; 1.72-10.1) The cc genotype showed a similar behaviour (OR = 3.96; 95% CI; 1.21-12.9). In men, all the combinations with MM genotype presented a high risk, with OR values between 1.10 and 7.22. In women, the cc genotype increased in the /"MI"/ > 55 group (OR = 6.66; 95% CI; 2.02-21.9). All the combinations with the cc genotype showed OR values between 1.71 and 13.3. The MM genotype in men and cc genotype in men and women, are independent risk factors for /"MI"/. We propose that the study of the allele frequency evolution in an H population at different ages is essential to determine risk factors for /"MI"/ in case-control studies, since data from isolated age-matched groups can be misinterpreted. | [
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10508521 | Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). | Retinitis pigmentosa (RP) comprises a clinically and genetically heterogeneous group of diseases that afflicts approximately 1.5 million people worldwide. Affected individuals suffer from a progressive degeneration of the photoreceptors, eventually resulting in severe visual impairment. To isolate candidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method. One of these cDNAs (RET3C11) mapped to chromosome 1q31-q32.1, a region harbouring a gene involved in a severe form of autosomal recessive RP characterized by a typical preservation of the para-arteriolar RPE (RP12; ref. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-like domains, 3 laminin A G-like domains and a C-type lectin domain. This protein is homologous to the Drosophila melanogaster protein crumbs (CRB), and denoted CRB1 (crumbs homologue 1). In ten unrelated RP patients with preserved para-arteriolar RPE, we identified a homozygous AluY insertion disrupting the ORF, five homozygous missense mutations and four compound heterozygous mutations in CRB1. The similarity to CRB suggests a role for CRB1 in cell-cell interaction and possibly in the maintenance of cell polarity in the retina. The distinct RPE abnormalities observed in RP12 patients suggest that CRB1 mutations trigger a novel mechanism of photoreceptor degeneration. | Mutations in a human homologue of Drosophila crumbs cause /"retinitis pigmentosa"/ (/"RP12"/). | /"Retinitis pigmentosa"/ (/"RP"/) comprises a clinically and genetically heterogeneous group of diseases that afflicts approximately 1.5 million people worldwide. Affected individuals suffer from a progressive degeneration of the photoreceptors, eventually resulting in severe visual impairment. To isolate candidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method. One of these cDNAs (RET3C11) mapped to chromosome 1q31-q32.1, a region harbouring a gene involved in a severe form of /"autosomal recessive RP"/ characterized by a typical preservation of the para-arteriolar RPE (/"RP12"/; ref. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-like domains, 3 laminin A G-like domains and a C-type lectin domain. This protein is homologous to the Drosophila melanogaster protein crumbs (CRB), and denoted /"CRB1"/ (crumbs homologue 1). In ten unrelated /"RP"/ patients with preserved para-arteriolar RPE, we identified a homozygous AluY insertion disrupting the ORF, five homozygous missense mutations and four compound heterozygous mutations in /"CRB1"/. The similarity to CRB suggests a role for /"CRB1"/ in cell-cell interaction and possibly in the maintenance of cell polarity in the retina. The distinct RPE abnormalities observed in /"RP12"/ patients suggest that /"CRB1"/ mutations trigger a novel mechanism of photoreceptor degeneration. | [
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10508521 | Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). | Retinitis pigmentosa (RP) comprises a clinically and genetically heterogeneous group of diseases that afflicts approximately 1.5 million people worldwide. Affected individuals suffer from a progressive degeneration of the photoreceptors, eventually resulting in severe visual impairment. To isolate candidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method. One of these cDNAs (RET3C11) mapped to chromosome 1q31-q32.1, a region harbouring a gene involved in a severe form of autosomal recessive RP characterized by a typical preservation of the para-arteriolar RPE (RP12; ref. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-like domains, 3 laminin A G-like domains and a C-type lectin domain. This protein is homologous to the Drosophila melanogaster protein crumbs (CRB), and denoted CRB1 (crumbs homologue 1). In ten unrelated RP patients with preserved para-arteriolar RPE, we identified a homozygous AluY insertion disrupting the ORF, five homozygous missense mutations and four compound heterozygous mutations in CRB1. The similarity to CRB suggests a role for CRB1 in cell-cell interaction and possibly in the maintenance of cell polarity in the retina. The distinct RPE abnormalities observed in RP12 patients suggest that CRB1 mutations trigger a novel mechanism of photoreceptor degeneration. | Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (/"RP12"/12"/). | Retinitis pigmentosa (RP) comprises a clinically and genetically heterogeneous group of diseases that afflicts approximately 1.5 million people worldwide. Affected individuals suffer from a progressive degeneration of the photoreceptors, eventually resulting in severe visual impairment. To isolate candidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method. One of these cDNAs (RET3C11) mapped to chromosome 1q31-q32.1, a region harbouring a gene involved in a severe form of autosomal recessive RP characterized by a typical preservation of the para-arteriolar RPE (/"RP12"/12"/; ref. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-like domains, 3 laminin A G-like domains and a C-type lectin domain. This protein is homologous to the Drosophila melanogaster protein crumbs (CRB), and denoted /"CRB1"/ (crumbs homologue 1). In ten unrelated RP patients with preserved para-arteriolar RPE, we identified a homozygous AluY insertion disrupting the ORF, five homozygous missense mutations and four compound heterozygous mutations in /"CRB1"/. The similarity to CRB suggests a role for /"CRB1"/ in cell-cell interaction and possibly in the maintenance of cell polarity in the retina. The distinct RPE abnormalities observed in /"RP12"/12"/ patients suggest that /"CRB1"/ mutations trigger a novel mechanism of photoreceptor degeneration. | [
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10527839 | Association between an alpha(2) macroglobulin DNA polymorphism and late-onset Alzheimer's disease. | An association between a five-base-pair deletion/insertion DNA polymorphism at the alpha(2) macroglobulin gene (A2M) and late-onset Alzheimer's disease (LOAD) has been recently described. We developed a PCR assay to analyze this polymorphism in 190 LOAD patients (older than 65 years) and 400 controls from Spain. Controls were stratified into three groups: <65 years (n = 200), 65 to 80 years (n = 100), and 81 years or older (n = 100). We found a significantly higher frequency of carriers of the D allele in patients older than 81 years compared to controls older than 81 years (p = 0.0012). In addition, the frequency of the D allele was significantly lower in controls older than 81 years compared to controls younger than 65 (p = 0.048). Our work suggests that the D allele confers an age-dependent increased risk to develop late-onset Alzheimer's disease. | Association between an /"alpha(2) macroglobulin"/ DNA polymorphism and /"late-onset Alzheimer's disease"/. | An association between a five-base-pair deletion/insertion DNA polymorphism at the /"alpha(2) macroglobulin"/ gene (/"A2M"/) and /"late-onset Alzheimer's disease"/ (/"LOAD"/) has been recently described. We developed a PCR assay to analyze this polymorphism in 190 /"LOAD"/ patients (older than 65 years) and 400 controls from Spain. Controls were stratified into three groups: <65 years (n = 200), 65 to 80 years (n = 100), and 81 years or older (n = 100). We found a significantly higher frequency of carriers of the D allele in patients older than 81 years compared to controls older than 81 years (p = 0.0012). In addition, the frequency of the D allele was significantly lower in controls older than 81 years compared to controls younger than 65 (p = 0.048). Our work suggests that the D allele confers an age-dependent increased risk to develop /"late-onset Alzheimer's disease"/. | [
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10532948 | Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. | The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the alpha subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states. | Ionic mechanisms responsible for the electrocardiographic phenotype of the /"Brugada syndrome"/ are temperature dependent. | The /"Brugada syndrome"/ is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in /"SCN5A"/, the gene encoding for the alpha subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states. | [
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10532948 | Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. | The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the alpha subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states. | Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. | The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic /"ventricular tachycardia"/ that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in /"SCN5A"/, the gene encoding for the alpha subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states. | [
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10533957 | Lipolysis is an important determinant of isoproterenol-induced myocardial necrosis. | The cardiotoxic effect of isoproterenol (ISO) is associated with, and possibly due to, calcium overload. Prior work suggests that calcium entry into cardiac myocytes after ISO administration occurs in two phases: an early rapid phase, followed by a slow phase beginning about 1 hour after ISO injection, leading to a peak myocardial calcium level after about 4 hours. We have tested the relationship of these phases to myocardial necrosis (MN) by determining the time after ISO administration at which the commitment to MN occurs. This was done by administration of propranolol at various times before and after ISO. In addition, since ISO induces lipolysis, and lipids can be toxic, experiments were conducted to determine if adrenergically-activated lipolysis could play a significant role in ISO-MN. We found that propranolol protected the myocardium equally well when administered anytime within 2 hours of ISO injection, but had no effect when given 4 hours after ISO. This showed that metabolic events taking place more than two hours after ISO injection are required for ISO-MN. As expected from prior work, there was a small and consistent amount of propranolol-resistant ISO-MN. Lipolysis, assessed by measuring serum glycerol levels, increased to tenfold above base line at one hour after ISO administration and returned to near basal levels at 4 hours. Potentiation of lipolysis by intravenous injections of phospholipase A2 (PLA2) or lipoprotein lipase (LPL) to rats treated with ISO substantially augmented MN. Propranolol completely blocked the increase in necrosis produced by PLA2 when given with ISO. Lipases induced only minimal necrosis in the absence of ISO. Administration of adenosine (an anti-lipolytic agent), oxfenicine (an inhibitor of mitochondrial palmitoyl carnitine transferase), or vitamin C (an anti-oxidant) resulted in a 55-60% reduction in MN. These results suggest that critical necrosis-determining events occur between 2 and 4 hours after ISO administration and imply a relationship between ISO-induced lipolysis, calcium influx, and ISO-MN. We hypothesize that importance of lipolysis as a determinant of ISO-MN is related to the generation of free fatty acids, their oxidized/metabolic products, or direct damage to plasma membrane. | Lipolysis is an important determinant of isoproterenol-induced myocardial necrosis. | The cardiotoxic effect of isoproterenol (ISO) is associated with, and possibly due to, calcium overload. Prior work suggests that calcium entry into cardiac myocytes after ISO administration occurs in two phases: an early rapid phase, followed by a slow phase beginning about 1 hour after ISO injection, leading to a peak myocardial calcium level after about 4 hours. We have tested the relationship of these phases to myocardial necrosis (MN) by determining the time after ISO administration at which the commitment to MN occurs. This was done by administration of propranolol at various times before and after ISO. In addition, since ISO induces lipolysis, and lipids can be toxic, experiments were conducted to determine if adrenergically-activated lipolysis could play a significant role in ISO-MN. We found that propranolol protected the myocardium equally well when administered anytime within 2 hours of ISO injection, but had no effect when given 4 hours after ISO. This showed that metabolic events taking place more than two hours after ISO injection are required for ISO-MN. As expected from prior work, there was a small and consistent amount of propranolol-resistant ISO-MN. Lipolysis, assessed by measuring serum glycerol levels, increased to tenfold above base line at one hour after ISO administration and returned to near basal levels at 4 hours. Potentiation of lipolysis by intravenous injections of phospholipase A2 (PLA2) or /"lipoprotein lipase"/ (/"LPL"/) to rats treated with ISO substantially augmented MN. Propranolol completely blocked the increase in /"necrosis"/ produced by PLA2 when given with ISO. Lipases induced only minimal /"necrosis"/ in the absence of ISO. Administration of adenosine (an anti-lipolytic agent), oxfenicine (an inhibitor of mitochondrial palmitoyl carnitine transferase), or vitamin C (an anti-oxidant) resulted in a 55-60% reduction in MN. These results suggest that critical /"necrosis"/-determining events occur between 2 and 4 hours after ISO administration and imply a relationship between ISO-induced lipolysis, calcium influx, and ISO-MN. We hypothesize that importance of lipolysis as a determinant of ISO-MN is related to the generation of free fatty acids, their oxidized/metabolic products, or direct damage to plasma membrane. | [
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10533957 | Lipolysis is an important determinant of isoproterenol-induced myocardial necrosis. | The cardiotoxic effect of isoproterenol (ISO) is associated with, and possibly due to, calcium overload. Prior work suggests that calcium entry into cardiac myocytes after ISO administration occurs in two phases: an early rapid phase, followed by a slow phase beginning about 1 hour after ISO injection, leading to a peak myocardial calcium level after about 4 hours. We have tested the relationship of these phases to myocardial necrosis (MN) by determining the time after ISO administration at which the commitment to MN occurs. This was done by administration of propranolol at various times before and after ISO. In addition, since ISO induces lipolysis, and lipids can be toxic, experiments were conducted to determine if adrenergically-activated lipolysis could play a significant role in ISO-MN. We found that propranolol protected the myocardium equally well when administered anytime within 2 hours of ISO injection, but had no effect when given 4 hours after ISO. This showed that metabolic events taking place more than two hours after ISO injection are required for ISO-MN. As expected from prior work, there was a small and consistent amount of propranolol-resistant ISO-MN. Lipolysis, assessed by measuring serum glycerol levels, increased to tenfold above base line at one hour after ISO administration and returned to near basal levels at 4 hours. Potentiation of lipolysis by intravenous injections of phospholipase A2 (PLA2) or lipoprotein lipase (LPL) to rats treated with ISO substantially augmented MN. Propranolol completely blocked the increase in necrosis produced by PLA2 when given with ISO. Lipases induced only minimal necrosis in the absence of ISO. Administration of adenosine (an anti-lipolytic agent), oxfenicine (an inhibitor of mitochondrial palmitoyl carnitine transferase), or vitamin C (an anti-oxidant) resulted in a 55-60% reduction in MN. These results suggest that critical necrosis-determining events occur between 2 and 4 hours after ISO administration and imply a relationship between ISO-induced lipolysis, calcium influx, and ISO-MN. We hypothesize that importance of lipolysis as a determinant of ISO-MN is related to the generation of free fatty acids, their oxidized/metabolic products, or direct damage to plasma membrane. | Lipolysis is an important determinant of isoproterenol-induced /"myocardial necrosis"/. | The cardiotoxic effect of isoproterenol (ISO) is associated with, and possibly due to, calcium overload. Prior work suggests that calcium entry into cardiac myocytes after ISO administration occurs in two phases: an early rapid phase, followed by a slow phase beginning about 1 hour after ISO injection, leading to a peak myocardial calcium level after about 4 hours. We have tested the relationship of these phases to /"myocardial necrosis"/ (/"MN"/) by determining the time after ISO administration at which the commitment to /"MN"/ occurs. This was done by administration of propranolol at various times before and after ISO. In addition, since ISO induces lipolysis, and lipids can be toxic, experiments were conducted to determine if adrenergically-activated lipolysis could play a significant role in ISO-/"MN"/. We found that propranolol protected the myocardium equally well when administered anytime within 2 hours of ISO injection, but had no effect when given 4 hours after ISO. This showed that metabolic events taking place more than two hours after ISO injection are required for ISO-/"MN"/. As expected from prior work, there was a small and consistent amount of propranolol-resistant ISO-/"MN"/. Lipolysis, assessed by measuring serum glycerol levels, increased to tenfold above base line at one hour after ISO administration and returned to near basal levels at 4 hours. Potentiation of lipolysis by intravenous injections of phospholipase A2 (PLA2) or /"lipoprotein lipase"/ (/"LPL"/) to rats treated with ISO substantially augmented /"MN"/. Propranolol completely blocked the increase in necrosis produced by PLA2 when given with ISO. Lipases induced only minimal necrosis in the absence of ISO. Administration of adenosine (an anti-lipolytic agent), oxfenicine (an inhibitor of mitochondrial palmitoyl carnitine transferase), or vitamin C (an anti-oxidant) resulted in a 55-60% reduction in /"MN"/. These results suggest that critical necrosis-determining events occur between 2 and 4 hours after ISO administration and imply a relationship between ISO-induced lipolysis, calcium influx, and ISO-/"MN"/. We hypothesize that importance of lipolysis as a determinant of ISO-/"MN"/ is related to the generation of free fatty acids, their oxidized/metabolic products, or direct damage to plasma membrane. | [
