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11739440 | Insulin gene variable number of tandem repeat genotype and the low birth weight, precocious pubarche, and hyperinsulinism sequence. | Low birth weight associations with hyperinsulinemia and other adulthood disease risk factors have been described in several cohorts, including girls who present with precocious pubarche (pubic hair <8 yr). We hypothesized that these associations might be influenced by the insulin gene (INS) variable number of tandem repeat (VNTR), a common polymorphism related to INS transcription levels. In 141 Caucasian girls, who presented with precocious pubarche, hyperinsulinemia was assessed from mean insulin levels during an oral glucose load (MSI), and insulin sensitivity was determined from fasting glucose and insulin levels. Fasting blood lipid profiles were also measured. DNA was genotyped for INS VNTR allele class (I or III) in precocious pubarche girls and in 140 age- and body mass index-matched control girls. INS VNTR genotype distribution was similar in precocious pubarche and control girls. However among precocious pubarche girls, INS VNTR genotype was related to the severity of phenotype; I/I and I/III genotypes had lower birth weights (P < 0.01), higher MSI (P < 0.005), and lower insulin sensitivity (P < 0.005) than III/III girls. In precocious pubarche girls, birth weight was also inversely related to MSI (r = -0.29; P < 0.0005), total cholesterol (r = -0.38; P < 0.0005), and low density lipoprotein cholesterol (r = -0.44; P < 0.0005). Using logistic regression, additive adverse effects of I/* genotype and low birth weight were seen on MSI (P = 0.03 and P = 0.004, respectively) and total cholesterol levels (P = 0.01 and P < 0.0001). In summary, in girls who presented with precocious pubarche, hyperinsulinemia and dyslipidemia were related to both low birth weight and INS VNTR class I alleles. A similar interaction between genotype and intrauterine growth restraint may underlie other reported links between low birth weight and adulthood disease risks. | /"Insulin"/ gene variable number of tandem repeat genotype and the low birth weight, /"precocious pubarche"/, and hyperinsulinism sequence. | Low birth weight associations with hyperinsulinemia and other adulthood disease risk factors have been described in several cohorts, including girls who present with /"precocious pubarche"/ (pubic hair <8 yr). We hypothesized that these associations might be influenced by the /"insulin"/ gene (INS) variable number of tandem repeat (VNTR), a common polymorphism related to INS transcription levels. In 141 Caucasian girls, who presented with /"precocious pubarche"/, hyperinsulinemia was assessed from mean /"insulin"/ levels during an oral glucose load (MSI), and /"insulin"/ sensitivity was determined from fasting glucose and /"insulin"/ levels. Fasting blood lipid profiles were also measured. DNA was genotyped for INS VNTR allele class (I or III) in /"precocious pubarche"/ girls and in 140 age- and body mass index-matched control girls. INS VNTR genotype distribution was similar in /"precocious pubarche"/ and control girls. However among /"precocious pubarche"/ girls, INS VNTR genotype was related to the severity of phenotype; I/I and I/III genotypes had lower birth weights (P < 0.01), higher MSI (P < 0.005), and lower insulin sensitivity (P < 0.005) than III/III girls. In /"precocious pubarche"/ girls, birth weight was also inversely related to MSI (r = -0.29; P < 0.0005), total cholesterol (r = -0.38; P < 0.0005), and low density lipoprotein cholesterol (r = -0.44; P < 0.0005). Using logistic regression, additive adverse effects of I/* genotype and low birth weight were seen on MSI (P = 0.03 and P = 0.004, respectively) and total cholesterol levels (P = 0.01 and P < 0.0001). In summary, in girls who presented with /"precocious pubarche"/, hyperinsulinemia and dyslipidemia were related to both low birth weight and INS VNTR class I alleles. A similar interaction between genotype and intrauterine growth restraint may underlie other reported links between low birth weight and adulthood disease risks. | [
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11746272 | Association of codon 72 polymorphism of p53 with lower prostate cancer risk. | BACKGROUND: A common germline polymorphism of p53 produces a protein with an Arg to Pro change at codon 72. This Pro variant has altered biochemical properties suggesting altered cancer susceptibility. METHODS: A case control study with 115 men with prostate cancer and 181 community control male subjects was conducted. Demographics, family history of cancer, and blood were obtained. Codon 72 genotypes were determined using PCR. RESULTS: The Pro/Pro genotype was associated with a markedly lower risk of prostate cancer (OR = 0.23, CI = 0.07-0.79, P = 0.012). Similar reduction in risk was observed when the analysis was limited to Caucasian subjects (86% of total). Reduction in risk remained significant in a logistic regression model after correcting for age and family history of prostate cancer (OR = 0.14, CI = 0.03-0.71, P = 0.017). CONCLUSIONS: Men with the p53 codon 72 Pro/Pro genotype appear to be at reduced risk of prostate cancer. | Association of codon 72 polymorphism of /"p53"/ with /"lower prostate cancer"/ risk. | BACKGROUND: A common germline polymorphism of /"p53"/ produces a protein with an Arg to Pro change at codon 72. This Pro variant has altered biochemical properties suggesting altered cancer susceptibility. METHODS: A case control study with 115 men with /"prostate cancer"/ and 181 community control male subjects was conducted. Demographics, family history of cancer, and blood were obtained. Codon 72 genotypes were determined using PCR. RESULTS: The Pro/Pro genotype was associated with a markedly lower risk of /"prostate cancer"/ (OR = 0.23, CI = 0.07-0.79, P = 0.012). Similar reduction in risk was observed when the analysis was limited to Caucasian subjects (86% of total). Reduction in risk remained significant in a logistic regression model after correcting for age and family history of /"prostate cancer"/ (OR = 0.14, CI = 0.03-0.71, P = 0.017). CONCLUSIONS: Men with the /"p53"/ codon 72 Pro/Pro genotype appear to be at reduced risk of /"prostate cancer"/. | [
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11746272 | Association of codon 72 polymorphism of p53 with lower prostate cancer risk. | BACKGROUND: A common germline polymorphism of p53 produces a protein with an Arg to Pro change at codon 72. This Pro variant has altered biochemical properties suggesting altered cancer susceptibility. METHODS: A case control study with 115 men with prostate cancer and 181 community control male subjects was conducted. Demographics, family history of cancer, and blood were obtained. Codon 72 genotypes were determined using PCR. RESULTS: The Pro/Pro genotype was associated with a markedly lower risk of prostate cancer (OR = 0.23, CI = 0.07-0.79, P = 0.012). Similar reduction in risk was observed when the analysis was limited to Caucasian subjects (86% of total). Reduction in risk remained significant in a logistic regression model after correcting for age and family history of prostate cancer (OR = 0.14, CI = 0.03-0.71, P = 0.017). CONCLUSIONS: Men with the p53 codon 72 Pro/Pro genotype appear to be at reduced risk of prostate cancer. | Association of codon 72 polymorphism of /"p53"/ with lower prostate cancer risk. | BACKGROUND: A common germline polymorphism of /"p53"/ produces a protein with an Arg to Pro change at codon 72. This Pro variant has altered biochemical properties suggesting altered /"cancer"/ susceptibility. METHODS: A case control study with 115 men with prostate cancer and 181 community control male subjects was conducted. Demographics, family history of /"cancer"/, and blood were obtained. Codon 72 genotypes were determined using PCR. RESULTS: The Pro/Pro genotype was associated with a markedly lower risk of prostate cancer (OR = 0.23, CI = 0.07-0.79, P = 0.012). Similar reduction in risk was observed when the analysis was limited to Caucasian subjects (86% of total). Reduction in risk remained significant in a logistic regression model after correcting for age and family history of prostate cancer (OR = 0.14, CI = 0.03-0.71, P = 0.017). CONCLUSIONS: Men with the /"p53"/ codon 72 Pro/Pro genotype appear to be at reduced risk of prostate cancer. | [
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11750770 | Temporal concordance of cocaine effects on mood states and neuroendocrine hormones. | Cocaine stimulates the release of adrenocorticotropin hormone (ACTH) and cortisol in both clinical and preclinical studies, but the temporal sequence of cocaine-induced changes in other hormones and affective states is unclear. The purpose of this study was to analyze the pattern and temporal concordance of cocaine-induced changes in ACTH, cortisol, dihydroepiandrosterone (DHEA), epinephrine, heart rate and subjective reports of euphoria. Six healthy men who met Diagnostic and Statistical Manual-IV (DSM-IV) criteria for cocaine abuse provided informed consent for participation. Cocaine (0.4 mg/kg) or saline placebo was infused intravenously over 1 min under double-blind conditions. Euphoria, ACTH, epinephrine and heart rate increased significantly within 8 to 12 min after i.v. cocaine administration in all subjects (P<0.01-0.001). Moreover, the increases in euphoria, ACTH, epinephrine and heart rate each were significantly correlated with increases in plasma cocaine levels (P<0.001). Euphoria increased significantly within 2 min after i.v. cocaine injection, as plasma cocaine levels were increasing, and peak euphoria was reported at 10 min (P<0.001). Peak ACTH values were measured at 8.7 (+/-0.8) min after cocaine injection (P<0.01). Peak levels of epinephrine were measured at 10 (+/-1) min after cocaine injection (P<0.05). Peak increases in heart rate occurred at 11.7 (+/-1.1) min after cocaine injection (P<0.05). Peak levels of cortisol and DHEA were measured at 36 (+/-4.0) and 28.7 (+/-4.3) min after cocaine injection (P<0.01 and P<0.01). The temporal concordance between cocaine-induced stimulation of ACTH, epinephrine and subjective euphoria suggests that these hormonal changes are significant concomitants of the abuse-related effects of cocaine. The similarities between these hormonal profiles, the subjective effects of cocaine and the effects of "stress" are discussed. | Temporal concordance of cocaine effects on mood states and neuroendocrine