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10533957 | Lipolysis is an important determinant of isoproterenol-induced myocardial necrosis. | The cardiotoxic effect of isoproterenol (ISO) is associated with, and possibly due to, calcium overload. Prior work suggests that calcium entry into cardiac myocytes after ISO administration occurs in two phases: an early rapid phase, followed by a slow phase beginning about 1 hour after ISO injection, leading to a peak myocardial calcium level after about 4 hours. We have tested the relationship of these phases to myocardial necrosis (MN) by determining the time after ISO administration at which the commitment to MN occurs. This was done by administration of propranolol at various times before and after ISO. In addition, since ISO induces lipolysis, and lipids can be toxic, experiments were conducted to determine if adrenergically-activated lipolysis could play a significant role in ISO-MN. We found that propranolol protected the myocardium equally well when administered anytime within 2 hours of ISO injection, but had no effect when given 4 hours after ISO. This showed that metabolic events taking place more than two hours after ISO injection are required for ISO-MN. As expected from prior work, there was a small and consistent amount of propranolol-resistant ISO-MN. Lipolysis, assessed by measuring serum glycerol levels, increased to tenfold above base line at one hour after ISO administration and returned to near basal levels at 4 hours. Potentiation of lipolysis by intravenous injections of phospholipase A2 (PLA2) or lipoprotein lipase (LPL) to rats treated with ISO substantially augmented MN. Propranolol completely blocked the increase in necrosis produced by PLA2 when given with ISO. Lipases induced only minimal necrosis in the absence of ISO. Administration of adenosine (an anti-lipolytic agent), oxfenicine (an inhibitor of mitochondrial palmitoyl carnitine transferase), or vitamin C (an anti-oxidant) resulted in a 55-60% reduction in MN. These results suggest that critical necrosis-determining events occur between 2 and 4 hours after ISO administration and imply a relationship between ISO-induced lipolysis, calcium influx, and ISO-MN. We hypothesize that importance of lipolysis as a determinant of ISO-MN is related to the generation of free fatty acids, their oxidized/metabolic products, or direct damage to plasma membrane. | Lipolysis is an important determinant of isoproterenol-induced myocardial necrosis. | The /"cardiotoxic"/ effect of isoproterenol (ISO) is associated with, and possibly due to, calcium overload. Prior work suggests that calcium entry into cardiac myocytes after ISO administration occurs in two phases: an early rapid phase, followed by a slow phase beginning about 1 hour after ISO injection, leading to a peak myocardial calcium level after about 4 hours. We have tested the relationship of these phases to myocardial necrosis (MN) by determining the time after ISO administration at which the commitment to MN occurs. This was done by administration of propranolol at various times before and after ISO. In addition, since ISO induces lipolysis, and lipids can be toxic, experiments were conducted to determine if adrenergically-activated lipolysis could play a significant role in ISO-MN. We found that propranolol protected the myocardium equally well when administered anytime within 2 hours of ISO injection, but had no effect when given 4 hours after ISO. This showed that metabolic events taking place more than two hours after ISO injection are required for ISO-MN. As expected from prior work, there was a small and consistent amount of propranolol-resistant ISO-MN. Lipolysis, assessed by measuring serum glycerol levels, increased to tenfold above base line at one hour after ISO administration and returned to near basal levels at 4 hours. Potentiation of lipolysis by intravenous injections of phospholipase A2 (PLA2) or /"lipoprotein lipase"/ (/"LPL"/) to rats treated with ISO substantially augmented MN. Propranolol completely blocked the increase in necrosis produced by PLA2 when given with ISO. Lipases induced only minimal necrosis in the absence of ISO. Administration of adenosine (an anti-lipolytic agent), oxfenicine (an inhibitor of mitochondrial palmitoyl carnitine transferase), or vitamin C (an anti-oxidant) resulted in a 55-60% reduction in MN. These results suggest that critical necrosis-determining events occur between 2 and 4 hours after ISO administration and imply a relationship between ISO-induced lipolysis, calcium influx, and ISO-MN. We hypothesize that importance of lipolysis as a determinant of ISO-MN is related to the generation of free fatty acids, their oxidized/metabolic products, or direct damage to plasma membrane. | [
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10533957 | Lipolysis is an important determinant of isoproterenol-induced myocardial necrosis. | The cardiotoxic effect of isoproterenol (ISO) is associated with, and possibly due to, calcium overload. Prior work suggests that calcium entry into cardiac myocytes after ISO administration occurs in two phases: an early rapid phase, followed by a slow phase beginning about 1 hour after ISO injection, leading to a peak myocardial calcium level after about 4 hours. We have tested the relationship of these phases to myocardial necrosis (MN) by determining the time after ISO administration at which the commitment to MN occurs. This was done by administration of propranolol at various times before and after ISO. In addition, since ISO induces lipolysis, and lipids can be toxic, experiments were conducted to determine if adrenergically-activated lipolysis could play a significant role in ISO-MN. We found that propranolol protected the myocardium equally well when administered anytime within 2 hours of ISO injection, but had no effect when given 4 hours after ISO. This showed that metabolic events taking place more than two hours after ISO injection are required for ISO-MN. As expected from prior work, there was a small and consistent amount of propranolol-resistant ISO-MN. Lipolysis, assessed by measuring serum glycerol levels, increased to tenfold above base line at one hour after ISO administration and returned to near basal levels at 4 hours. Potentiation of lipolysis by intravenous injections of phospholipase A2 (PLA2) or lipoprotein lipase (LPL) to rats treated with ISO substantially augmented MN. Propranolol completely blocked the increase in necrosis produced by PLA2 when given with ISO. Lipases induced only minimal necrosis in the absence of ISO. Administration of adenosine (an anti-lipolytic agent), oxfenicine (an inhibitor of mitochondrial palmitoyl carnitine transferase), or vitamin C (an anti-oxidant) resulted in a 55-60% reduction in MN. These results suggest that critical necrosis-determining events occur between 2 and 4 hours after ISO administration and imply a relationship between ISO-induced lipolysis, calcium influx, and ISO-MN. We hypothesize that importance of lipolysis as a determinant of ISO-MN is related to the generation of free fatty acids, their oxidized/metabolic products, or direct damage to plasma membrane. | Lipolysis is an important determinant of isoproterenol-induced myocardial necrosis. | The /"cardiotoxic"/ effect of isoproterenol (ISO) is associated with, and possibly due to, calcium overload. Prior work suggests that calcium entry into cardiac myocytes after ISO administration occurs in two phases: an early rapid phase, followed by a slow phase beginning about 1 hour after ISO injection, leading to a peak myocardial calcium level after about 4 hours. We have tested the relationship of these phases to myocardial necrosis (MN) by determining the time after ISO administration at which the commitment to MN occurs. This was done by administration of propranolol at various times before and after ISO. In addition, since ISO induces lipolysis, and lipids can be toxic, experiments were conducted to determine if adrenergically-activated lipolysis could play a significant role in ISO-MN. We found that propranolol protected the myocardium equally well when administered anytime within 2 hours of ISO injection, but had no effect when given 4 hours after ISO. This showed that metabolic events taking place more than two hours after ISO injection are required for ISO-MN. As expected from prior work, there was a small and consistent amount of propranolol-resistant ISO-MN. Lipolysis, assessed by measuring serum glycerol levels, increased to tenfold above base line at one hour after ISO administration and returned to near basal levels at 4 hours. Potentiation of lipolysis by intravenous injections of phospholipase A2 (PLA2) or /"lipoprotein lipase"/ (/"LPL"/) to rats treated with ISO substantially augmented MN. Propranolol completely blocked the increase in necrosis produced by PLA2 when given with ISO. Lipases induced only minimal necrosis in the absence of ISO. Administration of adenosine (an anti-lipolytic agent), oxfenicine (an inhibitor of mitochondrial palmitoyl carnitine transferase), or vitamin C (an anti-oxidant) resulted in a 55-60% reduction in MN. These results suggest that critical necrosis-determining events occur between 2 and 4 hours after ISO administration and imply a relationship between ISO-induced lipolysis, calcium influx, and ISO-MN. We hypothesize that importance of lipolysis as a determinant of ISO-MN is related to the generation of free fatty acids, their oxidized/metabolic products, or direct damage to plasma membrane. | [
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} | No |
10541293 | Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease. | It is estimated that approximately 15% of families with autosomal dominant polycystic kidney disease (ADPKD) have mutations in PKD2. Identification of these mutations is central to identifying functionally important regions of gene and to understanding the mechanisms underlying the pathogenesis of the disorder. The current study describes mutations in six type 2 ADPKD families. Two single base substitution mutations discovered in the ORF in exon 14 constitute the most COOH-terminal pathogenic variants described to date. One of these mutations is a nonsense change and the other encodes an apparent missense variant. Reverse transcription-PCR from patient lymphoblast RNA showed that, in addition, both mutations resulted in out-of-frame splice variants by activating cryptic splice sites via different mechanisms. The apparent missense variant produced such a strong splicing signal that the processed transcript from the mutant chromosome did not contain any of the normally spliced, missense product. A third mutation, a nonconservative missense change effecting a negatively charged residue in the third transmembrane span, is likely pathogenic and defines a highly conserved residue consistent with a potential channel subunit function for polycystin-2. The remaining three mutations included two frame shifts resulting from deletion of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due to a single base substitution in exon 4. The study also defined a novel intragenic polymorphism in exon 1 that will be useful in analyzing "second hits" in PKD2. Finally, the study demonstrates that there are reduced levels of normal polycystin-2 protein in lymphoblast lines from PKD2-affected individuals and that truncated mutant polycystin-2 cannot be detected in patient lymphoblasts, suggesting that the latter may be unstable in at least some tissues. The mutations described will serve as critical reagents for future functional studies in PKD2. | Aberrant splicing in the /"PKD2"/D2"/ gene as a cause of polycystic kidney disease. | It is estimated that approximately 15% of families with autosomal dominant polycystic kidney disease (ADPKD) have mutations in /"PKD2"/D2"/. Identification of these mutations is central to identifying functionally important regions of gene and to understanding the mechanisms underlying the pathogenesis of the disorder. The current study describes mutations in six type 2 ADPKD families. Two single base substitution mutations discovered in the ORF in exon 14 constitute the most COOH-terminal pathogenic variants described to date. One of these mutations is a nonsense change and the other encodes an apparent missense variant. Reverse transcription-PCR from patient lymphoblast RNA showed that, in addition, both mutations resulted in out-of-frame splice variants by activating cryptic splice sites via different mechanisms. The apparent missense variant produced such a strong splicing signal that the processed transcript from the mutant chromosome did not contain any of the normally spliced, missense product. A third mutation, a nonconservative missense change effecting a negatively charged residue in the third transmembrane span, is likely pathogenic and defines a highly conserved residue consistent with a potential channel subunit function for polycystin-2. The remaining three mutations included two frame shifts resulting from deletion of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due to a single base substitution in exon 4. The study also defined a novel intragenic polymorphism in exon 1 that will be useful in analyzing "second hits" in /"PKD2"/D2"/. Finally, the study demonstrates that there are reduced levels of normal polycystin-2 protein in lymphoblast lines from /"PKD2"/D2"/-affected individuals and that truncated mutant polycystin-2 cannot be detected in patient lymphoblasts, suggesting that the latter may be unstable in at least some tissues. The mutations described will serve as critical reagents for future functional studies in /"PKD2"/D2"/. | [
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10541293 | Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease. | It is estimated that approximately 15% of families with autosomal dominant polycystic kidney disease (ADPKD) have mutations in PKD2. Identification of these mutations is central to identifying functionally important regions of gene and to understanding the mechanisms underlying the pathogenesis of the disorder. The current study describes mutations in six type 2 ADPKD families. Two single base substitution mutations discovered in the ORF in exon 14 constitute the most COOH-terminal pathogenic variants described to date. One of these mutations is a nonsense change and the other encodes an apparent missense variant. Reverse transcription-PCR from patient lymphoblast RNA showed that, in addition, both mutations resulted in out-of-frame splice variants by activating cryptic splice sites via different mechanisms. The apparent missense variant produced such a strong splicing signal that the processed transcript from the mutant chromosome did not contain any of the normally spliced, missense product. A third mutation, a nonconservative missense change effecting a negatively charged residue in the third transmembrane span, is likely pathogenic and defines a highly conserved residue consistent with a potential channel subunit function for polycystin-2. The remaining three mutations included two frame shifts resulting from deletion of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due to a single base substitution in exon 4. The study also defined a novel intragenic polymorphism in exon 1 that will be useful in analyzing "second hits" in PKD2. Finally, the study demonstrates that there are reduced levels of normal polycystin-2 protein in lymphoblast lines from PKD2-affected individuals and that truncated mutant polycystin-2 cannot be detected in patient lymphoblasts, suggesting that the latter may be unstable in at least some tissues. The mutations described will serve as critical reagents for future functional studies in PKD2. | Aberrant splicing in the /"PKD2"/ gene as a cause of /"polycystic kidney disease"/. | It is estimated that approximately 15% of families with /"autosomal dominant polycystic kidney disease"/ (/"ADPKD"/) have mutations in /"PKD2"/. Identification of these mutations is central to identifying functionally important regions of gene and to understanding the mechanisms underlying the pathogenesis of the disorder. The current study describes mutations in six type 2 /"ADPKD"/ families. Two single base substitution mutations discovered in the ORF in exon 14 constitute the most COOH-terminal pathogenic variants described to date. One of these mutations is a nonsense change and the other encodes an apparent missense variant. Reverse transcription-PCR from patient lymphoblast RNA showed that, in addition, both mutations resulted in out-of-frame splice variants by activating cryptic splice sites via different mechanisms. The apparent missense variant produced such a strong splicing signal that the processed transcript from the mutant chromosome did not contain any of the normally spliced, missense product. A third mutation, a nonconservative missense change effecting a negatively charged residue in the third transmembrane span, is likely pathogenic and defines a highly conserved residue consistent with a potential channel subunit function for polycystin-2. The remaining three mutations included two frame shifts resulting from deletion of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due to a single base substitution in exon 4. The study also defined a novel intragenic polymorphism in exon 1 that will be useful in analyzing "second hits" in /"PKD2"/. Finally, the study demonstrates that there are reduced levels of normal polycystin-2 protein in lymphoblast lines from /"PKD2"/-affected individuals and that truncated mutant polycystin-2 cannot be detected in patient lymphoblasts, suggesting that the latter may be unstable in at least some tissues. The mutations described will serve as critical reagents for future functional studies in /"PKD2"/. | [
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} | No |
10619808 | Association between plasma CC16 levels, the A38G polymorphism, and asthma. | The effect of the A38G polymorphism on Clara cell secretory protein (CC16) gene expression and asthma was investigated by measuring plasma CC16 levels in 100 asthmatic and nonasthmatic children. Restriction digestion determined the A38G genotype and plasma CC16 levels were analyzed using a sensitive latex immunoassay. Asthmatics had lower mean plasma CC16 levels adjusted for age and gender (7.96 microg/L; 95% confidence interval [CI] = 6.79 to 9.31) than nonasthmatic subjects (9.98 microg/L; 95% CI = 8.83 to 11.26) (p = 0. 006). Similarly adjusted, mean plasma CC16 levels were also lower in 38A/38A (6.79 microg/L; 95% CI = 4.56 to 9.02) than 38G/38G subjects (10.01 microg/L; 95% CI = 7.90 to 12.12; p = 0.003). The odds ratio for asthma diagnosis of 38A/38A subjects was 4.78 (95% CI = 1.08 to 21.18; p = 0.04) compared with 38G/38G subjects. However, this was reduced when corrected from plasma CC16 level, suggesting that the odds of asthma was largely mediated through altered plasma CC16 levels. The 38A sequence was associated with reduced plasma CC16 levels and individuals with lower plasma CC16 levels were more likely to have asthma. This provides further evidence for a significant role of the CC16 gene, 38A allele in the development of asthma. | Association between plasma /"CC16"/ levels, the A38G polymorphism, and /"asthma"/. | The effect of the A38G polymorphism on Clara cell secretory protein (/"CC16"/) gene expression and /"asthma"/ was investigated by measuring plasma /"CC16"/ levels in 100 asthmatic and nonasthmatic children. Restriction digestion determined the A38G genotype and plasma /"CC16"/ levels were analyzed using a sensitive latex immunoassay. Asthmatics had lower mean plasma /"CC16"/ levels adjusted for age and gender (7.96 microg/L; 95% confidence interval [CI] = 6.79 to 9.31) than nonasthmatic subjects (9.98 microg/L; 95% CI = 8.83 to 11.26) (p = 0. 006). Similarly adjusted, mean plasma /"CC16"/ levels were also lower in 38A/38A (6.79 microg/L; 95% CI = 4.56 to 9.02) than 38G/38G subjects (10.01 microg/L; 95% CI = 7.90 to 12.12; p = 0.003). The odds ratio for /"asthma"/ diagnosis of 38A/38A subjects was 4.78 (95% CI = 1.08 to 21.18; p = 0.04) compared with 38G/38G subjects. However, this was reduced when corrected from plasma /"CC16"/ level, suggesting that the odds of /"asthma"/ was largely mediated through altered plasma /"CC16"/ levels. The 38A sequence was associated with reduced plasma /"CC16"/ levels and individuals with lower plasma /"CC16"/ levels were more likely to have /"asthma"/. This provides further evidence for a significant role of the /"CC16"/ gene, 38A allele in the development of /"asthma"/. | [
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"entity_id": "D001249",
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"text_name": "asthma"
} | Yes |
10670188 | [The C1166 allele of the AT1R gene associated with ACE DD phenotype increases the risk for deep venous thrombosis]. | [The C1166 allele of the /"AT1R"/ gene associated with ACE DD phenotype increases the risk for /"deep venous thrombosis"/]. | [
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"text_name": "deep venous thrombosis"
} | Yes |
||
10670188 | [The C1166 allele of the AT1R gene associated with ACE DD phenotype increases the risk for deep venous thrombosis]. | [The C1166 allele of the AT1R gene associated with /"ACE"/ /"DD"/ phenotype increases the risk for deep venous thrombosis]. | [
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"entity_type": "Disease",
"text_name": "DD"
} | No |
||
10680585 | Orphanin FQ/nociceptin inhibits morphine withdrawal. | The influence of orphanin FQ/nociceptin (OFQ/N) on the morphine-withdrawal symptom was investigated. Withdrawal syndrome was induced in the morphine-dependent rats by an intraperitoneal (i.p.) injection of 2 mg/kg naloxone hydrochloride--an opioid receptors antagonist. Wet-dog shakes were used as a measure of the abstinence syndrome. Intraventricular injections of OFQ/N (5-20 microg/animal) caused significant inhibition of the withdrawal signs at doses between 15-20 microg, in the morphine-dependent rats. OFQ/N alone did not change behavior of the morphine-dependent animals. The obtained results indicate that OFQ/N can inhibit the morphine withdrawal symptoms induced by naloxone. | /"Orphanin FQ"///"nociceptin"/ inhibits morphine withdrawal. | The influence of /"orphanin FQ"///"nociceptin"/ (OFQ/N) on the morphine-withdrawal symptom was investigated. /"Withdrawal syndrome"/ was induced in the morphine-dependent rats by an intraperitoneal (i.p.) injection of 2 mg/kg naloxone hydrochloride--an opioid receptors antagonist. Wet-dog shakes were used as a measure of the abstinence syndrome. Intraventricular injections of OFQ/N (5-20 microg/animal) caused significant inhibition of the withdrawal signs at doses between 15-20 microg, in the morphine-dependent rats. OFQ/N alone did not change behavior of the morphine-dependent animals. The obtained results indicate that OFQ/N can inhibit the morphine withdrawal symptoms induced by naloxone. | [