hormones. | Cocaine stimulates the release of /"adrenocorticotropin"/ hormone (ACTH) and cortisol in both clinical and preclinical studies, but the temporal sequence of cocaine-induced changes in other hormones and affective states is unclear. The purpose of this study was to analyze the pattern and temporal concordance of cocaine-induced changes in ACTH, cortisol, dihydroepiandrosterone (DHEA), epinephrine, heart rate and subjective reports of euphoria. Six healthy men who met Diagnostic and Statistical Manual-IV (DSM-IV) criteria for /"cocaine abuse"/ provided informed consent for participation. Cocaine (0.4 mg/kg) or saline placebo was infused intravenously over 1 min under double-blind conditions. Euphoria, ACTH, epinephrine and heart rate increased significantly within 8 to 12 min after i.v. cocaine administration in all subjects (P<0.01-0.001). Moreover, the increases in euphoria, ACTH, epinephrine and heart rate each were significantly correlated with increases in plasma cocaine levels (P<0.001). Euphoria increased significantly within 2 min after i.v. cocaine injection, as plasma cocaine levels were increasing, and peak euphoria was reported at 10 min (P<0.001). Peak ACTH values were measured at 8.7 (+/-0.8) min after cocaine injection (P<0.01). Peak levels of epinephrine were measured at 10 (+/-1) min after cocaine injection (P<0.05). Peak increases in heart rate occurred at 11.7 (+/-1.1) min after cocaine injection (P<0.05). Peak levels of cortisol and DHEA were measured at 36 (+/-4.0) and 28.7 (+/-4.3) min after cocaine injection (P<0.01 and P<0.01). The temporal concordance between cocaine-induced stimulation of ACTH, epinephrine and subjective euphoria suggests that these hormonal changes are significant concomitants of the abuse-related effects of cocaine. The similarities between these hormonal profiles, the subjective effects of cocaine and the effects of "stress" are discussed. | [
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11756990 | Associations between human leukocyte antigens and nonresponsiveness to influenza vaccine. | Influenza remains a major cause of morbidity and mortality, particularly in at-risk groups where vaccination reduces complications of infection but is not universally protective. In order to determine whether human leukocyte antigen (HLA) class II polymorphisms modulate anti-influenza antibody responses to vaccination, a cohort of HLA-typed at-risk donors was investigated. The subjects were recruited from a single urban family practice. Hemagglutination-inhibition (HAI) titers were measured immediately before and 28 days after subunit vaccination. Nonresponsiveness was defined as failure to mount an HAI response to any component of the trivalent influenza vaccine. When the nonresponders and responders with HLA class II were compared, the nonresponder group had more HLA-DRB1*07-positive donors (13/32 vs. 6/41 responders; P=.016, Fisher's exact test) and fewer HLA-DQB1*0603-9/14-positive donors (2/32 vs. 14/41 responders; P=.0045). Thus, polymorphisms in HLA class II molecules appear to modulate antibody responses to influenza vaccination. | Associations between human leukocyte antigens and nonresponsiveness to /"influenza"/ vaccine. | Influenza remains a major cause of morbidity and mortality, particularly in at-risk groups where vaccination reduces complications of infection but is not universally protective. In order to determine whether human leukocyte antigen (HLA) class II polymorphisms modulate anti-/"influenza"/ antibody responses to vaccination, a cohort of HLA-typed at-risk donors was investigated. The subjects were recruited from a single urban family practice. Hemagglutination-inhibition (HAI) titers were measured immediately before and 28 days after subunit vaccination. Nonresponsiveness was defined as failure to mount an HAI response to any component of the trivalent /"influenza"/ vaccine. When the nonresponders and responders with HLA class II were compared, the nonresponder group had more /"HLA-DRB1"/*07-positive donors (13/32 vs. 6/41 responders; P=.016, Fisher's exact test) and fewer HLA-DQB1*0603-9/14-positive donors (2/32 vs. 14/41 responders; P=.0045). Thus, polymorphisms in HLA class II molecules appear to modulate antibody responses to /"influenza"/ vaccination. | [
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11756990 | Associations between human leukocyte antigens and nonresponsiveness to influenza vaccine. | Influenza remains a major cause of morbidity and mortality, particularly in at-risk groups where vaccination reduces complications of infection but is not universally protective. In order to determine whether human leukocyte antigen (HLA) class II polymorphisms modulate anti-influenza antibody responses to vaccination, a cohort of HLA-typed at-risk donors was investigated. The subjects were recruited from a single urban family practice. Hemagglutination-inhibition (HAI) titers were measured immediately before and 28 days after subunit vaccination. Nonresponsiveness was defined as failure to mount an HAI response to any component of the trivalent influenza vaccine. When the nonresponders and responders with HLA class II were compared, the nonresponder group had more HLA-DRB1*07-positive donors (13/32 vs. 6/41 responders; P=.016, Fisher's exact test) and fewer HLA-DQB1*0603-9/14-positive donors (2/32 vs. 14/41 responders; P=.0045). Thus, polymorphisms in HLA class II molecules appear to modulate antibody responses to influenza vaccination. | Associations between human leukocyte antigens and nonresponsiveness to /"influenza"/ vaccine. | Influenza remains a major cause of morbidity and mortality, particularly in at-risk groups where vaccination reduces complications of infection but is not universally protective. In order to determine whether human leukocyte antigen (HLA) class II polymorphisms modulate anti-/"influenza"/ antibody responses to vaccination, a cohort of HLA-typed at-risk donors was investigated. The subjects were recruited from a single urban family practice. Hemagglutination-inhibition (HAI) titers were measured immediately before and 28 days after subunit vaccination. Nonresponsiveness was defined as failure to mount an HAI response to any component of the trivalent /"influenza"/ vaccine. When the nonresponders and responders with HLA class II were compared, the nonresponder group had more HLA-DRB1*07-positive donors (13/32 vs. 6/41 responders; P=.016, Fisher's exact test) and fewer /"HLA-DQB1"/*0603-9/14-positive donors (2/32 vs. 14/41 responders; P=.0045). Thus, polymorphisms in HLA class II molecules appear to modulate antibody responses to /"influenza"/ vaccination. | [
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11756990 | Associations between human leukocyte antigens and nonresponsiveness to influenza vaccine. | Influenza remains a major cause of morbidity and mortality, particularly in at-risk groups where vaccination reduces complications of infection but is not universally protective. In order to determine whether human leukocyte antigen (HLA) class II polymorphisms modulate anti-influenza antibody responses to vaccination, a cohort of HLA-typed at-risk donors was investigated. The subjects were recruited from a single urban family practice. Hemagglutination-inhibition (HAI) titers were measured immediately before and 28 days after subunit vaccination. Nonresponsiveness was defined as failure to mount an HAI response to any component of the trivalent influenza vaccine. When the nonresponders and responders with HLA class II were compared, the nonresponder group had more HLA-DRB1*07-positive donors (13/32 vs. 6/41 responders; P=.016, Fisher's exact test) and fewer HLA-DQB1*0603-9/14-positive donors (2/32 vs. 14/41 responders; P=.0045). Thus, polymorphisms in HLA class II molecules appear to modulate antibody responses to influenza vaccination. | Associations between human leukocyte antigens and nonresponsiveness to influenza vaccine. | Influenza remains a major cause of morbidity and mortality, particularly in at-risk groups where vaccination reduces complications of /"infection"/ but is not universally protective. In order to determine whether human leukocyte antigen (HLA) class II polymorphisms modulate anti-influenza antibody responses to vaccination, a cohort of HLA-typed at-risk donors was investigated. The subjects were recruited from a single urban family practice. Hemagglutination-inhibition (HAI) titers were measured immediately before and 28 days after subunit vaccination. Nonresponsiveness was defined as failure to mount an HAI response to any component of the trivalent influenza vaccine. When the nonresponders and responders with HLA class II were compared, the nonresponder group had more /"HLA-DRB1"/*07-positive donors (13/32 vs. 6/41 responders; P=.016, Fisher's exact test) and fewer HLA-DQB1*0603-9/14-positive donors (2/32 vs. 14/41 responders; P=.0045). Thus, polymorphisms in HLA class II molecules appear to modulate antibody responses to influenza vaccination. | [
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11756990 | Associations between human leukocyte antigens and nonresponsiveness to influenza vaccine. | Influenza remains a major cause of morbidity and mortality, particularly in at-risk groups where vaccination reduces complications of infection but is not universally protective. In order to determine whether human leukocyte antigen (HLA) class II polymorphisms modulate anti-influenza antibody responses to vaccination, a cohort of HLA-typed at-risk donors was investigated. The subjects were recruited from a single urban family practice. Hemagglutination-inhibition (HAI) titers were measured immediately before and 28 days after subunit vaccination. Nonresponsiveness was defined as failure to mount an HAI response to any component of the trivalent influenza vaccine. When the nonresponders and responders with HLA class II were compared, the nonresponder group had more HLA-DRB1*07-positive donors (13/32 vs. 6/41 responders; P=.016, Fisher's exact test) and fewer HLA-DQB1*0603-9/14-positive donors (2/32 vs. 14/41 responders; P=.0045). Thus, polymorphisms in HLA class II molecules appear to modulate antibody responses to influenza vaccination. | Associations between human leukocyte antigens and nonresponsiveness to influenza vaccine. | Influenza remains a major cause of morbidity and mortality, particularly in at-risk groups where vaccination reduces complications of /"infection"/ but is not universally protective. In order to determine whether human leukocyte antigen (HLA) class