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"text_name": "Withdrawal syndrome"
} | Yes |
10680585 | Orphanin FQ/nociceptin inhibits morphine withdrawal. | The influence of orphanin FQ/nociceptin (OFQ/N) on the morphine-withdrawal symptom was investigated. Withdrawal syndrome was induced in the morphine-dependent rats by an intraperitoneal (i.p.) injection of 2 mg/kg naloxone hydrochloride--an opioid receptors antagonist. Wet-dog shakes were used as a measure of the abstinence syndrome. Intraventricular injections of OFQ/N (5-20 microg/animal) caused significant inhibition of the withdrawal signs at doses between 15-20 microg, in the morphine-dependent rats. OFQ/N alone did not change behavior of the morphine-dependent animals. The obtained results indicate that OFQ/N can inhibit the morphine withdrawal symptoms induced by naloxone. | /"Orphanin FQ"///"nociceptin"/ inhibits morphine withdrawal. | The influence of /"orphanin FQ"///"nociceptin"/ (OFQ/N) on the morphine-withdrawal symptom was investigated. Withdrawal syndrome was induced in the morphine-dependent rats by an intraperitoneal (i.p.) injection of 2 mg/kg naloxone hydrochloride--an opioid receptors antagonist. Wet-dog shakes were used as a measure of the /"abstinence syndrome"/. Intraventricular injections of OFQ/N (5-20 microg/animal) caused significant inhibition of the withdrawal signs at doses between 15-20 microg, in the morphine-dependent rats. OFQ/N alone did not change behavior of the morphine-dependent animals. The obtained results indicate that OFQ/N can inhibit the morphine withdrawal symptoms induced by naloxone. | [
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10702401 | Association of EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing's sarcoma. | The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-FLI1 are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway. | Association of EWS-/"FLI1"/ type 1 fusion with lower proliferative rate in /"Ewing's sarcoma"/. | The /"Ewing's sarcoma"/ (/"ES"/) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either /"FLI1"/ (90-95%) or ERG (5-10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and /"FLI1"/ (or ERG) in the fusion products. The most common type of EWS-/"FLI1"/ fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 /"ES"//PNET with defined EWS-ETS fusions (45 EWS-/"FLI1"/ type 1, 27 EWS-/"FLI1"/ non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with EWS-/"FLI1"/ type 1 than those with non-type 1 EWS-/"FLI1"/, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of /"type 1 EWS-FLI1"/ and lower IGF-1R expression (P = 0.04). Comparing EWS-/"FLI1"/ to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-/"FLI1"/ are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway. | [
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10702401 | Association of EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing's sarcoma. | The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-FLI1 are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway. | Association of /"EWS"/-FLI1 type 1 fusion with lower proliferative rate in Ewing's sarcoma. | The Ewing's sarcoma (ES) family of /"tumors"/, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the /"EWS"/ gene with a member of the ETS family of transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from /"EWS"/ and FLI1 (or ERG) in the fusion products. The most common type of /"EWS"/-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with /"tumor"/ cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined /"EWS"/-ETS fusions (45 /"EWS"/-FLI1 type 1, 27 /"EWS"/-FLI1 non-type 1, 14 /"EWS"/-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in /"tumors"/ with /"EWS"/-FLI1 type 1 than those with non-type 1 /"EWS"/-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing /"EWS"/-FLI1 to /"EWS"/-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of /"EWS"/-FLI1 are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway. | [
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10732801 | Mutation and polymorphism analysis in the tuberous sclerosis 2 (TSC2) gene. | Tuberous sclerosis complex (TSC) is an autosomal dominant multi-system disorder with two known disease loci on chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). TSC has a prevalence of approximately 1 in 5,000-6,000, exhibits incomplete penetrance, and occurs in all racial groups. Our laboratory has undertaken the complete mutation analysis of the TSC2 gene in 42 TSC families using single-strand conformation polymorphism analysis and reverse transcription-polymerase chain reaction. Of the total of 42 families, 16 show evidence of linkage to the chromosome 16 TSC2 locus and 26 are either sporadic or too small to establish chromosome linkage. The TSC2 gene spans at least 45 kilobases of genomic DNA, has 41 known exons, and codes for a 5,474-base pair transcript. After complete gene analysis, 16 TSC2 mutations have been identified, including DNA insertions, deletions, splice site mutations, and amino acid substitutions. The majority of putative TSC2 mutations were found in sporadic rather than TSC2-linked families. We have also detected 15 polymorphisms which occur in the TSC2 gene. | Mutation and polymorphism analysis in the /"tuberous sclerosis 2"/ 2"/ (/"TSC2"/C2"/) gene. | Tuberous sclerosis complex (TSC) is an autosomal dominant multi-system disorder with two known disease loci on chromosomes 9q34 (TSC1) and 16p13.3 (/"TSC2"/C2"/). TSC has a prevalence of approximately 1 in 5,000-6,000, exhibits incomplete penetrance, and occurs in all racial groups. Our laboratory has undertaken the complete mutation analysis of the /"TSC2"/C2"/ gene in 42 TSC families using single-strand conformation polymorphism analysis and reverse transcription-polymerase chain reaction. Of the total of 42 families, 16 show evidence of linkage to the chromosome 16 /"TSC2"/C2"/ locus and 26 are either sporadic or too small to establish chromosome linkage. The /"TSC2"/C2"/ gene spans at least 45 kilobases of genomic DNA, has 41 known exons, and codes for a 5,474-base pair transcript. After complete gene analysis, 16 /"TSC2"/C2"/ mutations have been identified, including DNA insertions, deletions, splice site mutations, and amino acid substitutions. The majority of putative /"TSC2"/C2"/ mutations were found in sporadic rather than /"TSC2"/C2"/-linked families. We have also detected 15 polymorphisms which occur in the /"TSC2"/C2"/ gene. | [
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10732801 | Mutation and polymorphism analysis in the tuberous sclerosis 2 (TSC2) gene. | Tuberous sclerosis complex (TSC) is an autosomal dominant multi-system disorder with two known disease loci on chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). TSC has a prevalence of approximately 1 in 5,000-6,000, exhibits incomplete penetrance, and occurs in all racial groups. Our laboratory has undertaken the complete mutation analysis of the TSC2 gene in 42 TSC families using single-strand conformation polymorphism analysis and reverse transcription-polymerase chain reaction. Of the total of 42 families, 16 show evidence of linkage to the chromosome 16 TSC2 locus and 26 are either sporadic or too small to establish chromosome linkage. The TSC2 gene spans at least 45 kilobases of genomic DNA, has 41 known exons, and codes for a 5,474-base pair transcript. After complete gene analysis, 16 TSC2 mutations have been identified, including DNA insertions, deletions, splice site mutations, and amino acid substitutions. The majority of putative TSC2 mutations were found in sporadic rather than TSC2-linked families. We have also detected 15 polymorphisms which occur in the TSC2 gene. | Mutation and polymorphism analysis in the /"tuberous sclerosis 2"/ (/"TSC2"/) gene. | /"Tuberous sclerosis complex"/ (/"TSC"/) is an autosomal dominant multi-system disorder with two known disease loci on chromosomes 9q34 (TSC1) and 16p13.3 (/"TSC2"/). /"TSC"/ has a prevalence of approximately 1 in 5,000-6,000, exhibits incomplete penetrance, and occurs in all racial groups. Our laboratory has undertaken the complete mutation analysis of the /"TSC2"/ gene in 42 /"TSC"/ families using single-strand conformation polymorphism analysis and reverse transcription-polymerase chain reaction. Of the total of 42 families, 16 show evidence of linkage to the chromosome 16 /"TSC2"/ locus and 26 are either sporadic or too small to establish chromosome linkage. The /"TSC2"/ gene spans at least 45 kilobases of genomic DNA, has 41 known exons, and codes for a 5,474-base pair transcript. After complete gene analysis, 16 /"TSC2"/ mutations have been identified, including DNA insertions, deletions, splice site mutations, and amino acid substitutions. The majority of putative /"TSC2"/ mutations were found in sporadic rather than /"TSC2"/-linked families. We have also detected 15 polymorphisms which occur in the /"TSC2"/ gene. | [
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10732801 | Mutation and polymorphism analysis in the tuberous sclerosis 2 (TSC2) gene. | Tuberous sclerosis complex (TSC) is an autosomal dominant multi-system disorder with two known disease loci on chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). TSC has a prevalence of approximately 1 in 5,000-6,000, exhibits incomplete penetrance, and occurs in all racial groups. Our laboratory has undertaken the complete mutation analysis of the TSC2 gene in 42 TSC families using single-strand conformation polymorphism analysis and reverse transcription-polymerase chain reaction. Of the total of 42 families, 16 show evidence of linkage to the chromosome 16 TSC2 locus and 26 are either sporadic or too small to establish chromosome linkage. The TSC2 gene spans at least 45 kilobases of genomic DNA, has 41 known exons, and codes for a 5,474-base pair transcript. After complete gene analysis, 16 TSC2 mutations have been identified, including DNA insertions, deletions, splice site mutations, and amino acid substitutions. The majority of putative TSC2 mutations were found in sporadic rather than TSC2-linked families. We have also detected 15 polymorphisms which occur in the TSC2 gene. | Mutation and polymorphism analysis in the tuberous sclerosis 2 (TSC2) gene. | /"Tuberous sclerosis complex"/ (/"TSC"/) is an autosomal dominant multi-system disorder with two known disease loci on chromosomes 9q34 (/"TSC1"/) and 16p13.3 (TSC2). /"TSC"/ has a prevalence of approximately 1 in 5,000-6,000, exhibits incomplete penetrance, and occurs in all racial groups. Our laboratory has undertaken the complete mutation analysis of the TSC2 gene in 42 /"TSC"/ families using single-strand conformation polymorphism analysis and reverse transcription-polymerase chain reaction. Of the total of 42 families, 16 show evidence of linkage to the chromosome 16 TSC2 locus and 26 are either sporadic or too small to establish chromosome linkage. The TSC2 gene spans at least 45 kilobases of genomic DNA, has 41 known exons, and codes for a 5,474-base pair transcript. After complete gene analysis, 16 TSC2 mutations have been identified, including DNA insertions, deletions, splice site mutations, and amino acid substitutions. The majority of putative TSC2 mutations were found in sporadic rather than TSC2-linked families. We have also detected 15 polymorphisms which occur in the TSC2 gene. | [
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10732801 | Mutation and polymorphism analysis in the tuberous sclerosis 2 (TSC2) gene. | Tuberous sclerosis complex (TSC) is an autosomal dominant multi-system disorder with two known disease loci on chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). TSC has a prevalence of approximately 1 in 5,000-6,000, exhibits incomplete penetrance, and occurs in all racial groups. Our laboratory has undertaken the complete mutation analysis of the TSC2 gene in 42 TSC families using single-strand conformation polymorphism analysis and reverse transcription-polymerase chain reaction. Of the total of 42 families, 16 show evidence of linkage to the chromosome 16 TSC2 locus and 26 are either sporadic or too small to establish chromosome linkage. The TSC2 gene spans at least 45 kilobases of genomic DNA, has 41 known exons, and codes for a 5,474-base pair transcript. After complete gene analysis, 16 TSC2 mutations have been identified, including DNA insertions, deletions, splice site mutations, and amino acid substitutions. The majority of putative TSC2 mutations were found in sporadic rather than TSC2-linked families. We have also detected 15 polymorphisms which occur in the TSC2 gene. | Mutation and polymorphism analysis in the /"tuberous sclerosis 2"/ (/"TSC2"/) gene. | Tuberous sclerosis complex (TSC) is an /"autosomal dominant multi-system disorder"/ with two known disease loci on chromosomes 9q34 (TSC1) and 16p13.3 (/"TSC2"/). TSC has a prevalence of approximately 1 in 5,000-6,000, exhibits incomplete penetrance, and occurs in all racial groups. Our laboratory has undertaken the complete mutation analysis of the /"TSC2"/ gene in 42 TSC families using single-strand conformation polymorphism analysis and reverse transcription-polymerase chain reaction. Of the total of 42 families, 16 show evidence of linkage to the chromosome 16 /"TSC2"/ locus and 26 are either sporadic or too small to establish chromosome linkage. The /"TSC2"/ gene spans at least 45 kilobases of genomic DNA, has 41 known exons, and codes for a 5,474-base pair transcript. After complete gene analysis, 16 /"TSC2"/ mutations have been identified, including DNA insertions, deletions, splice site mutations, and amino acid substitutions. The majority of putative /"TSC2"/ mutations were found in sporadic rather than /"TSC2"/-linked families. We have also detected 15 polymorphisms which occur in the /"TSC2"/ gene. | [
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"end_idx": "1160",
"entity_id": "7249",
"entity_type": "Gene",
"text_name": "TSC2"
}
] | {
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"end_idx": "68",
"entity_id": "7249",
"entity_type": "Gene",
"text_name": "TSC2"
} | {
"begin_idx": "115",
"end_idx": "155",
"entity_id": "D030342",
"entity_type": "Disease",
"text_name": "autosomal dominant multi-system disorder"
} | No |
10800171 | Experience of a single Italian center in genetic counseling for hemophilia: from linkage analysis to molecular diagnosis. | BACKGROUND AND OBJECTIVE: We describe our three year experience in genetic counseling at the Castelfranco Veneto Hemophilia Center, Italy. DESIGN AND METHODS: A total of 258 individuals were involved in the study of 142 females. These formed 40 families with hemophilia A and 6 families with hemophilia B. Following pedigree analysis, the FVIII inversion was first examined in severe hemophilia A patients by polymerase chain reaction (PCR) analysis. DNA polymorphisms were used to track the affected gene through the remaining families. In uninformative cases, we initiated analysis of the FVIII or FIX gene coding region by conformation sensitive gel electrophoresis and DNA sequencing to identify the mutation responsible for the disease. RESULTS: The FVIII gene inversion was present in 16 of the 32 patients (50%) affected by severe hemophilia A and was informative for 44 females. For hemophilia A, 45 cases (55%) were informative by linkage analysis, however 37 (45%) were uninformative because of lack of key individuals, homozygosity, or sporadic disease. Information from extragenic linked polymorphisms alone was present in 9 cases (6%). For hemophilia B, linkage analysis was informative in only 50% of females (8 out of 16). To date, nine mutations have been identified in patients with hemophilia A and three in patients with hemophilia B. Six novel missense mutations in hemophilia A are discussed briefly. INTERPRETATION AND CONCLUSIONS: Using this approach we are now able to offer accurate genetic analysis to virtually all families with hemophilia. | Experience of a single Italian center in genetic counseling for /"hemophilia"/: from linkage analysis to molecular diagnosis. | BACKGROUND AND OBJECTIVE: We describe our three year experience in genetic counseling at the Castelfranco Veneto /"Hemophilia"/ Center, Italy. DESIGN AND METHODS: A total of 258 individuals were involved in the study of 142 females. These formed 40 families with /"hemophilia A"/ and 6 families with hemophilia B. Following pedigree analysis, the /"FVIII"/ inversion was first examined in severe /"hemophilia A"/ patients by polymerase chain reaction (PCR) analysis. DNA polymorphisms were used to track the affected gene through the remaining families. In uninformative cases, we initiated analysis of the /"FVIII"/ or FIX gene coding region by conformation sensitive gel electrophoresis and DNA sequencing to identify the mutation responsible for the disease. RESULTS: The /"FVIII"/ gene inversion was present in 16 of the 32 patients (50%) affected by severe /"hemophilia A"/ and was informative for 44 females. For /"hemophilia A"/, 45 cases (55%) were informative by linkage analysis, however 37 (45%) were uninformative because of lack of key individuals, homozygosity, or sporadic disease. Information from extragenic linked polymorphisms alone was present in 9 cases (6%). For hemophilia B, linkage analysis was informative in only 50% of females (8 out of 16). To date, nine mutations have been identified in patients with /"hemophilia A"/ and three in patients with hemophilia B. Six novel missense mutations in /"hemophilia A"/ are discussed briefly. INTERPRETATION AND CONCLUSIONS: Using this approach we are now able to offer accurate genetic analysis to virtually all families with /"hemophilia"/. | [
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"entity_type": "Disease",
"text_name": "hemophilia B"
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},
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},
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"text_name": "hemophilia A"
},
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"text_name": "hemophilia A"
},
{
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"entity_id": "D006467",
"entity_type": "Disease",
"text_name": "hemophilia"
},
{
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},
{
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},
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},
{
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"end_idx": "725",
"entity_id": "2158",
"entity_type": "Gene",
"text_name": "FIX"
}
] | {
"begin_idx": "461",
"end_idx": "466",
"entity_id": "2157",
"entity_type": "Gene",
"text_name": "FVIII"
} | {
"begin_idx": "381",
"end_idx": "393",
"entity_id": "D006467",
"entity_type": "Disease",
"text_name": "hemophilia A"
} | Yes |
10800171 | Experience of a single Italian center in genetic counseling for hemophilia: from linkage analysis to molecular diagnosis. | BACKGROUND AND OBJECTIVE: We describe our three year experience in genetic counseling at the Castelfranco Veneto Hemophilia Center, Italy. DESIGN AND METHODS: A total of 258 individuals were involved in the study of 142 females. These formed 40 families with hemophilia A and 6 families with hemophilia B. Following pedigree analysis, the FVIII inversion was first examined in severe hemophilia A patients by polymerase chain reaction (PCR) analysis. DNA polymorphisms were used to track the affected gene through the remaining families. In uninformative cases, we initiated analysis of the FVIII or FIX gene coding region by conformation sensitive gel electrophoresis and DNA sequencing to identify the mutation responsible for the disease. RESULTS: The FVIII gene inversion was present in 16 of the 32 patients (50%) affected by severe hemophilia A and was informative for 44 females. For hemophilia A, 45 cases (55%) were informative by linkage analysis, however 37 (45%) were uninformative because of lack of key individuals, homozygosity, or sporadic disease. Information from extragenic linked polymorphisms alone was present in 9 cases (6%). For hemophilia B, linkage analysis was informative in only 50% of females (8 out of 16). To date, nine mutations have been identified in patients with hemophilia A and three in patients with hemophilia B. Six novel missense mutations in hemophilia A are discussed briefly. INTERPRETATION AND CONCLUSIONS: Using this approach we are now able to offer accurate genetic analysis to virtually all families with hemophilia. | Experience of a single Italian center in genetic counseling for hemophilia: from linkage analysis to molecular diagnosis. | BACKGROUND AND OBJECTIVE: We describe our three year experience in genetic counseling at the Castelfranco Veneto Hemophilia Center, Italy. DESIGN AND METHODS: A total of 258 individuals were involved in the study of 142 females. These formed 40 families with hemophilia A and 6 families with /"hemophilia B"/. Following pedigree analysis, the /"FVIII"/ inversion was first examined in severe hemophilia A patients by polymerase chain reaction (PCR) analysis. DNA polymorphisms were used to track the affected gene through the remaining families. In uninformative cases, we initiated analysis of the /"FVIII"/ or FIX gene coding region by conformation sensitive gel electrophoresis and DNA sequencing to identify the mutation responsible for the disease. RESULTS: The /"FVIII"/ gene inversion was present in 16 of the 32 patients (50%) affected by severe hemophilia A and was informative for 44 females. For hemophilia A, 45 cases (55%) were informative by linkage analysis, however 37 (45%) were uninformative because of lack of key individuals, homozygosity, or sporadic disease. Information from extragenic linked polymorphisms alone was present in 9 cases (6%). For /"hemophilia B"/, linkage analysis was informative in only 50% of females (8 out of 16). To date, nine mutations have been identified in patients with hemophilia A and three in patients with /"hemophilia B"/. Six novel missense mutations in hemophilia A are discussed briefly. INTERPRETATION AND CONCLUSIONS: Using this approach we are now able to offer accurate genetic analysis to virtually all families with hemophilia. | [