II polymorphisms modulate anti-influenza antibody responses to vaccination, a cohort of HLA-typed at-risk donors was investigated. The subjects were recruited from a single urban family practice. Hemagglutination-inhibition (HAI) titers were measured immediately before and 28 days after subunit vaccination. Nonresponsiveness was defined as failure to mount an HAI response to any component of the trivalent influenza vaccine. When the nonresponders and responders with HLA class II were compared, the nonresponder group had more HLA-DRB1*07-positive donors (13/32 vs. 6/41 responders; P=.016, Fisher's exact test) and fewer /"HLA-DQB1"/*0603-9/14-positive donors (2/32 vs. 14/41 responders; P=.0045). Thus, polymorphisms in HLA class II molecules appear to modulate antibody responses to influenza vaccination. | [
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11762699 | A novel mutation in Ca2+-sensing receptor gene in familial hypocalciuric hypercalcemia. | Missense mutations in the calcium-sensing receptor (CaSR) gene have previously been identified in patients with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism. We identified a newborn with hypercalcemia in our hospital by mass screening. The family members were studied, and we found a novel CaSR missense mutation with polymerase chain reaction single-strand conformational polymorphism analysis. The mother, grandmother, and aunt of the baby all had FHH. A heterozygous missense mutation in exon 6 that substitutes a glutamic acid for the glycine at codon 557 (Gly557Glu), which corresponds to the extracellular domain of CaSR, was identified and shown to cosegregate with the disease. Identification of the mutation responsible for the FHH phenotype in this family may facilitate rapid testing of individuals at risk for FHH. | A novel mutation in Ca2+-sensing receptor gene in /"familial hypocalciuric hypercalcemia"/. | Missense mutations in the /"calcium-sensing receptor"/ (/"CaSR"/) gene have previously been identified in patients with /"familial hypocalciuric hypercalcemia"/ (/"FHH"/) and neonatal severe hyperparathyroidism. We identified a newborn with hypercalcemia in our hospital by mass screening. The family members were studied, and we found a novel /"CaSR"/ missense mutation with polymerase chain reaction single-strand conformational polymorphism analysis. The mother, grandmother, and aunt of the baby all had /"FHH"/. A heterozygous missense mutation in exon 6 that substitutes a glutamic acid for the glycine at codon 557 (Gly557Glu), which corresponds to the extracellular domain of /"CaSR"/, was identified and shown to cosegregate with the disease. Identification of the mutation responsible for the /"FHH"/ phenotype in this family may facilitate rapid testing of individuals at risk for /"FHH"/. | [
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11762699 | A novel mutation in Ca2+-sensing receptor gene in familial hypocalciuric hypercalcemia. | Missense mutations in the calcium-sensing receptor (CaSR) gene have previously been identified in patients with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism. We identified a newborn with hypercalcemia in our hospital by mass screening. The family members were studied, and we found a novel CaSR missense mutation with polymerase chain reaction single-strand conformational polymorphism analysis. The mother, grandmother, and aunt of the baby all had FHH. A heterozygous missense mutation in exon 6 that substitutes a glutamic acid for the glycine at codon 557 (Gly557Glu), which corresponds to the extracellular domain of CaSR, was identified and shown to cosegregate with the disease. Identification of the mutation responsible for the FHH phenotype in this family may facilitate rapid testing of individuals at risk for FHH. | A novel mutation in Ca2+-sensing receptor gene in familial hypocalciuric hypercalcemia. | Missense mutations in the /"calcium-sensing receptor"/ (/"CaSR"/) gene have previously been identified in patients with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism. We identified a newborn with /"hypercalcemia"/ in our hospital by mass screening. The family members were studied, and we found a novel /"CaSR"/ missense mutation with polymerase chain reaction single-strand conformational polymorphism analysis. The mother, grandmother, and aunt of the baby all had FHH. A heterozygous missense mutation in exon 6 that substitutes a glutamic acid for the glycine at codon 557 (Gly557Glu), which corresponds to the extracellular domain of /"CaSR"/, was identified and shown to cosegregate with the disease. Identification of the mutation responsible for the FHH phenotype in this family may facilitate rapid testing of individuals at risk for FHH. | [