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"end_idx": "426",
"entity_id": "D002836",
"entity_type": "Disease",
"text_name": "hemophilia B"
},
{
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"end_idx": "1287",
"entity_id": "D002836",
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},
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"entity_id": "D002836",
"entity_type": "Disease",
"text_name": "hemophilia B"
},
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"entity_type": "Disease",
"text_name": "sporadic disease"
},
{
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"entity_type": "Disease",
"text_name": "hemophilia"
},
{
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"entity_id": "D006467",
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"text_name": "Hemophilia"
},
{
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"entity_id": "D006467",
"entity_type": "Disease",
"text_name": "hemophilia A"
},
{
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"entity_id": "D006467",
"entity_type": "Disease",
"text_name": "hemophilia A"
},
{
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"entity_id": "D006467",
"entity_type": "Disease",
"text_name": "hemophilia A"
},
{
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"end_idx": "1025",
"entity_id": "D006467",
"entity_type": "Disease",
"text_name": "hemophilia A"
},
{
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"end_idx": "1434",
"entity_id": "D006467",
"entity_type": "Disease",
"text_name": "hemophilia A"
},
{
"begin_idx": "1508",
"end_idx": "1520",
"entity_id": "D006467",
"entity_type": "Disease",
"text_name": "hemophilia A"
},
{
"begin_idx": "1678",
"end_idx": "1688",
"entity_id": "D006467",
"entity_type": "Disease",
"text_name": "hemophilia"
},
{
"begin_idx": "461",
"end_idx": "466",
"entity_id": "2157",
"entity_type": "Gene",
"text_name": "FVIII"
},
{
"begin_idx": "713",
"end_idx": "718",
"entity_id": "2157",
"entity_type": "Gene",
"text_name": "FVIII"
},
{
"begin_idx": "877",
"end_idx": "882",
"entity_id": "2157",
"entity_type": "Gene",
"text_name": "FVIII"
},
{
"begin_idx": "722",
"end_idx": "725",
"entity_id": "2158",
"entity_type": "Gene",
"text_name": "FIX"
}
] | {
"begin_idx": "713",
"end_idx": "718",
"entity_id": "2157",
"entity_type": "Gene",
"text_name": "FVIII"
} | {
"begin_idx": "1275",
"end_idx": "1287",
"entity_id": "D002836",
"entity_type": "Disease",
"text_name": "hemophilia B"
} | No |
10822820 | [Analysis of the association between the T113M polymorphism of the human il-9 gene and bronchial asthma]. | The T113M polymorphism resulting from the missense mutation in exon 5 of the human interleukin 9 (IL9) gene was tested for association with bronchial asthma (BA). The genotype frequency analysis did not reveal a deviation from the Hardy-Weinberg equilibrium. A comparison of the genotype frequency distributions in a control group of healthy individuals and in patients with BA suggested an association between T113M and the clinical phenotype. However, this association was not confirmed by the affected family-based association control (AFBAC) or the transmission/disequilibrium test (TDT). | [Analysis of the association between the T113M polymorphism of the human /"il-9"/ gene and /"bronchial asthma"/]. | The T113M polymorphism resulting from the missense mutation in exon 5 of the human /"interleukin 9"/ (/"IL9"/) gene was tested for association with /"bronchial asthma"/ (/"BA"/). The genotype frequency analysis did not reveal a deviation from the Hardy-Weinberg equilibrium. A comparison of the genotype frequency distributions in a control group of healthy individuals and in patients with /"BA"/ suggested an association between T113M and the clinical phenotype. However, this association was not confirmed by the affected family-based association control (AFBAC) or the transmission/disequilibrium test (TDT). | [
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"entity_id": "D001249",
"entity_type": "Disease",
"text_name": "bronchial asthma"
},
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"end_idx": "262",
"entity_id": "D001249",
"entity_type": "Disease",
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},
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"text_name": "BA"
},
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"text_name": "il-9"
},
{
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"text_name": "interleukin 9"
},
{
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"end_idx": "207",
"entity_id": "3578",
"entity_type": "Gene",
"text_name": "IL9"
}
] | {
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"text_name": "interleukin 9"
} | {
"begin_idx": "87",
"end_idx": "103",
"entity_id": "D001249",
"entity_type": "Disease",
"text_name": "bronchial asthma"
} | Yes |
10835642 | Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. | Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by calcification of elastic fibres in skin, arteries and retina that results in dermal lesions with associated laxity and loss of elasticity, arterial insufficiency and retinal haemorrhages leading to macular degeneration. PXE is usually found as a sporadic disorder, but examples of both autosomal recessive and autosomal dominant forms of PXE have been observed. Partial manifestations of the PXE phenotype have also been described in presumed carriers in PXE families. Linkage of both dominant and recessive forms of PXE to a 5-cM domain on chromosome 16p13.1 has been reported (refs 8,9). We have refined this locus to an 820-kb region containing 6 candidate genes. Here we report the exclusion of five of these genes and the identification of the first mutations responsible for the development of PXE in a gene encoding a protein associated with multidrug resistance (ABCC6). | Mutations in a gene encoding an ABC transporter cause /"pseudoxanthoma elasticum"/. | /"Pseudoxanthoma elasticum"/ (/"PXE"/) is a heritable disorder characterized by calcification of elastic fibres in skin, arteries and retina that results in dermal lesions with associated laxity and loss of elasticity, arterial insufficiency and retinal haemorrhages leading to macular degeneration. /"PXE"/ is usually found as a sporadic disorder, but examples of both autosomal recessive and autosomal dominant forms of /"PXE"/ have been observed. Partial manifestations of the /"PXE"/ phenotype have also been described in presumed carriers in /"PXE"/ families. Linkage of both dominant and recessive forms of /"PXE"/ to a 5-cM domain on chromosome 16p13.1 has been reported (refs 8,9). We have refined this locus to an 820-kb region containing 6 candidate genes. Here we report the exclusion of five of these genes and the identification of the first mutations responsible for the development of /"PXE"/ in a gene encoding a protein associated with multidrug resistance (/"ABCC6"/). | [
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"entity_id": "D001927",
"entity_type": "Disease",
"text_name": "dermal lesions"
},
{
"begin_idx": "350",
"end_idx": "370",
"entity_id": "D008268",
"entity_type": "Disease",
"text_name": "macular degeneration"
},
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},
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"entity_id": "D012166",
"entity_type": "Disease",
"text_name": "retinal haemorrhages"
},
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"entity_id": "D014715",
"entity_type": "Disease",
"text_name": "arterial insufficiency"
},
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"entity_id": "D025063",
"entity_type": "Disease",
"text_name": "sporadic disorder"
},
{
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"entity_id": "368",
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"text_name": "ABCC6"
}
] | {
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"entity_id": "368",
"entity_type": "Gene",
"text_name": "ABCC6"
} | {
"begin_idx": "54",
"end_idx": "78",
"entity_id": "D011561",
"entity_type": "Disease",
"text_name": "pseudoxanthoma elasticum"
} | Yes |
10835642 | Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. | Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by calcification of elastic fibres in skin, arteries and retina that results in dermal lesions with associated laxity and loss of elasticity, arterial insufficiency and retinal haemorrhages leading to macular degeneration. PXE is usually found as a sporadic disorder, but examples of both autosomal recessive and autosomal dominant forms of PXE have been observed. Partial manifestations of the PXE phenotype have also been described in presumed carriers in PXE families. Linkage of both dominant and recessive forms of PXE to a 5-cM domain on chromosome 16p13.1 has been reported (refs 8,9). We have refined this locus to an 820-kb region containing 6 candidate genes. Here we report the exclusion of five of these genes and the identification of the first mutations responsible for the development of PXE in a gene encoding a protein associated with multidrug resistance (ABCC6). | Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. | Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by calcification of elastic fibres in skin, arteries and retina that results in dermal lesions with associated laxity and loss of elasticity, arterial insufficiency and retinal haemorrhages leading to /"macular degeneration"/. PXE is usually found as a sporadic disorder, but examples of both autosomal recessive and autosomal dominant forms of PXE have been observed. Partial manifestations of the PXE phenotype have also been described in presumed carriers in PXE families. Linkage of both dominant and recessive forms of PXE to a 5-cM domain on chromosome 16p13.1 has been reported (refs 8,9). We have refined this locus to an 820-kb region containing 6 candidate genes. Here we report the exclusion of five of these genes and the identification of the first mutations responsible for the development of PXE in a gene encoding a protein associated with multidrug resistance (/"ABCC6"/). | [
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"entity_type": "Disease",
"text_name": "dermal lesions"
},
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"entity_id": "D008268",
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},
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},
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},
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},
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},
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"text_name": "retinal haemorrhages"
},
{
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"entity_id": "D014715",
"entity_type": "Disease",
"text_name": "arterial insufficiency"
},
{
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"entity_id": "D025063",
"entity_type": "Disease",
"text_name": "sporadic disorder"
},
{
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"end_idx": "1028",
"entity_id": "368",
"entity_type": "Gene",
"text_name": "ABCC6"
}
] | {
"begin_idx": "1023",
"end_idx": "1028",
"entity_id": "368",
"entity_type": "Gene",
"text_name": "ABCC6"
} | {
"begin_idx": "350",
"end_idx": "370",
"entity_id": "D008268",
"entity_type": "Disease",
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} | No |
10889552 | A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia. | Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the CYP1A2 enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of CYP1A2 induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the CYP1A2 gene was found to be associated with variation in CYP1A2 inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in CYP1A2 in relation to TD severity. A total of 85 patients with schizophrenia were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in CYP1A2. The mean AIMS score in patients with the (C/C) genotype (associated with reduced CYP1A2 inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the CYP1A2 gene may serve as a genetic risk factor for the development of TD in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications. | A functional polymorphism of the /"cytochrome P450 1A2"/ (/"CYP1A2"/) gene: association with tardive dyskinesia in /"schizophrenia"/. | Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with /"schizophrenia"/ are smokers. Smoking is a potent inducer of the /"CYP1A2"/ enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of /"CYP1A2"/ induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the /"CYP1A2"/ gene was found to be associated with variation in /"CYP1A2"/ inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in /"CYP1A2"/ in relation to TD severity. A total of 85 patients with /"schizophrenia"/ were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in /"CYP1A2"/. The mean AIMS score in patients with the (C/C) genotype (associated with reduced /"CYP1A2"/ inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the /"CYP1A2"/ gene may serve as a genetic risk factor for the development of TD in patients with /"schizophrenia"/. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications. | [
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10889552 | A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia. | Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the CYP1A2 enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of CYP1A2 induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the CYP1A2 gene was found to be associated with variation in CYP1A2 inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in CYP1A2 in relation to TD severity. A total of 85 patients with schizophrenia were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in CYP1A2. The mean AIMS score in patients with the (C/C) genotype (associated with reduced CYP1A2 inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the CYP1A2 gene may serve as a genetic risk factor for the development of TD in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications. | A functional polymorphism of the /"cytochrome P450 1A2"/ (/"CYP1A2"/) gene: association with /"tardive dyskinesia"/ in schizophrenia. | /"Tardive dyskinesia"/ (/"TD"/) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the /"CYP1A2"/ enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of /"CYP1A2"/ induction by smoking may contribute to risk for the development of /"TD"/. Recently, a (C-->A) genetic polymorphism in the first intron of the /"CYP1A2"/ gene was found to be associated with variation in /"CYP1A2"/ inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in /"CYP1A2"/ in relation to /"TD"/ severity. A total of 85 patients with schizophrenia were assessed for /"TD"/ severity using the /"Abnormal Involuntary Movement"/ Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in /"CYP1A2"/. The mean AIMS score in patients with the (C/C) genotype (associated with reduced /"CYP1A2"/ inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the /"CYP1A2"/ gene may serve as a genetic risk factor for the development of /"TD"/ in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications. | [
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10993992 | A polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer's disease. | OBJECTIVE: To investigate whether or not a coding polymorphism in the cystatin C gene (CST3) contributes risk for AD. DESIGN: A case-control genetic association study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls. RESULTS: The authors find a signficant interaction between the GG genotype of CST3 and age/age of onset on risk for AD, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease. The authors also see a trend toward interaction between APOE epsilon4-carrying genotype and age/age of onset in this dataset, but in the case of APOE the risk decreases with age. Analysis of only the community-based cases versus controls reveals a significant three-way interaction between APOE, CST3 and age/age of onset. CONCLUSION: The reduced or absent risk for AD conferred by APOE in older populations has been well reported in the literature, prompting the suggestion that additional genetic risk factors confer risk for later-onset AD. In the author's dataset the opposite effects of APOE and CST3 genotype on risk for AD with increasing age suggest that CST3 is one of the risk factors for later-onset AD. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variation in an amyloidogenic cysteine protease inhibitor may have pathologic consequences for AD. | A polymorphism in the /"cystatin C"/ gene is a novel risk factor for late-onset /"Alzheimer's disease"/. | OBJECTIVE: To investigate whether or not a coding polymorphism in the /"cystatin C"/ gene (/"CST3"/) contributes risk for /"AD"/. DESIGN: A case-control genetic association study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls. RESULTS: The authors find a signficant interaction between the GG genotype of /"CST3"/ and age/age of onset on risk for /"AD"/, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease. The authors also see a trend toward interaction between APOE epsilon4-carrying genotype and age/age of onset in this dataset, but in the case of APOE the risk decreases with age. Analysis of only the community-based cases versus controls reveals a significant three-way interaction between APOE, /"CST3"/ and age/age of onset. CONCLUSION: The reduced or absent risk for /"AD"/ conferred by APOE in older populations has been well reported in the literature, prompting the suggestion that additional genetic risk factors confer risk for later-onset /"AD"/. In the author's dataset the opposite effects of APOE and /"CST3"/ genotype on risk for /"AD"/ with increasing age suggest that /"CST3"/ is one of the risk factors for later-onset /"AD"/. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variation in an amyloidogenic cysteine protease inhibitor may have pathologic consequences for /"AD"/. | [
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10993992 | A polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer's disease. | OBJECTIVE: To investigate whether or not a coding polymorphism in the cystatin C gene (CST3) contributes risk for AD. DESIGN: A case-control genetic association study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls. RESULTS: The authors find a signficant interaction between the GG genotype of CST3 and age/age of onset on risk for AD, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease. The authors also see a trend toward interaction between APOE epsilon4-carrying genotype and age/age of onset in this dataset, but in the case of APOE the risk decreases with age. Analysis of only the community-based cases versus controls reveals a significant three-way interaction between APOE, CST3 and age/age of onset. CONCLUSION: The reduced or absent risk for AD conferred by APOE in older populations has been well reported in the literature, prompting the suggestion that additional genetic risk factors confer risk for later-onset AD. In the author's dataset the opposite effects of APOE and CST3 genotype on risk for AD with increasing age suggest that CST3 is one of the risk factors for later-onset AD. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variation in an amyloidogenic cysteine protease inhibitor may have pathologic consequences for AD. | A polymorphism in the cystatin C gene is a novel risk factor for late-onset /"Alzheimer's disease"/. | OBJECTIVE: To investigate whether or not a coding polymorphism in the cystatin C gene (CST3) contributes risk for /"AD"/. DESIGN: A case-control genetic association study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls. RESULTS: The authors find a signficant interaction between the GG genotype of CST3 and age/age of onset on risk for /"AD"/, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease. The authors also see a trend toward interaction between /"APOE"/ epsilon4-carrying genotype and age/age of onset in this dataset, but in the case of /"APOE"/ the risk decreases with age. Analysis of only the community-based cases versus controls reveals a significant three-way interaction between /"APOE"/, CST3 and age/age of onset. CONCLUSION: The reduced or absent risk for /"AD"/ conferred by /"APOE"/ in older populations has been well reported in the literature, prompting the suggestion that additional genetic risk factors confer risk for later-onset /"AD"/. In the author's dataset the opposite effects of /"APOE"/ and CST3 genotype on risk for /"AD"/ with increasing age suggest that CST3 is one of the risk factors for later-onset /"AD"/. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variation in an amyloidogenic cysteine protease inhibitor may have pathologic consequences for /"AD"/. | [
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11043512 | Association of essential hypertension in elderly Japanese with I/D polymorphism of the angiotensin-converting enzyme (ACE) gene. | Recent evidence suggests that an insertion/deletion (I/D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE) is associated with myocardial infarction and related cardiovascular diseases. We investigated a possible association of the ACE polymorphism with essential hypertension in a total of 263 cases/controls from among the elderly (age, over 70 years) and middle-aged (age between 30 and 60 years) Japanese population. The frequency of the I/I homozygote was significantly higher in hypertensive subjects than in controls in the elderly age group (33/57 vs 16/46; P = 0.02), but no association was observed in the middle-aged group (25/75 vs 26/85; P = 0.71). Similarly, having at least one insertion allele was associated with essential hypertension in the elderly age group (83/114 vs 46/92 in controls; P = 0.001), but not in the middle-aged group (78/150 vs 94/170; P = 0.524). These data suggest that genetic variation at the ACE locus may be associated with some determinants for blood pressure in elderly persons, and imply the involvement of the ACE insertion/deletion polymorphism in the etiology of age-related essential hypertension in the Japanese population. | Association of essential /"hypertension"/ in elderly Japanese with I/D polymorphism of the /"angiotensin-converting enzyme"/ (/"ACE"/) gene. | Recent evidence suggests that an insertion/deletion (I/D) polymorphism of the gene encoding /"angiotensin-converting enzyme"/ (/"ACE"/) is associated with myocardial infarction and related cardiovascular diseases. We investigated a possible association of the /"ACE"/ polymorphism with essential /"hypertension"/ in a total of 263 cases/controls from among the elderly (age, over 70 years) and middle-aged (age between 30 and 60 years) Japanese population. The frequency of the I/I homozygote was significantly higher in /"hypertensive"/ subjects than in controls in the elderly age group (33/57 vs 16/46; P = 0.02), but no association was observed in the middle-aged group (25/75 vs 26/85; P = 0.71). Similarly, having at least one insertion allele was associated with essential /"hypertension"/ in the elderly age group (83/114 vs 46/92 in controls; P = 0.001), but not in the middle-aged group (78/150 vs 94/170; P = 0.524). These data suggest that genetic variation at the /"ACE"/ locus may be associated with some determinants for blood pressure in elderly persons, and imply the involvement of the /"ACE"/ insertion/deletion polymorphism in the etiology of age-related essential /"hypertension"/ in the Japanese population. | [
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11043512 | Association of essential hypertension in elderly Japanese with I/D polymorphism of the angiotensin-converting enzyme (ACE) gene. | Recent evidence suggests that an insertion/deletion (I/D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE) is associated with myocardial infarction and related cardiovascular diseases. We investigated a possible association of the ACE polymorphism with essential hypertension in a total of 263 cases/controls from among the elderly (age, over 70 years) and middle-aged (age between 30 and 60 years) Japanese population. The frequency of the I/I homozygote was significantly higher in hypertensive subjects than in controls in the elderly age group (33/57 vs 16/46; P = 0.02), but no association was observed in the middle-aged group (25/75 vs 26/85; P = 0.71). Similarly, having at least one insertion allele was associated with essential hypertension in the elderly age group (83/114 vs 46/92 in controls; P = 0.001), but not in the middle-aged group (78/150 vs 94/170; P = 0.524). These data suggest that genetic variation at the ACE locus may be associated with some determinants for blood pressure in elderly persons, and imply the involvement of the ACE insertion/deletion polymorphism in the etiology of age-related essential hypertension in the Japanese population. | Association of essential hypertension in elderly Japanese with I/D polymorphism of the /"angiotensin-converting enzyme"/ (/"ACE"/) gene. | Recent evidence suggests that an insertion/deletion (I/D) polymorphism of the gene encoding /"angiotensin-converting enzyme"/ (/"ACE"/) is associated with myocardial infarction and related /"cardiovascular diseases"/. We investigated a possible association of the /"ACE"/ polymorphism with essential hypertension in a total of 263 cases/controls from among the elderly (age, over 70 years) and middle-aged (age between 30 and 60 years) Japanese population. The frequency of the I/I homozygote was significantly higher in hypertensive subjects than in controls in the elderly age group (33/57 vs 16/46; P = 0.02), but no association was observed in the middle-aged group (25/75 vs 26/85; P = 0.71). Similarly, having at least one insertion allele was associated with essential hypertension in the elderly age group (83/114 vs 46/92 in controls; P = 0.001), but not in the middle-aged group (78/150 vs 94/170; P = 0.524). These data suggest that genetic variation at the /"ACE"/ locus may be associated with some determinants for blood pressure in elderly persons, and imply the involvement of the /"ACE"/ insertion/deletion polymorphism in the etiology of age-related essential hypertension in the Japanese population. | [
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11044587 | Promoter polymorphism of the 5-HT transporter and Alzheimer's disease. | The role of the deletion/insertion polymorphism within the promoter region of the serotonin transporter gene (5-HTT) is under discussion as a potential genetic risk factor for Alzheimers's disease (AD). Here we report significant differences in the allelic distribution of this polymorphism with a higher frequency of the short variant allele in AD patients when compared to controls. This difference was independent of the apolipoproteinE genotype. Thus, our study supports the notion that genetic alterations in the serontonergic neurotransmitter system may be involved in the etiopathogenesis of AD. However, given the reported negative findings, we are presently trying to identify diagnostic subgroups for which the 5-HTT promoter polymorphism represents a susceptibility locus. | Promoter polymorphism of the 5-HT transporter and /"Alzheimer's disease"/. | The role of the deletion/insertion polymorphism within the promoter region of the /"serotonin transporter"/ gene (/"5-HTT"/) is under discussion as a potential genetic risk factor for /"Alzheimers's disease"/ (/"AD"/). Here we report significant differences in the allelic distribution of this polymorphism with a higher frequency of the short variant allele in /"AD"/ patients when compared to controls. This difference was independent of the apolipoproteinE genotype. Thus, our study supports the notion that genetic alterations in the serontonergic neurotransmitter system may be involved in the etiopathogenesis of /"AD"/. However, given the reported negative findings, we are presently trying to identify diagnostic subgroups for which the /"5-HTT"/ promoter polymorphism represents a susceptibility locus. | [
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11069835 | Lung disease associated with the IVS8 5T allele of the CFTR gene. | Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The 5T allele in intron 8 (IVS8) causes abnormal splicing in the CFTR gene, and is associated with lung disease when it occurs in cis with a missense mutation in the CFTR gene, R117H. However, the 5T variant alone has not been reported to cause lung disease. We describe two adult female patients with CF-like lung disease associated with the 5T allele. One patient's genotype is 5T-TG12-M470V/5T-TG12-M470V, and the other is DeltaF508/5T-TG12-M470V; full sequencing of the CFTR gene revealed no other mutation on the same allele as the 5T variant. The levels of full-length CFTR mRNA in respiratory epithelia were very low in these patients (11 and 6%, respectively, of total CFTR mRNA expression). Both patients had defective CFTR-mediated chloride conductance in the sweat ductal and/or acinar epithelia (sweat chloride, mmol/L, mean +/- SEM: 40.0 +/- 5.0 [n = 8 samples] and 80. 0 +/- 3.5 [n = 6 samples]) and airway epithelia (mV, mean +/- SEM CFTR-mediated Cl(-) conductance of 1.2 +/- 2.2 [n = 5 studies] and -6.75 +/- 8.1 [n = 4 studies]). These data suggest that the 5T polythymidine tract sequence on specific haplotype backgrounds (TG12 and M470V) may cause a low level of full-length functional CFTR protein and CF-like lung disease. | /"Lung disease"/ associated with the IVS8 5T allele of the /"CFTR"/ gene. | Cystic fibrosis is caused by mutations in the /"cystic fibrosis transmembrane regulator"/ (/"CFTR"/) gene. The 5T allele in intron 8 (IVS8) causes abnormal splicing in the /"CFTR"/ gene, and is associated with /"lung disease"/ when it occurs in cis with a missense mutation in the /"CFTR"/ gene, R117H. However, the 5T variant alone has not been reported to cause /"lung disease"/. We describe two adult female patients with /"CF-like lung disease"/ associated with the 5T allele. One patient's genotype is 5T-TG12-M470V/5T-TG12-M470V, and the other is DeltaF508/5T-TG12-M470V; full sequencing of the /"CFTR"/ gene revealed no other mutation on the same allele as the 5T variant. The levels of full-length /"CFTR"/ mRNA in respiratory epithelia were very low in these patients (11 and 6%, respectively, of total /"CFTR"/ mRNA expression). Both patients had defective /"CFTR"/-mediated chloride conductance in the sweat ductal and/or acinar epithelia (sweat chloride, mmol/L, mean +/- SEM: 40.0 +/- 5.0 [n = 8 samples] and 80. 0 +/- 3.5 [n = 6 samples]) and airway epithelia (mV, mean +/- SEM /"CFTR"/-mediated Cl(-) conductance of 1.2 +/- 2.2 [n = 5 studies] and -6.75 +/- 8.1 [n = 4 studies]). These data suggest that the 5T polythymidine tract sequence on specific haplotype backgrounds (TG12 and M470V) may cause a low level of full-length functional /"CFTR"/ protein and /"CF-like lung disease"/. | [
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} | Yes |
11069835 | Lung disease associated with the IVS8 5T allele of the CFTR gene. | Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The 5T allele in intron 8 (IVS8) causes abnormal splicing in the CFTR gene, and is associated with lung disease when it occurs in cis with a missense mutation in the CFTR gene, R117H. However, the 5T variant alone has not been reported to cause lung disease. We describe two adult female patients with CF-like lung disease associated with the 5T allele. One patient's genotype is 5T-TG12-M470V/5T-TG12-M470V, and the other is DeltaF508/5T-TG12-M470V; full sequencing of the CFTR gene revealed no other mutation on the same allele as the 5T variant. The levels of full-length CFTR mRNA in respiratory epithelia were very low in these patients (11 and 6%, respectively, of total CFTR mRNA expression). Both patients had defective CFTR-mediated chloride conductance in the sweat ductal and/or acinar epithelia (sweat chloride, mmol/L, mean +/- SEM: 40.0 +/- 5.0 [n = 8 samples] and 80. 0 +/- 3.5 [n = 6 samples]) and airway epithelia (mV, mean +/- SEM CFTR-mediated Cl(-) conductance of 1.2 +/- 2.2 [n = 5 studies] and -6.75 +/- 8.1 [n = 4 studies]). These data suggest that the 5T polythymidine tract sequence on specific haplotype backgrounds (TG12 and M470V) may cause a low level of full-length functional CFTR protein and CF-like lung disease. | Lung disease associated with the IVS8 5T allele of the /"CFTR"/TR"/ gene. | /"Cystic fibrosis"/ is caused by mutations in the /"cystic fibrosis transmembrane regulator"/or"/ (/"CFTR"/TR"/) gene. The 5T allele in intron 8 (IVS8) causes abnormal splicing in the /"CFTR"/TR"/ gene, and is associated with lung disease when it occurs in cis with a missense mutation in the /"CFTR"/TR"/ gene, R117H. However, the 5T variant alone has not been reported to cause lung disease. We describe two adult female patients with CF-like lung disease associated with the 5T allele. One patient's genotype is 5T-TG12-M470V/5T-TG12-M470V, and the other is DeltaF508/5T-TG12-M470V; full sequencing of the /"CFTR"/TR"/ gene revealed no other mutation on the same allele as the 5T variant. The levels of full-length /"CFTR"/TR"/ mRNA in respiratory epithelia were very low in these patients (11 and 6%, respectively, of total /"CFTR"/TR"/ mRNA expression). Both patients had defective /"CFTR"/TR"/-mediated chloride conductance in the sweat ductal and/or acinar epithelia (sweat chloride, mmol/L, mean +/- SEM: 40.0 +/- 5.0 [n = 8 samples] and 80. 0 +/- 3.5 [n = 6 samples]) and airway epithelia (mV, mean +/- SEM /"CFTR"/TR"/-mediated Cl(-) conductance of 1.2 +/- 2.2 [n = 5 studies] and -6.75 +/- 8.1 [n = 4 studies]). These data suggest that the 5T polythymidine tract sequence on specific haplotype backgrounds (TG12 and M470V) may cause a low level of full-length functional /"CFTR"/TR"/ protein and CF-like lung disease. | [
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"entity_id": "D003550",
"entity_type": "Disease",
"text_name": "CFTR"
} | No |
11079451 | Androgen receptor polymorphisms and mutations in male infertility. | Normal spermatogenesis depends on a sequential cascade of genetic events triggered by factors encoded by sex chromosomes. To determine the contribution of genetic aberrations to male infertility, the X-linked androgen receptor (AR) gene was examined for mutations and polymorphisms in a large cohort of infertile men. Genetic screening of over 400 patients and controls showed that defects in the AR gene lead to the production of dysfunctional receptor protein in up to 10% of males with abnormally low sperm production and male infertility. The dozens of mutations and polymorphisms uncovered were associated with subtly reduced intrinsic AR activity, and are of two main categories: polymorphic changes in length of a trinucleotide CAG tract in the N-terminal transactivation domain, and missense mutations in the C-terminal ligand-binding domain. These polymorphisms and mutations are associated with reduced AR function due to defective intermolecular protein-protein interactions with coactivator molecules. Genetic screening for AR mutations and polymorphism should be offered to severely oligospermic and azoospermic patients. These traits can be transmitted to progeny, and counseling can be offered to affected families. Clarification of the molecular mechanisms of pathogenesis has led to rational hormonal therapy. | /"Androgen receptor"/ polymorphisms and mutations in /"male infertility"/. | Normal spermatogenesis depends on a sequential cascade of genetic events triggered by factors encoded by sex chromosomes. To determine the contribution of genetic aberrations to /"male infertility"/, the X-linked /"androgen receptor"/ (AR) gene was examined for mutations and polymorphisms in a large cohort of infertile men. Genetic screening of over 400 patients and controls showed that defects in the AR gene lead to the production of dysfunctional receptor protein in up to 10% of males with abnormally low sperm production and /"male infertility"/. The dozens of mutations and polymorphisms uncovered were associated with subtly reduced intrinsic AR activity, and are of two main categories: polymorphic changes in length of a trinucleotide CAG tract in the N-terminal transactivation domain, and missense mutations in the C-terminal ligand-binding domain. These polymorphisms and mutations are associated with reduced AR function due to defective intermolecular protein-protein interactions with coactivator molecules. Genetic screening for AR mutations and polymorphism should be offered to severely oligospermic and azoospermic patients. These traits can be transmitted to progeny, and counseling can be offered to affected families. Clarification of the molecular mechanisms of pathogenesis has led to rational hormonal therapy. | [
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"entity_id": "D007248",
"entity_type": "Disease",
"text_name": "male infertility"
} | Yes |
11117918 | Hereditary catalase deficiencies and increased risk of diabetes. | Partial or near-total lack of erythrocyte catalase activity is a rare condition, generally thought to be benign. However, little is known of the frequency of common diseases of adult onset in human beings with catalase deficiency. We report that, in a series of Hungarian patients with catalase deficiency, there is a higher frequency of diabetes than in unaffected first-degree relatives and the general Hungarian population. We speculate that quantitative deficiency of catalase might predispose to cumulative oxidant damage of pancreatic beta-cells and diabetes. | /"Hereditary catalase deficiencies"/ and increased risk of diabetes. | Partial or near-total lack of erythrocyte /"catalase"/ activity is a rare condition, generally thought to be benign. However, little is known of the frequency of common diseases of adult onset in human beings with /"catalase deficiency"/. We report that, in a series of Hungarian patients with /"catalase deficiency"/, there is a higher frequency of diabetes than in unaffected first-degree relatives and the general Hungarian population. We speculate that quantitative /"deficiency of catalase"/se"/ might predispose to cumulative oxidant damage of pancreatic beta-cells and diabetes. | [
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"text_name": "Hereditary catalase deficiencies"
} | Yes |
11117918 | Hereditary catalase deficiencies and increased risk of diabetes. | Partial or near-total lack of erythrocyte catalase activity is a rare condition, generally thought to be benign. However, little is known of the frequency of common diseases of adult onset in human beings with catalase deficiency. We report that, in a series of Hungarian patients with catalase deficiency, there is a higher frequency of diabetes than in unaffected first-degree relatives and the general Hungarian population. We speculate that quantitative deficiency of catalase might predispose to cumulative oxidant damage of pancreatic beta-cells and diabetes. | Hereditary catalase deficiencies and increased risk of /"diabetes"/. | Partial or near-total lack of erythrocyte /"catalase"/ activity is a rare condition, generally thought to be benign. However, little is known of the frequency of common diseases of adult onset in human beings with catalase deficiency. We report that, in a series of Hungarian patients with catalase deficiency, there is a higher frequency of /"diabetes"/ than in unaffected first-degree relatives and the general Hungarian population. We speculate that quantitative deficiency of /"catalase"/ might predispose to cumulative oxidant damage of pancreatic beta-cells and /"diabetes"/. | [
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"text_name": "diabetes"
} | Yes |
11136712 | Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. | We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the HESX1 gene. | Heterozygous /"HESX1"/ mutations associated with isolated congenital pituitary hypoplasia and /"septo-optic dysplasia"/. | We have previously shown that /"familial septo-optic dysplasia"/ (/"SOD"/), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene /"HESX1"///"Hesx1"/ in man and mouse. However, as most /"SOD"//congenital hypopituitarism occurs sporadically, the possible contribution of /"HESX1"/ mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the /"Hesx1"/ null allele show a milder /"SOD"/ phenocopy, implying that heterozygous mutations in human /"HESX1"/ could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for /"HESX1"/ mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to /"SOD"/ with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or /"SOD"/, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the /"HESX1"/-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the /"HESX1"/ locus, indicated that only one /"HESX1"/ mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the /"HESX1"/ gene. | [