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11769724 | [Apolipoprotein E 4 gene is a risk factor for Alzheimer's disease]. | OBJECTIVE: To study the association of Alzheimer disease (AD) with apolipoprotein E (ApoE) epsilon 4 allele and to find the biological peripheral markers for the laboratory diagnosis of AD. METHODS: 107 patients with AD, 68 patients with vascular dementia (VD) and 74 sex- and age-matched non-demented healthy individuals (NDC) were collected. DNA from patients and healthy individuals was extracted from peripheral blood samples with the phenol-chloroform procedure and ApoE was investigated with the methods of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The frequency of epsilon 4 was significantly higher in AD than that in VD and NDC and there was no difference in the frequency of epsilon 4 between VD and NDC. The age at onset of the disease in the group carrying two epsilon 4 alleles was significantly younger than that in the group with one epsilon 4 allele in AD. Moreover, in comparison with AD patients without epsilon 4 allele, the age at onset in the group with one epsilon 4 allele was younger. Patients with epsilon 4 or without epsilon 4 allele in VD patients did not differ significantly in age at onset. Meanwhile, 3 familial AD cases were found, all carrying epsilon 4 allele. CONCLUSION: AD and ApoE4 were closely related. ApoE epsilon 4 was a dangerous factor of AD and ApoE 4 allele made contribution to the heterogenicity of AD. | [/"Apolipoprotein E 4"/ gene is a risk factor for /"Alzheimer's disease"/]. | OBJECTIVE: To study the association of /"Alzheimer disease"/ (/"AD"/) with /"apolipoprotein E"/ (/"ApoE"/) epsilon 4 allele and to find the biological peripheral markers for the laboratory diagnosis of /"AD"/. METHODS: 107 patients with /"AD"/, 68 patients with vascular dementia (VD) and 74 sex- and age-matched non-demented healthy individuals (NDC) were collected. DNA from patients and healthy individuals was extracted from peripheral blood samples with the phenol-chloroform procedure and /"ApoE"/ was investigated with the methods of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The frequency of epsilon 4 was significantly higher in /"AD"/ than that in VD and NDC and there was no difference in the frequency of epsilon 4 between VD and NDC. The age at onset of the disease in the group carrying two epsilon 4 alleles was significantly younger than that in the group with one epsilon 4 allele in /"AD"/. Moreover, in comparison with /"AD"/ patients without epsilon 4 allele, the age at onset in the group with one epsilon 4 allele was younger. Patients with epsilon 4 or without epsilon 4 allele in VD patients did not differ significantly in age at onset. Meanwhile, 3 familial /"AD"/ cases were found, all carrying epsilon 4 allele. CONCLUSION: /"AD"/ and /"ApoE4"/ were closely related. /"ApoE"/ epsilon 4 was a dangerous factor of /"AD"/ and /"ApoE 4"/ allele made contribution to the heterogenicity of /"AD"/. | [
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} | Yes |
11769724 | [Apolipoprotein E 4 gene is a risk factor for Alzheimer's disease]. | OBJECTIVE: To study the association of Alzheimer disease (AD) with apolipoprotein E (ApoE) epsilon 4 allele and to find the biological peripheral markers for the laboratory diagnosis of AD. METHODS: 107 patients with AD, 68 patients with vascular dementia (VD) and 74 sex- and age-matched non-demented healthy individuals (NDC) were collected. DNA from patients and healthy individuals was extracted from peripheral blood samples with the phenol-chloroform procedure and ApoE was investigated with the methods of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The frequency of epsilon 4 was significantly higher in AD than that in VD and NDC and there was no difference in the frequency of epsilon 4 between VD and NDC. The age at onset of the disease in the group carrying two epsilon 4 alleles was significantly younger than that in the group with one epsilon 4 allele in AD. Moreover, in comparison with AD patients without epsilon 4 allele, the age at onset in the group with one epsilon 4 allele was younger. Patients with epsilon 4 or without epsilon 4 allele in VD patients did not differ significantly in age at onset. Meanwhile, 3 familial AD cases were found, all carrying epsilon 4 allele. CONCLUSION: AD and ApoE4 were closely related. ApoE epsilon 4 was a dangerous factor of AD and ApoE 4 allele made contribution to the heterogenicity of AD. | [/"Apolipoprotein E 4"/ gene is a risk factor for Alzheimer's disease]. | OBJECTIVE: To study the association of Alzheimer disease (AD) with /"apolipoprotein E"/ (/"ApoE"/) epsilon 4 allele and to find the biological peripheral markers for the laboratory diagnosis of AD. METHODS: 107 patients with AD, 68 patients with /"vascular dementia"/ (/"VD"/) and 74 sex- and age-matched non-demented healthy individuals (NDC) were collected. DNA from patients and healthy individuals was extracted from peripheral blood samples with the phenol-chloroform procedure and /"ApoE"/ was investigated with the methods of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The frequency of epsilon 4 was significantly higher in AD than that in /"VD"/ and NDC and there was no difference in the frequency of epsilon 4 between /"VD"/ and NDC. The age at onset of the disease in the group carrying two epsilon 4 alleles was significantly younger than that in the group with one epsilon 4 allele in AD. Moreover, in comparison with AD patients without epsilon 4 allele, the age at onset in the group with one epsilon 4 allele was younger. Patients with epsilon 4 or without epsilon 4 allele in /"VD"/ patients did not differ significantly in age at onset. Meanwhile, 3 familial AD cases were found, all carrying epsilon 4 allele. CONCLUSION: AD and /"ApoE4"/ were closely related. /"ApoE"/ epsilon 4 was a dangerous factor of AD and /"ApoE 4"/ allele made contribution to the heterogenicity of AD. | [