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"entity_id": "D025962",
"entity_type": "Disease",
"text_name": "familial septo-optic dysplasia"
} | Yes |
11136712 | Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. | We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the HESX1 gene. | Heterozygous /"HESX1"/ mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. | We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of /"congenital hypopituitarism"/ involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene /"HESX1"///"Hesx1"/ in man and mouse. However, as most SOD//"congenital hypopituitarism"/ occurs sporadically, the possible contribution of /"HESX1"/ mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the /"Hesx1"/ null allele show a milder SOD phenocopy, implying that heterozygous mutations in human /"HESX1"/ could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for /"HESX1"/ mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the /"HESX1"/-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the /"HESX1"/ locus, indicated that only one /"HESX1"/ mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the /"HESX1"/ gene. | [
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"text_name": "congenital hypopituitarism"
} | No |
11157139 | HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and APS development in different and heterogeneous fashion. | HLA class II gene polymorphisms in /"antiphospholipid syndrome"/: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and /"antiphospholipid syndrome"/ (/"APS"/). METHODS: HLA DRB1, /"DQB1"/ and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with /"APS"/. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: /"DQB1"/*0604/5/6/7/9-DQA1*0102-DRB1*1302 and /"DQB1"/*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with /"APS"/ [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary /"APS"/ patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and /"APS"/ development in different and heterogeneous fashion. | [
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} | Yes |
11157139 | HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and APS development in different and heterogeneous fashion. | HLA class II gene polymorphisms in /"antiphospholipid syndrome"/: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and /"antiphospholipid syndrome"/ (/"APS"/). METHODS: /"HLA DRB1"/, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with /"APS"/. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with /"APS"/ [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary /"APS"/ patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and /"APS"/ development in different and heterogeneous fashion. | [
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"text_name": "antiphospholipid syndrome"
} | Yes |
11157139 | HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and APS development in different and heterogeneous fashion. | HLA class II gene polymorphisms in /"antiphospholipid syndrome"/: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and /"antiphospholipid syndrome"/ (/"APS"/). METHODS: HLA DRB1, DQB1 and /"DQA1"/ genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with /"APS"/. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-/"DQA1"/*0102-DRB1*1302 and DQB1*0303-/"DQA1"/*0201-DRB1*0701 haplotypes showed significantly positive correlations with /"APS"/ [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary /"APS"/ patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and /"APS"/ development in different and heterogeneous fashion. | [
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} | Yes |
11157139 | HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and APS development in different and heterogeneous fashion. | HLA class II gene polymorphisms in /"antiphospholipid syndrome"/: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and /"antiphospholipid syndrome"/ (/"APS"/). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with /"APS"/. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with /"APS"/ [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary /"APS"/ patients with anti-beta 2-glycoprotein I antibodies (anti-/"beta 2GPI"/) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and /"APS"/ development in different and heterogeneous fashion. | [
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"text_name": "antiphospholipid syndrome"
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11157139 | HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and APS development in different and heterogeneous fashion. | HLA class II gene polymorphisms in /"antiphospholipid syndrome"/: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and /"antiphospholipid syndrome"/ (/"APS"/). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with /"APS"/. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with /"APS"/ [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary /"APS"/ patients with anti-beta 2-glycoprotein I antibodies (anti-/"beta 2GPI"/) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and /"APS"/ development in different and heterogeneous fashion. | [
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11157139 | HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and APS development in different and heterogeneous fashion. | HLA class II gene polymorphisms in /"antiphospholipid syndrome"/: haplotype analysis in 83 Caucasoid patients. | OBJECTIVES: We investigated the association between HLA class II haplotypes and /"antiphospholipid syndrome"/ (/"APS"/). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with /"APS"/. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with /"APS"/ [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary /"APS"/ patients with anti-beta 2-glycoprotein I antibodies (anti-/"beta 2GPI"/) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and /"APS"/ development in different and heterogeneous fashion. | [
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11159742 | GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer. | It is likely that heritable genetic factors contribute to the development of endometriosis, which is a putative precursor of the endometrioid and clear cell histological subtypes of ovarian cancer. The phase II glutathione S-transferases (GSTs) are a family of enzymes responsible for metabolism of a broad range of xenobiotics and carcinogens. Allelic variants of GSTs that have impaired detoxification function may increase the rate of genetic damage and thereby increase the susceptibility to cancer. The null genetic polymorphism in the gene encoding the GST class mu (GSTM1) enzyme has been reported to be significantly elevated in endometriosis patients and may represent an endometriosis susceptibility allele. In this study the frequency of the GSTM1 null genotype was investigated in 84 cases of endometriosis, 293 cases of ovarian cancer and 219 controls. All cases and controls were derived from women resident in the south east of England. The frequency of the GSTM1 null allele was not over-represented in the endometriosis patients (47.6%) compared with the controls (48.9%) (P = 0.898). In the ovarian cancer group the GSTM1 null genotype was significantly elevated compared with controls (59.0 versus 48.9%, P = 0.025). When stratified according to histological subtype a significantly increased GSTM1 null genotype was only observed for the endometrioid (65.4%, P = 0.013) and the combined endometrioid/clear cell ovarian cancers (67.0%, P = 0.004). We conclude that the GSTM1 null allele is not an endometriosis susceptibility allele, however, it may predispose endometriotic lesions to malignant transformation to endometrioid and clear cell ovarian cancer. | /"GSTM1"/ null polymorphism and susceptibility to /"endometriosis and ovarian cancer"/. | It is likely that heritable genetic factors contribute to the development of endometriosis, which is a putative precursor of the endometrioid and clear cell histological subtypes of /"ovarian cancer"/. The phase II glutathione S-transferases (GSTs) are a family of enzymes responsible for metabolism of a broad range of xenobiotics and carcinogens. Allelic variants of GSTs that have impaired detoxification function may increase the rate of genetic damage and thereby increase the susceptibility to cancer. The null genetic polymorphism in the gene encoding the GST class mu (/"GSTM1"/) enzyme has been reported to be significantly elevated in endometriosis patients and may represent an endometriosis susceptibility allele. In this study the frequency of the /"GSTM1"/ null genotype was investigated in 84 cases of endometriosis, 293 cases of /"ovarian cancer"/ and 219 controls. All cases and controls were derived from women resident in the south east of England. The frequency of the /"GSTM1"/ null allele was not over-represented in the endometriosis patients (47.6%) compared with the controls (48.9%) (P = 0.898). In the /"ovarian cancer"/ group the /"GSTM1"/ null genotype was significantly elevated compared with controls (59.0 versus 48.9%, P = 0.025). When stratified according to histological subtype a significantly increased /"GSTM1"/ null genotype was only observed for the endometrioid (65.4%, P = 0.013) and the combined endometrioid/clear cell /"ovarian cancers"/ (67.0%, P = 0.004). We conclude that the /"GSTM1"/ null allele is not an endometriosis susceptibility allele, however, it may predispose endometriotic lesions to /"malignant transformation to endometrioid and clear cell ovarian cancer"/. | [
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11159742 | GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer. | It is likely that heritable genetic factors contribute to the development of endometriosis, which is a putative precursor of the endometrioid and clear cell histological subtypes of ovarian cancer. The phase II glutathione S-transferases (GSTs) are a family of enzymes responsible for metabolism of a broad range of xenobiotics and carcinogens. Allelic variants of GSTs that have impaired detoxification function may increase the rate of genetic damage and thereby increase the susceptibility to cancer. The null genetic polymorphism in the gene encoding the GST class mu (GSTM1) enzyme has been reported to be significantly elevated in endometriosis patients and may represent an endometriosis susceptibility allele. In this study the frequency of the GSTM1 null genotype was investigated in 84 cases of endometriosis, 293 cases of ovarian cancer and 219 controls. All cases and controls were derived from women resident in the south east of England. The frequency of the GSTM1 null allele was not over-represented in the endometriosis patients (47.6%) compared with the controls (48.9%) (P = 0.898). In the ovarian cancer group the GSTM1 null genotype was significantly elevated compared with controls (59.0 versus 48.9%, P = 0.025). When stratified according to histological subtype a significantly increased GSTM1 null genotype was only observed for the endometrioid (65.4%, P = 0.013) and the combined endometrioid/clear cell ovarian cancers (67.0%, P = 0.004). We conclude that the GSTM1 null allele is not an endometriosis susceptibility allele, however, it may predispose endometriotic lesions to malignant transformation to endometrioid and clear cell ovarian cancer. | /"GSTM1"/ null polymorphism and susceptibility to endometriosis and ovarian cancer. | It is likely that heritable genetic factors contribute to the development of /"endometriosis"/, which is a putative precursor of the endometrioid and clear cell histological subtypes of ovarian cancer. The phase II glutathione S-transferases (GSTs) are a family of enzymes responsible for metabolism of a broad range of xenobiotics and carcinogens. Allelic variants of GSTs that have impaired detoxification function may increase the rate of genetic damage and thereby increase the susceptibility to cancer. The null genetic polymorphism in the gene encoding the GST class mu (/"GSTM1"/) enzyme has been reported to be significantly elevated in /"endometriosis"/ patients and may represent an /"endometriosis"/ susceptibility allele. In this study the frequency of the /"GSTM1"/ null genotype was investigated in 84 cases of /"endometriosis"/, 293 cases of ovarian cancer and 219 controls. All cases and controls were derived from women resident in the south east of England. The frequency of the /"GSTM1"/ null allele was not over-represented in the /"endometriosis"/ patients (47.6%) compared with the controls (48.9%) (P = 0.898). In the ovarian cancer group the /"GSTM1"/ null genotype was significantly elevated compared with controls (59.0 versus 48.9%, P = 0.025). When stratified according to histological subtype a significantly increased /"GSTM1"/ null genotype was only observed for the endometrioid (65.4%, P = 0.013) and the combined endometrioid/clear cell ovarian cancers (67.0%, P = 0.004). We conclude that the /"GSTM1"/ null allele is not an /"endometriosis"/ susceptibility allele, however, it may predispose endometriotic lesions to malignant transformation to endometrioid and clear cell ovarian cancer. | [
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11159940 | Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. | Hay-Wells syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (OMIM 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia syndromes, for example ectrodactyly--ectodermal dysplasia--cleft lip/palate (EEC; OMIM 604292), limb--mammary syndrome (LMS; OMIM 603543), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; OMIM 103285) and recessive cleft lip/palate--ectodermal dysplasia (CLPED1; OMIM 225060). We have recently demonstrated that heterozygous mutations in the p63 gene are the major cause of EEC syndrome. Linkage studies suggest that the related LMS and ADULT syndromes are also caused by mutations in the p63 gene. Thus, it appears that p63 gene mutations have highly pleiotropic effects. We have analysed p63 in AEC syndrome patients and identified missense mutations in eight families. All mutations give rise to amino acid substitutions in the sterile alpha motif (SAM) domain, and are predicted to affect protein--protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. Thus, a clear genotype--phenotype correlation can be recognized for EEC and AEC syndromes. | /"Hay-Wells syndrome"/ is caused by heterozygous missense mutations in the SAM domain of /"p63"/. | /"Hay-Wells syndrome"/, also known as /"ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome"/ (OMIM 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia syndromes, for example ectrodactyly--ectodermal dysplasia--cleft lip/palate (EEC; OMIM 604292), limb--mammary syndrome (LMS; OMIM 603543), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; OMIM 103285) and recessive cleft lip/palate--ectodermal dysplasia (CLPED1; OMIM 225060). We have recently demonstrated that heterozygous mutations in the /"p63"/ gene are the major cause of EEC syndrome. Linkage studies suggest that the related LMS and ADULT syndromes are also caused by mutations in the /"p63"/ gene. Thus, it appears that /"p63"/ gene mutations have highly pleiotropic effects. We have analysed /"p63"/ in /"AEC syndrome"/ patients and identified missense mutations in eight families. All mutations give rise to amino acid substitutions in the sterile alpha motif (SAM) domain, and are predicted to affect protein--protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. Thus, a clear genotype--phenotype correlation can be recognized for EEC and AEC syndromes. | [
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11159940 | Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. | Hay-Wells syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (OMIM 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia syndromes, for example ectrodactyly--ectodermal dysplasia--cleft lip/palate (EEC; OMIM 604292), limb--mammary syndrome (LMS; OMIM 603543), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; OMIM 103285) and recessive cleft lip/palate--ectodermal dysplasia (CLPED1; OMIM 225060). We have recently demonstrated that heterozygous mutations in the p63 gene are the major cause of EEC syndrome. Linkage studies suggest that the related LMS and ADULT syndromes are also caused by mutations in the p63 gene. Thus, it appears that p63 gene mutations have highly pleiotropic effects. We have analysed p63 in AEC syndrome patients and identified missense mutations in eight families. All mutations give rise to amino acid substitutions in the sterile alpha motif (SAM) domain, and are predicted to affect protein--protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. Thus, a clear genotype--phenotype correlation can be recognized for EEC and AEC syndromes. | Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of /"p63"/. | Hay-Wells syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (OMIM 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, /"ankyloblepharon"/ and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia syndromes, for example ectrodactyly--ectodermal dysplasia--cleft lip/palate (EEC; OMIM 604292), limb--mammary syndrome (LMS; OMIM 603543), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; OMIM 103285) and recessive cleft lip/palate--ectodermal dysplasia (CLPED1; OMIM 225060). We have recently demonstrated that heterozygous mutations in the /"p63"/ gene are the major cause of EEC syndrome. Linkage studies suggest that the related LMS and ADULT syndromes are also caused by mutations in the /"p63"/ gene. Thus, it appears that /"p63"/ gene mutations have highly pleiotropic effects. We have analysed /"p63"/ in AEC syndrome patients and identified missense mutations in eight families. All mutations give rise to amino acid substitutions in the sterile alpha motif (SAM) domain, and are predicted to affect protein--protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. Thus, a clear genotype--phenotype correlation can be recognized for EEC and AEC syndromes. | [
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11179016 | Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. | Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy. | Complex HLA-DR and -DQ interactions confer risk of /"narcolepsy-cataplexy"/ in three ethnic groups. | Human /"narcolepsy-cataplexy"/, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 /"narcoleptic"/ subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all /"narcoleptic"/ subjects were positive for both /"HLA-DQA1"/*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for /"narcolepsy"/ were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to /"narcolepsy"/ susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human /"narcolepsy"/ but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human /"narcolepsy-cataplexy"/. | [
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11179016 | Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. | Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy. | Complex HLA-DR and -DQ interactions confer risk of /"narcolepsy-cataplexy"/ in three ethnic groups. | Human /"narcolepsy-cataplexy"/, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with /"HLA-DQB1"/*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 /"narcoleptic"/ subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -/"DQB1"/ were analyzed. As reported elsewhere, almost all /"narcoleptic"/ subjects were positive for both HLA-DQA1*0102 and -/"DQB1"/*0602. A strong predisposing effect was observed in /"DQB1"/*0602 homozygotes, across all ethnic groups. Relative risks for /"narcolepsy"/ were next calculated for heterozygous /"DQB1"/*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with /"DQB1"/*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including /"DQB1"/*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-/"DQB1"/*0601, /"DQB1"/*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to /"narcolepsy"/ susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human /"narcolepsy"/ but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human /"narcolepsy-cataplexy"/. | [
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11179016 | Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. | Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy. | Complex HLA-DR and -DQ interactions confer risk of /"narcolepsy-cataplexy"/ in three ethnic groups. | Human /"narcolepsy-cataplexy"/, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 /"narcoleptic"/ subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of /"HLA-DRB1"/, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all /"narcoleptic"/ subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for /"narcolepsy"/ were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, /"DRB1"/*04, /"DRB1"/*08, /"DRB1"/*11, and /"DRB1"/*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to /"narcolepsy"/ susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human /"narcolepsy"/ but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human /"narcolepsy-cataplexy"/. | [
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11179016 | Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. | Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy. | Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. | Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated /"hypocretin (orexin) deficiency"/, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of /"HLA-DRB1"/, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, /"DRB1"/*04, /"DRB1"/*08, /"DRB1"/*11, and /"DRB1"/*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy. | [
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11179016 | Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. | Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy. | Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. | Human narcolepsy-cataplexy, a /"sleep disorder"/ associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of /"HLA-DRB1"/, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, /"DRB1"/*04, /"DRB1"/*08, /"DRB1"/*11, and /"DRB1"/*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy. | [
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11179016 | Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. | Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy. | Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. | Human narcolepsy-cataplexy, a /"sleep disorder"/ associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with /"HLA-DQB1"/*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -/"DQB1"/ were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -/"DQB1"/*0602. A strong predisposing effect was observed in /"DQB1"/*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous /"DQB1"/*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with /"DQB1"/*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including /"DQB1"/*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-/"DQB1"/*0601, /"DQB1"/*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy. | [
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11186891 | Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study. | More than 900 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been reported to the cystic fibrosis (CF) consortium. A missense mutation, S1235R, was originally reported in a CF patient with a second mutation (G628R) on the same chromosome. The clinical significance of S1235R was not clear. S1235R is not among the commonly reported mutations, and it is not routinely screened for in most laboratories. However, we have detected the S1235R allele at a frequency that is significantly higher than that of many other CF mutations. Among more than 3,000 patients tested for either a possible diagnosis of CF or to determine CF carrier status, we identified 51 patients heterozygous for S1235R. No patients were homozygous for S1235R. Five patients were compound heterozygotes for a second CFTR mutation: two cases (one family) were N1303K/S1235R and three unrelated cases were deltaF508/S1235R. Our data suggest that S1235R, when combined with a second CF mutation, may be pathogenic, although phenotypic manifestations appear to be variable. The possibility that this represents a rare polymorphism cannot be discounted completely. Genetic counseling is difficult when S1235R is identified, even in the presence of a second known mutation, especially in prenatal cases. | Frequency and clinical significance of the S1235R mutation in the /"cystic fibrosis transmembrane conductance regulator"/ gene: results from a collaborative study. | More than 900 mutations in the /"cystic fibrosis transmembrane conductance regulator"/ (/"CFTR"/) gene have been reported to the /"cystic fibrosis"/ (/"CF"/) consortium. A missense mutation, S1235R, was originally reported in a /"CF"/ patient with a second mutation (G628R) on the same chromosome. The clinical significance of S1235R was not clear. S1235R is not among the commonly reported mutations, and it is not routinely screened for in most laboratories. However, we have detected the S1235R allele at a frequency that is significantly higher than that of many other /"CF"/ mutations. Among more than 3,000 patients tested for either a possible diagnosis of /"CF"/ or to determine /"CF"/ carrier status, we identified 51 patients heterozygous for S1235R. No patients were homozygous for S1235R. Five patients were compound heterozygotes for a second /"CFTR"/ mutation: two cases (one family) were N1303K/S1235R and three unrelated cases were deltaF508/S1235R. Our data suggest that S1235R, when combined with a second /"CF"/ mutation, may be pathogenic, although phenotypic manifestations appear to be variable. The possibility that this represents a rare polymorphism cannot be discounted completely. Genetic counseling is difficult when S1235R is identified, even in the presence of a second known mutation, especially in prenatal cases. | [
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11192234 | The influence of polymorphism at position 16 of the beta2-adrenoceptor on the development of tolerance to beta-agonist. | Polymorphism at position 16 of the beta2-adrenoceptor alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to beta-agonist in homozygous Gly-16 patients with patients harboring the "wild" genotype (homozygous Arg-16) during regular treatment with salmeterol. In a prospective, randomized, double-blind, placebo-controlled, cross-over study, 20 subjects with mild to moderate asthma (10 Gly-16, 10 Arg-16) received 2 weeks of treatment with inhaled salmeterol 100 microg b.i.d. Thereafter, dose responses to inhaled salbutamol were constructed for forced expiratory volume in 1 sec (FEV1), heart rate, QTc interval, serum potassium and glucose, and finger tremor. The protective effect of salbutamol against adenosine monophosphate (AMP) challenge was also measured. Salmeterol resulted in a significant reduction in the area under curve (AUC) for FEV1 (p = 0.01), heart rate (p = 0.01), QTc interval (p = 0.01), and tremor (p = 0.05), and in the maximum responses for FEV1 (p = 0.05), heart rate (p = 0.02), and glucose (p = 0.02). The protective effect of salbutamol against AMP was reduced by 3.61 doubling doses (p < 0.001). However, differences between Gly-16 and Arg-16 patients were small and nonsignificant. Thus, although tolerance is influenced in vitro by polymorphism of the beta2-adrenoceptor, the magnitude of between-genotype differences in vivo is unlikely to be significant. | The influence of polymorphism at position 16 of the /"beta2-adrenoceptor"/ on the development of tolerance to beta-agonist. | Polymorphism at position 16 of the /"beta2-adrenoceptor"/ alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to beta-agonist in homozygous Gly-16 patients with patients harboring the "wild" genotype (homozygous Arg-16) during regular treatment with salmeterol. In a prospective, randomized, double-blind, placebo-controlled, cross-over study, 20 subjects with mild to moderate /"asthma"/ (10 Gly-16, 10 Arg-16) received 2 weeks of treatment with inhaled salmeterol 100 microg b.i.d. Thereafter, dose responses to inhaled salbutamol were constructed for forced expiratory volume in 1 sec (FEV1), heart rate, QTc interval, serum potassium and glucose, and finger tremor. The protective effect of salbutamol against adenosine monophosphate (AMP) challenge was also measured. Salmeterol resulted in a significant reduction in the area under curve (AUC) for FEV1 (p = 0.01), heart rate (p = 0.01), QTc interval (p = 0.01), and tremor (p = 0.05), and in the maximum responses for FEV1 (p = 0.05), heart rate (p = 0.02), and glucose (p = 0.02). The protective effect of salbutamol against AMP was reduced by 3.61 doubling doses (p < 0.001). However, differences between Gly-16 and Arg-16 patients were small and nonsignificant. Thus, although tolerance is influenced in vitro by polymorphism of the /"beta2-adrenoceptor"/, the magnitude of between-genotype differences in vivo is unlikely to be significant. | [
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11192234 | The influence of polymorphism at position 16 of the beta2-adrenoceptor on the development of tolerance to beta-agonist. | Polymorphism at position 16 of the beta2-adrenoceptor alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to beta-agonist in homozygous Gly-16 patients with patients harboring the "wild" genotype (homozygous Arg-16) during regular treatment with salmeterol. In a prospective, randomized, double-blind, placebo-controlled, cross-over study, 20 subjects with mild to moderate asthma (10 Gly-16, 10 Arg-16) received 2 weeks of treatment with inhaled salmeterol 100 microg b.i.d. Thereafter, dose responses to inhaled salbutamol were constructed for forced expiratory volume in 1 sec (FEV1), heart rate, QTc interval, serum potassium and glucose, and finger tremor. The protective effect of salbutamol against adenosine monophosphate (AMP) challenge was also measured. Salmeterol resulted in a significant reduction in the area under curve (AUC) for FEV1 (p = 0.01), heart rate (p = 0.01), QTc interval (p = 0.01), and tremor (p = 0.05), and in the maximum responses for FEV1 (p = 0.05), heart rate (p = 0.02), and glucose (p = 0.02). The protective effect of salbutamol against AMP was reduced by 3.61 doubling doses (p < 0.001). However, differences between Gly-16 and Arg-16 patients were small and nonsignificant. Thus, although tolerance is influenced in vitro by polymorphism of the beta2-adrenoceptor, the magnitude of between-genotype differences in vivo is unlikely to be significant. | The influence of polymorphism at position 16 of the /"beta2-adrenoceptor"/ on the development of tolerance to beta-agonist. | Polymorphism at position 16 of the /"beta2-adrenoceptor"/ alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to beta-agonist in homozygous Gly-16 patients with patients harboring the "wild" genotype (homozygous Arg-16) during regular treatment with salmeterol. In a prospective, randomized, double-blind, placebo-controlled, cross-over study, 20 subjects with mild to moderate asthma (10 Gly-16, 10 Arg-16) received 2 weeks of treatment with inhaled salmeterol 100 microg b.i.d. Thereafter, dose responses to inhaled salbutamol were constructed for forced expiratory volume in 1 sec (FEV1), heart rate, QTc interval, serum potassium and glucose, and finger /"tremor"/. The protective effect of salbutamol against adenosine monophosphate (AMP) challenge was also measured. Salmeterol resulted in a significant reduction in the area under curve (AUC) for FEV1 (p = 0.01), heart rate (p = 0.01), QTc interval (p = 0.01), and /"tremor"/ (p = 0.05), and in the maximum responses for FEV1 (p = 0.05), heart rate (p = 0.02), and glucose (p = 0.02). The protective effect of salbutamol against AMP was reduced by 3.61 doubling doses (p < 0.001). However, differences between Gly-16 and Arg-16 patients were small and nonsignificant. Thus, although tolerance is influenced in vitro by polymorphism of the /"beta2-adrenoceptor"/, the magnitude of between-genotype differences in vivo is unlikely to be significant. | [
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11216915 | CYP19 gene polymorphism in endometrial cancer patients. | PURPOSE: Initiation/promotion of endometrial cancer is known to be associated with estrogenic influence. Therefore, it is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to endometrial cancer susceptibility. METHODS: Here, we compared CYP19 (aromatase) gene polymorphism in 85 endometrial cancer patients and in 110 non-affected women. RESULTS: The genotypes containing the longest alleles (A6 and A7) of CYP19 were found to be over-represented in patients as compared to controls. In addition, these genotypes demonstrated a tendency to be associated with increased concentrations of estradiol and testosterone in postmenopausal patients. CONCLUSIONS: Thus, CYP19 polymorphism might be one of the genetic risk factors for endometrial cancer development. | /"CYP19"/ gene polymorphism in /"endometrial cancer"/ patients. | PURPOSE: Initiation/promotion of /"endometrial cancer"/ is known to be associated with estrogenic influence. Therefore, it is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to /"endometrial cancer"/ susceptibility. METHODS: Here, we compared /"CYP19"/ (aromatase) gene polymorphism in 85 /"endometrial cancer"/ patients and in 110 non-affected women. RESULTS: The genotypes containing the longest alleles (A6 and A7) of /"CYP19"/ were found to be over-represented in patients as compared to controls. In addition, these genotypes demonstrated a tendency to be associated with increased concentrations of estradiol and testosterone in postmenopausal patients. CONCLUSIONS: Thus, /"CYP19"/ polymorphism might be one of the genetic risk factors for /"endometrial cancer"/ development. | [
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11244459 | Molecular screening of the proopiomelanocortin (POMC ) gene in Italian obese children: report of three new mutations. | BACKGROUND: Although linkage studies strongly suggest that proopiomelanocortin (POMC) alterations could play a role in the genetic predisposition to obesity, systematic POMC mutational analysis did not completely confirm this hypothesis. OBJECTIVES: To verify the presence of mutations of the POMC coding region in Italian children with very early onset obesity. SUBJECTS AND METHODS: Eighty seven unrelated Italian obese children and adolescents were studied. Mean age at obesity onset was 4.7+/-2.5 y. The POMC gene coding region was screened using single-strand conformation polymorphism (SSCP) analysis. Bi-directional automatic sequencing of PCR products was performed for all individuals who showed an aberrant SSCP pattern. RESULTS: Three new mutations have been identified in the heterozygous state in three patients: (a) G3834C, resulting in the substitution of Ser with Thr at codon 7 within the POMC signal peptide; (b) C3840T, resulting in the substitution of Ser with Leu at codon 9 of the pre-proopiomelanocortin signal peptide; and (c) C7406G, producing the substitution of Arg with Gly at codon 236 within the beta-endorphin peptide. A polymorphism consisting of a 9 bp insertion, AGC AGC CGC, between position 6997 and 6998 has been found at the heterozygous state in nine patients. They showed leptin levels adjusted for BMI, gender and pubertal stage significantly higher than obese subjects homozyous for the POMC wild-type allele. CONCLUSIONS: Mutations in codons 7 and 9 of the signal peptide may alter the translocation of the pre-proopiomelanocortin into the endoplasmic reticulum and, therefore, can be implicated in obesity. Although further studies are required, the polymorphism between position 6997 and 6998 may represent one of the genetic variations that explain the linkage between obesity and POMC. International Journal of Obesity (2001) 25, 61-67 | Molecular screening of the /"proopiomelanocortin"/ (/"POMC"/ ) gene in Italian /"obese"/ children: report of three new mutations. | BACKGROUND: Although linkage studies strongly suggest that /"proopiomelanocortin"/ (/"POMC"/) alterations could play a role in the genetic predisposition to /"obesity"/, systematic /"POMC"/ mutational analysis did not completely confirm this hypothesis. OBJECTIVES: To verify the presence of mutations of the /"POMC"/ coding region in Italian children with very early onset /"obesity"/. SUBJECTS AND METHODS: Eighty seven unrelated Italian /"obese"/ children and adolescents were studied. Mean age at /"obesity"/ onset was 4.7+/-2.5 y. The /"POMC"/ gene coding region was screened using single-strand conformation polymorphism (SSCP) analysis. Bi-directional automatic sequencing of PCR products was performed for all individuals who showed an aberrant SSCP pattern. RESULTS: Three new mutations have been identified in the heterozygous state in three patients: (a) G3834C, resulting in the substitution of Ser with Thr at codon 7 within the /"POMC"/ signal peptide; (b) C3840T, resulting in the substitution of Ser with Leu at codon 9 of the pre-/"proopiomelanocortin"/ signal peptide; and (c) C7406G, producing the substitution of Arg with Gly at codon 236 within the beta-endorphin peptide. A polymorphism consisting of a 9 bp insertion, AGC AGC CGC, between position 6997 and 6998 has been found at the heterozygous state in nine patients. They showed leptin levels adjusted for BMI, gender and pubertal stage significantly higher than /"obese"/ subjects homozyous for the /"POMC"/ wild-type allele. CONCLUSIONS: Mutations in codons 7 and 9 of the signal peptide may alter the translocation of the pre-/"proopiomelanocortin"/ into the endoplasmic reticulum and, therefore, can be implicated in /"obesity"/. Although further studies are required, the polymorphism between position 6997 and 6998 may represent one of the genetic variations that explain the linkage between /"obesity"/ and /"POMC"/. International Journal of Obesity (2001) 25, 61-67 | [
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11244489 | Association between -G308A tumor necrosis factor alpha gene polymorphism and schizophrenia. | Dysregulation of the inflammatory response system has been linked to pathophysiology of schizophrenia. Evidence of immune activation has derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from schizophrenic patients. Cytokines are involved in normal CNS development as well as in the pathogenesis of many neuro-psychiatric disorders, acting directly on neural cells or modulating neurotransmitter and neuropeptide systems. In particular tumor necrosis factor alpha (TNFalpha), depending on its concentration, can exert both neurotrophic and neurotoxic effects and influence neural cell growth and proliferation. Moreover, TNFalpha gene is located on the small arm of chromosome 6 (6p21.1-21.3), a locus associated with genetic susceptibility to schizophrenia. We studied the distribution of -G308A TNFalpha gene polymorphism in 84 schizophrenic patients and in 138 healthy volunteers. This biallelic base exchange polymorphism directly affects TNFalpha plasma levels. Frequency of the TNF2(A) allele is significantly increased in schizophrenic patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). These data suggest a potential role of TNFalpha as a candidate gene for susceptibility to schizophrenia and suggest that immune dysregulation in schizophrenic patients could also have a genetic component. | Association between -G308A /"tumor necrosis factor alpha"/ gene polymorphism and /"schizophrenia"/. | Dysregulation of the inflammatory response system has been linked to pathophysiology of /"schizophrenia"/. Evidence of immune activation has derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from /"schizophrenic"/ patients. Cytokines are involved in normal CNS development as well as in the pathogenesis of many neuro-psychiatric disorders, acting directly on neural cells or modulating neurotransmitter and neuropeptide systems. In particular /"tumor necrosis factor alpha"/ (/"TNFalpha"/), depending on its concentration, can exert both neurotrophic and neurotoxic effects and influence neural cell growth and proliferation. Moreover, /"TNFalpha"/ gene is located on the small arm of chromosome 6 (6p21.1-21.3), a locus associated with genetic susceptibility to /"schizophrenia"/. We studied the distribution of -G308A /"TNFalpha"/ gene polymorphism in 84 /"schizophrenic"/ patients and in 138 healthy volunteers. This biallelic base exchange polymorphism directly affects /"TNFalpha"/ plasma levels. Frequency of the TNF2(A) allele is significantly increased in /"schizophrenic"/ patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). These data suggest a potential role of /"TNFalpha"/ as a candidate gene for susceptibility to /"schizophrenia"/ and suggest that immune dysregulation in /"schizophrenic"/ patients could also have a genetic component. | [
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11244489 | Association between -G308A tumor necrosis factor alpha gene polymorphism and schizophrenia. | Dysregulation of the inflammatory response system has been linked to pathophysiology of schizophrenia. Evidence of immune activation has derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from schizophrenic patients. Cytokines are involved in normal CNS development as well as in the pathogenesis of many neuro-psychiatric disorders, acting directly on neural cells or modulating neurotransmitter and neuropeptide systems. In particular tumor necrosis factor alpha (TNFalpha), depending on its concentration, can exert both neurotrophic and neurotoxic effects and influence neural cell growth and proliferation. Moreover, TNFalpha gene is located on the small arm of chromosome 6 (6p21.1-21.3), a locus associated with genetic susceptibility to schizophrenia. We studied the distribution of -G308A TNFalpha gene polymorphism in 84 schizophrenic patients and in 138 healthy volunteers. This biallelic base exchange polymorphism directly affects TNFalpha plasma levels. Frequency of the TNF2(A) allele is significantly increased in schizophrenic patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). These data suggest a potential role of TNFalpha as a candidate gene for susceptibility to schizophrenia and suggest that immune dysregulation in schizophrenic patients could also have a genetic component. | Association between -G308A /"tumor necrosis factor alpha"/ gene polymorphism and schizophrenia. | Dysregulation of the inflammatory response system has been linked to pathophysiology of schizophrenia. Evidence of immune activation has derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from schizophrenic patients. Cytokines are involved in normal CNS development as well as in the pathogenesis of many neuro-psychiatric disorders, acting directly on neural cells or modulating neurotransmitter and neuropeptide systems. In particular /"tumor necrosis factor alpha"/ (/"TNFalpha"/), depending on its concentration, can exert both neurotrophic and /"neurotoxic"/ effects and influence neural cell growth and proliferation. Moreover, /"TNFalpha"/ gene is located on the small arm of chromosome 6 (6p21.1-21.3), a locus associated with genetic susceptibility to schizophrenia. We studied the distribution of -G308A /"TNFalpha"/ gene polymorphism in 84 schizophrenic patients and in 138 healthy volunteers. This biallelic base exchange polymorphism directly affects /"TNFalpha"/ plasma levels. Frequency of the TNF2(A) allele is significantly increased in schizophrenic patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). These data suggest a potential role of /"TNFalpha"/ as a candidate gene for susceptibility to schizophrenia and suggest that immune dysregulation in schizophrenic patients could also have a genetic component. | [
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11245417 | Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes. | Mutations in N-acetyltransferase 2 (NAT2), a highly polymorphic enzyme involved in the metabolism of xenobiotics and carcinogens, may affect risk for colorectal cancer (CRC), especially among individuals with germ-line mutations in DNA mismatch repair genes. We determined the NAT2 genotypes and allele frequencies for 86 individuals with CRC who had mutations in hMLH1, hMSH2, or hPMS1. No significant difference in time to onset was observed between rapid (NAT2*4) and slow (NAT2*5, NAT2*6, and NAT2*7) acetylators. However, when individuals were stratified separately by NAT2 polymorphism (NAT2*5, NAT2*6, and NAT2*7), those who were heterozygous at the mutant locus NAT2*7 after adjustment for the NAT2 mutant loci NAT2*5 and NAT2*6 had a significantly higher risk of CRC (hazard ratio, 2.96; P = 0.012) and all of the cancers (hazard ratio, 3.37; P = 0.00004) than individuals homozygous for wild type at the NAT2*7 allele. These findings suggest that NAT2 genotype may be an important factor in tumorigenesis of CRC and cancers related to hereditary nonpolyposis CRC among individuals with mismatch repair defects. | Age-associated risk of cancer among individuals with /"N-acetyltransferase 2"/ (/"NAT2"/) mutations and mutations in DNA mismatch repair genes. | Mutations in /"N-acetyltransferase 2"/ (/"NAT2"/), a highly polymorphic enzyme involved in the metabolism of xenobiotics and carcinogens, may affect risk for /"colorectal cancer"/ (/"CRC"/), especially among individuals with germ-line mutations in DNA mismatch repair genes. We determined the /"NAT2"/ genotypes and allele frequencies for 86 individuals with /"CRC"/ who had mutations in hMLH1, hMSH2, or hPMS1. No significant difference in time to onset was observed between rapid (/"NAT2"/*4) and slow (/"NAT2"/*5, /"NAT2"/*6, and /"NAT2"/*7) acetylators. However, when individuals were stratified separately by /"NAT2"/ polymorphism (/"NAT2"/*5, /"NAT2"/*6, and /"NAT2"/*7), those who were heterozygous at the mutant locus /"NAT2"/*7 after adjustment for the /"NAT2"/ mutant loci /"NAT2"/*5 and /"NAT2"/*6 had a significantly higher risk of /"CRC"/ (hazard ratio, 2.96; P = 0.012) and all of the cancers (hazard ratio, 3.37; P = 0.00004) than individuals homozygous for wild type at the /"NAT2"/*7 allele. These findings suggest that /"NAT2"/ genotype may be an important factor in tumorigenesis of /"CRC"/ and cancers related to /"hereditary nonpolyposis CRC"/ among individuals with mismatch repair defects. | [
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11245417 | Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes. | Mutations in N-acetyltransferase 2 (NAT2), a highly polymorphic enzyme involved in the metabolism of xenobiotics and carcinogens, may affect risk for colorectal cancer (CRC), especially among individuals with germ-line mutations in DNA mismatch repair genes. We determined the NAT2 genotypes and allele frequencies for 86 individuals with CRC who had mutations in hMLH1, hMSH2, or hPMS1. No significant difference in time to onset was observed between rapid (NAT2*4) and slow (NAT2*5, NAT2*6, and NAT2*7) acetylators. However, when individuals were stratified separately by NAT2 polymorphism (NAT2*5, NAT2*6, and NAT2*7), those who were heterozygous at the mutant locus NAT2*7 after adjustment for the NAT2 mutant loci NAT2*5 and NAT2*6 had a significantly higher risk of CRC (hazard ratio, 2.96; P = 0.012) and all of the cancers (hazard ratio, 3.37; P = 0.00004) than individuals homozygous for wild type at the NAT2*7 allele. These findings suggest that NAT2 genotype may be an important factor in tumorigenesis of CRC and cancers related to hereditary nonpolyposis CRC among individuals with mismatch repair defects. | Age-associated risk of /"cancer"/ among individuals with /"N-acetyltransferase 2"/ (/"NAT2"/) mutations and mutations in DNA mismatch repair genes. | Mutations in /"N-acetyltransferase 2"/ (/"NAT2"/), a highly polymorphic enzyme involved in the metabolism of xenobiotics and carcinogens, may affect risk for colorectal cancer (CRC), especially among individuals with germ-line mutations in DNA mismatch repair genes. We determined the /"NAT2"/ genotypes and allele frequencies for 86 individuals with CRC who had mutations in hMLH1, hMSH2, or hPMS1. No significant difference in time to onset was observed between rapid (/"NAT2"/*4) and slow (/"NAT2"/*5, /"NAT2"/*6, and /"NAT2"/*7) acetylators. However, when individuals were stratified separately by /"NAT2"/ polymorphism (/"NAT2"/*5, /"NAT2"/*6, and /"NAT2"/*7), those who were heterozygous at the mutant locus /"NAT2"/*7 after adjustment for the /"NAT2"/ mutant loci /"NAT2"/*5 and /"NAT2"/*6 had a significantly higher risk of CRC (hazard ratio, 2.96; P = 0.012) and all of the /"cancers"/ (hazard ratio, 3.37; P = 0.00004) than individuals homozygous for wild type at the /"NAT2"/*7 allele. These findings suggest that /"NAT2"/ genotype may be an important factor in tumorigenesis of CRC and /"cancers"/ related to hereditary nonpolyposis CRC among individuals with mismatch repair defects. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not /"BRCA1"/ carriers. | /"BRCA1"/ and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The /"BRCA1"/ and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases /"breast cancer"/ risk in /"BRCA1"/ and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common /"BRCA1"/ (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among /"BRCA1"/ carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to /"increased breast cancer"/ risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for /"breast cancer"/ in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising /"breast cancer"/ risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not /"BRCA1"/ carriers. | /"BRCA1"/ and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The /"BRCA1"/ and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in /"BRCA1"/ and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common /"BRCA1"/ (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among /"BRCA1"/ carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect /"ovarian cancer"/ risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the /"RAD51"/ gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with /"RAD51"/. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of /"RAD51"/ (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. /"RAD51"/ genotyping was performed on all subjects. Among BRCA1 carriers, /"RAD51"/-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in /"RAD51"/-135C heterozygotes, not significant]. However, in BRCA2 carriers, /"RAD51"/-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed /"RAD51"/-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were /"RAD51"/-135C heterozygotes. /"RAD51"/ status did not affect /"ovarian cancer"/ risk. These results show /"RAD51"/-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in /"BRCA2"/ but not BRCA1 carriers. | BRCA1 and /"BRCA2"/ carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and /"BRCA2"/ proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and /"BRCA2"/ carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or /"BRCA2"/ (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in /"BRCA2"/ carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in /"BRCA2"/ carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in /"BRCA2"/ carriers who were RAD51-135C heterozygotes. RAD51 status did not affect /"ovarian cancer"/ risk. These results show RAD51-135C is a clinically significant modifier of /"BRCA2"/ penetrance, specifically in raising breast cancer risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the /"RAD51"/ gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with /"RAD51"/. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of /"RAD51"/ (135C/G) increases /"breast cancer"/ risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. /"RAD51"/ genotyping was performed on all subjects. Among BRCA1 carriers, /"RAD51"/-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in /"RAD51"/-135C heterozygotes, not significant]. However, in BRCA2 carriers, /"RAD51"/-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed /"RAD51"/-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to /"increased breast cancer"/ risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for /"breast cancer"/ in BRCA2 carriers who were /"RAD51"/-135C heterozygotes. /"RAD51"/ status did not affect ovarian cancer risk. These results show /"RAD51"/-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising /"breast cancer"/ risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in /"BRCA2"/ but not BRCA1 carriers. | BRCA1 and /"BRCA2"/ carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and /"BRCA2"/ proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases /"breast cancer"/ risk in BRCA1 and /"BRCA2"/ carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or /"BRCA2"/ (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in /"BRCA2"/ carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in /"BRCA2"/ carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to /"increased breast cancer"/ risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for /"breast cancer"/ in /"BRCA2"/ carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of /"BRCA2"/ penetrance, specifically in raising /"breast cancer"/ risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not /"BRCA1"/ carriers. | /"BRCA1"/ and BRCA2 carriers are at increased risk for both /"breast and ovarian cancer"/, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The /"BRCA1"/ and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in /"BRCA1"/ and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common /"BRCA1"/ (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with /"breast and/or ovarian cancer"/ and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among /"BRCA1"/ carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of /"breast and/or ovarian cancer"/ with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the /"RAD51"/ gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both /"breast and ovarian cancer"/, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with /"RAD51"/. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of /"RAD51"/ (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with /"breast and/or ovarian cancer"/ and 93 were unaffected. /"RAD51"/ genotyping was performed on all subjects. Among BRCA1 carriers, /"RAD51"/-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in /"RAD51"/-135C heterozygotes, not significant]. However, in BRCA2 carriers, /"RAD51"/-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed /"RAD51"/-135C increased risk of /"breast and/or ovarian cancer"/ with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were /"RAD51"/-135C heterozygotes. /"RAD51"/ status did not affect ovarian cancer risk. These results show /"RAD51"/-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not /"BRCA1"/ carriers. | /"BRCA1"/ and BRCA2 carriers are at increased risk for both /"breast and ovarian cancer"/, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The /"BRCA1"/ and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in /"BRCA1"/ and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common /"BRCA1"/ (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with /"breast and/or ovarian cancer"/ and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among /"BRCA1"/ carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of /"breast and/or ovarian cancer"/ with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the RAD51 gene modifies /"cancer"/ risk in /"BRCA2"/ but not BRCA1 carriers. | BRCA1 and /"BRCA2"/ carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and /"BRCA2"/ proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and /"BRCA2"/ carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or /"BRCA2"/ (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of /"cancer"/ diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in /"BRCA2"/ carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in /"BRCA2"/ carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in /"BRCA2"/ carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of /"BRCA2"/ penetrance, specifically in raising breast cancer risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the /"RAD51"/ gene modifies /"cancer"/ risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with /"RAD51"/. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of /"RAD51"/ (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. /"RAD51"/ genotyping was performed on all subjects. Among BRCA1 carriers, /"RAD51"/-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of /"cancer"/ diagnosis [Hazard ratio (HR) = 1.18 for disease in /"RAD51"/-135C heterozygotes, not significant]. However, in BRCA2 carriers, /"RAD51"/-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed /"RAD51"/-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were /"RAD51"/-135C heterozygotes. /"RAD51"/ status did not affect ovarian cancer risk. These results show /"RAD51"/-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | [
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11248061 | A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | A single nucleotide polymorphism in the /"RAD51"/ gene modifies cancer risk in BRCA2 but not BRCA1 carriers. | BRCA1 and BRCA2 carriers are at increased risk for both /"breast and ovarian cancer"/, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with /"RAD51"/. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of /"RAD51"/ (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with /"breast and/or ovarian cancer"/ and 93 were unaffected. /"RAD51"/ genotyping was performed on all subjects. Among BRCA1 carriers, /"RAD51"/-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in /"RAD51"/-135C heterozygotes, not significant]. However, in BRCA2 carriers, /"RAD51"/-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed /"RAD51"/-135C increased risk of /"breast and/or ovarian cancer"/ with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were /"RAD51"/-135C heterozygotes. /"RAD51"/ status did not affect ovarian cancer risk. These results show /"RAD51"/-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. | [
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11263767 | Influence of shared epitope-negative HLA-DRB1 alleles on genetic susceptibility to rheumatoid arthritis. | OBJECTIVE: Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE-negative HLA-DRB1 alleles influence the development of RA. This study examined the influence of SE-negative HLA-DR alleles (DRB1*X) on the development of RA in 3 different French populations. METHODS: HLA-DRB1 alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. SE-negative alleles were classified according to the electric charge of their P4 pocket. HLA-DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA-DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p. RESULTS: Among the SE-negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose SE-positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients. CONCLUSION: The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA. | Influence of shared epitope-negative /"HLA-DRB1"/ alleles on genetic susceptibility to /"rheumatoid arthritis"/. | OBJECTIVE: Most patients with /"rheumatoid arthritis"/ (/"RA"/) express the shared epitope (SE). It is not known whether SE-negative /"HLA-DRB1"/ alleles influence the development of /"RA"/. This study examined the influence of SE-negative HLA-DR alleles (/"DRB1"/*X) on the development of /"RA"/ in 3 different French populations. METHODS: /"HLA-DRB1"/ alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. SE-negative alleles were classified according to the electric charge of their P4 pocket. /"HLA-DRB1"/ alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called /"DRB1"/*XP4n. /"HLA-DRB1"/*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called /"DRB1"/*XP4p. RESULTS: Among the SE-negative subjects, /"DRB1"/ genotypes with 1 or 2 /"DRB1"/*XP4n alleles were significantly overrepresented in the control subjects compared with the /"RA"/ patients, whereas /"DRB1"/*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose SE-positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the /"RA"/ patients. CONCLUSION: The /"DRB1"/*X allele polymorphism influences susceptibility to /"RA"/. Alleles that have a neutral or negative electric charge in their P4 pocket (/"DRB1"/*XP4n), such as /"DRB1"/*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against /"RA"/. Alleles that have a positive electric charge in their P4 pocket (/"DRB1"/*XP4p), such as /"DRB1"/*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to /"RA"/. | [
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11263767 | Influence of shared epitope-negative HLA-DRB1 alleles on genetic susceptibility to rheumatoid arthritis. | OBJECTIVE: Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE-negative HLA-DRB1 alleles influence the development of RA. This study examined the influence of SE-negative HLA-DR alleles (DRB1*X) on the development of RA in 3 different French populations. METHODS: HLA-DRB1 alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. SE-negative alleles were classified according to the electric charge of their P4 pocket. HLA-DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA-DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p. RESULTS: Among the SE-negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose SE-positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients. CONCLUSION: The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA. | Influence of /"shared epitope"/-negative /"HLA-DRB1"/ alleles on genetic susceptibility to rheumatoid arthritis. | OBJECTIVE: Most patients with rheumatoid arthritis (RA) express the /"shared epitope"/ (/"SE"/). It is not known whether /"SE"/-negative /"HLA-DRB1"/ alleles influence the development of RA. This study examined the influence of /"SE"/-negative HLA-DR alleles (/"DRB1"/*X) on the development of RA in 3 different French populations. METHODS: /"HLA-DRB1"/ alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. /"SE"/-negative alleles were classified according to the electric charge of their P4 pocket. /"HLA-DRB1"/ alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called /"DRB1"/*XP4n. /"HLA-DRB1"/*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called /"DRB1"/*XP4p. RESULTS: Among the /"SE"/-negative subjects, /"DRB1"/ genotypes with 1 or 2 /"DRB1"/*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas /"DRB1"/*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose /"SE"/-positive subjects, /"SE"//XP4n genotypes were equally represented in the patients and controls. However, /"SE"//XP4p genotypes were significantly overrepresented in the RA patients. CONCLUSION: The /"DRB1"/*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (/"DRB1"/*XP4n), such as /"DRB1"/*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (/"DRB1"/*XP4p), such as /"DRB1"/*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA. | [
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