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"text_name": "apolipoprotein E"
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11774187 | Hemochromatosis (HFE) gene sequence analysis of formalin-fixed, paraffin-embedded liver biopsy specimens. | BACKGROUND: Hereditary hemochromatosis (HH) is a common disease predominantly characterized by mutations of the HFE gene. METHODS AND RESULTS: We investigated the utility of HFE gene sequence analysis in the diagnosis of HH in 61 prospectively accrued formalin-fixed, paraffin-embedded liver biopsy specimens with clinical or histologic features suggestive of HH. Mutations in codons 63 or 282 of the HFE gene were identified by direct sequencing; in 21 of these samples, quantitative hepatic iron testing was also performed. Changes characteristic of HH were present in 16 (26%) of the cases, and 54% of the cases showed HFE gene mutations. The most common alteration was homozygous mutation of codon 282 (11 cases, 18%), followed by the combined 63 + 282 heterozygous mutation (3 cases, 5%). Two cases (3%) showed biallelic mutation of codon 63. The other 28 cases (46%) showed no sequence abnormalities. Weak iron staining did not exclude HH; intense staining did not reliably predict HH. CONCLUSION: When HH is clinically and/or histologically suspected, HFE gene sequencing of formalin-fixed, paraffin-embedded liver biopsy specimens is a rapid and cost-effective approach to genotypic diagnosis of HH. | /"Hemochromatosis"/ (/"HFE"/) gene sequence analysis of formalin-fixed, paraffin-embedded liver biopsy specimens. | BACKGROUND: /"Hereditary hemochromatosis"/ (/"HH"/) is a common disease predominantly characterized by mutations of the /"HFE"/ gene. METHODS AND RESULTS: We investigated the utility of /"HFE"/ gene sequence analysis in the diagnosis of /"HH"/ in 61 prospectively accrued formalin-fixed, paraffin-embedded liver biopsy specimens with clinical or histologic features suggestive of /"HH"/. Mutations in codons 63 or 282 of the /"HFE"/ gene were identified by direct sequencing; in 21 of these samples, quantitative hepatic iron testing was also performed. Changes characteristic of /"HH"/ were present in 16 (26%) of the cases, and 54% of the cases showed /"HFE"/ gene mutations. The most common alteration was homozygous mutation of codon 282 (11 cases, 18%), followed by the combined 63 + 282 heterozygous mutation (3 cases, 5%). Two cases (3%) showed biallelic mutation of codon 63. The other 28 cases (46%) showed no sequence abnormalities. Weak iron staining did not exclude /"HH"/; intense staining did not reliably predict /"HH"/. CONCLUSION: When /"HH"/ is clinically and/or histologically suspected, /"HFE"/ gene sequencing of formalin-fixed, paraffin-embedded liver biopsy specimens is a rapid and cost-effective approach to genotypic diagnosis of /"HH"/. | [
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11778498 | [Study on beta 2 adrenergic receptor genetic polymorphisms in asthmatics in the people of the Han nationality of northern China]. | OBJECTIVE: To analyze the association between beta 2-AR genetic polymorphism and asthma in the people of the Han nationality of northern China. METHODS: Allele Specific-PCR techniques were used to determine 16, 27 and 164 locus alleles of beta 2-AR genetic polymorphisms in 58 unrelated patients with asthma and 89 healthy controls from the people of the Han nationality of northern China. RESULTS: (1) The distribution frequency of genotype beta 2-AR 16 loci: Arg/Arg genotype accounts for 13%, Arg/Gly 76% and Gly/Gly 11%. The beta 2-AR 27 loci: Gln/Gln genotype accounts for 36%, Gln/Glu 55% and Glu/Glu 9%. The beta 2-AR 164 loci: Thr/Thr genotype accounts for 30%, Thr/Ile 53% and Ile/Ile 17%. (2) The frequency of genotype beta 2-AR 16 loci in asthmatics: Arg/Arg genotype accounts for 24%, Arg/Gly 45% and Gly/Gly 31%. There was a significant increase in the frequency of Gly/Gly genotype in asthmatics compared with healthy group(OR = 4.0, 95% CI 1.7-9.7), but there was no significant difference in the allele frequency of asthmatics compared with healthy group. The frequency of genotype beta 2-AR 27 loci in asthmatics: Gln/Gln genotype accounts for 34%, Gln/Glu 56% and Glu/Glu 10%. There was no significant difference in the allele frequency of asthmatics compared with healthy group. The frequency of genotype beta 2-AR 164 loci in asthmatics: Thr/Thr genotype accounts for 10%, Thr/Ile 83% and Ile/Ile 7%. There was no significant difference in the frequency of Ile/Ile genotype in asthmatics compared with healthy group, and in the allele frequency of asthmatics compared with healthy group. In addition, our study reveals that beta 2-AR 16 locus genetic polymorphism is in association with asthmatic severity. CONCLUSIONS: These results suggest that beta 2-AR 16 locus genetic polymorphism is correlated with asthma severity in the people of the Han nationality of northern China. | [Study on beta 2 adrenergic receptor genetic polymorphisms in asthmatics in the people of the Han nationality of northern China]. | OBJECTIVE: To analyze the association between /"beta 2-AR"/ genetic polymorphism and /"asthma"/ in the people of the Han nationality of northern China. METHODS: Allele Specific-PCR techniques were used to determine 16, 27 and 164 locus alleles of /"beta 2-AR"/ genetic polymorphisms in 58 unrelated patients with /"asthma"/ and 89 healthy controls from the people of the Han nationality of northern China. RESULTS: (1) The distribution frequency of genotype /"beta 2-AR"/ 16 loci: Arg/Arg genotype accounts for 13%, Arg/Gly 76% and Gly/Gly 11%. The /"beta 2-AR"/ 27 loci: Gln/Gln genotype accounts for 36%, Gln/Glu 55% and Glu/Glu 9%. The /"beta 2-AR"/ 164 loci: Thr/Thr genotype accounts for 30%, Thr/Ile 53% and Ile/Ile 17%. (2) The frequency of genotype /"beta 2-AR"/ 16 loci in asthmatics: Arg/Arg genotype accounts for 24%, Arg/Gly 45% and Gly/Gly 31%. There was a significant increase in the frequency of Gly/Gly genotype in asthmatics compared with healthy group(OR = 4.0, 95% CI 1.7-9.7), but there was no significant difference in the allele frequency of asthmatics compared with healthy group. The frequency of genotype /"beta 2-AR"/ 27 loci in asthmatics: Gln/Gln genotype accounts for 34%, Gln/Glu 56% and Glu/Glu 10%. There was no significant difference in the allele frequency of asthmatics compared with healthy group. The frequency of genotype /"beta 2-AR"/ 164 loci in asthmatics: Thr/Thr genotype accounts for 10%, Thr/Ile 83% and Ile/Ile 7%. There was no significant difference in the frequency of Ile/Ile genotype in asthmatics compared with healthy group, and in the allele frequency of asthmatics compared with healthy group. In addition, our study reveals that /"beta 2-AR"/ 16 locus genetic polymorphism is in association with asthmatic severity. CONCLUSIONS: These results suggest that /"beta 2-AR"/ 16 locus genetic polymorphism is correlated with /"asthma"/ severity in the people of the Han nationality of northern China. | [
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11778498 | [Study on beta 2 adrenergic receptor genetic polymorphisms in asthmatics in the people of the Han nationality of northern China]. | OBJECTIVE: To analyze the association between beta 2-AR genetic polymorphism and asthma in the people of the Han nationality of northern China. METHODS: Allele Specific-PCR techniques were used to determine 16, 27 and 164 locus alleles of beta 2-AR genetic polymorphisms in 58 unrelated patients with asthma and 89 healthy controls from the people of the Han nationality of northern China. RESULTS: (1) The distribution frequency of genotype beta 2-AR 16 loci: Arg/Arg genotype accounts for 13%, Arg/Gly 76% and Gly/Gly 11%. The beta 2-AR 27 loci: Gln/Gln genotype accounts for 36%, Gln/Glu 55% and Glu/Glu 9%. The beta 2-AR 164 loci: Thr/Thr genotype accounts for 30%, Thr/Ile 53% and Ile/Ile 17%. (2) The frequency of genotype beta 2-AR 16 loci in asthmatics: Arg/Arg genotype accounts for 24%, Arg/Gly 45% and Gly/Gly 31%. There was a significant increase in the frequency of Gly/Gly genotype in asthmatics compared with healthy group(OR = 4.0, 95% CI 1.7-9.7), but there was no significant difference in the allele frequency of asthmatics compared with healthy group. The frequency of genotype beta 2-AR 27 loci in asthmatics: Gln/Gln genotype accounts for 34%, Gln/Glu 56% and Glu/Glu 10%. There was no significant difference in the allele frequency of asthmatics compared with healthy group. The frequency of genotype beta 2-AR 164 loci in asthmatics: Thr/Thr genotype accounts for 10%, Thr/Ile 83% and Ile/Ile 7%. There was no significant difference in the frequency of Ile/Ile genotype in asthmatics compared with healthy group, and in the allele frequency of asthmatics compared with healthy group. In addition, our study reveals that beta 2-AR 16 locus genetic polymorphism is in association with asthmatic severity. CONCLUSIONS: These results suggest that beta 2-AR 16 locus genetic polymorphism is correlated with asthma severity in the people of the Han nationality of northern China. | [Study on beta 2 adrenergic receptor genetic polymorphisms in /"asthmatics"/ in the people of the Han nationality of northern China]. | OBJECTIVE: To analyze the association between /"beta 2-AR"/ genetic polymorphism and asthma in the people of the Han nationality of northern China. METHODS: Allele Specific-PCR techniques were used to determine 16, 27 and 164 locus alleles of /"beta 2-AR"/ genetic polymorphisms in 58 unrelated patients with asthma and 89 healthy controls from the people of the Han nationality of northern China. RESULTS: (1) The distribution frequency of genotype /"beta 2-AR"/ 16 loci: Arg/Arg genotype accounts for 13%, Arg/Gly 76% and Gly/Gly 11%. The /"beta 2-AR"/ 27 loci: Gln/Gln genotype accounts for 36%, Gln/Glu 55% and Glu/Glu 9%. The /"beta 2-AR"/ 164 loci: Thr/Thr genotype accounts for 30%, Thr/Ile 53% and Ile/Ile 17%. (2) The frequency of genotype /"beta 2-AR"/ 16 loci in /"asthmatics"/: Arg/Arg genotype accounts for 24%, Arg/Gly 45% and Gly/Gly 31%. There was a significant increase in the frequency of Gly/Gly genotype in /"asthmatics"/ compared with healthy group(OR = 4.0, 95% CI 1.7-9.7), but there was no significant difference in the allele frequency of /"asthmatics"/ compared with healthy group. The frequency of genotype /"beta 2-AR"/ 27 loci in /"asthmatics"/: Gln/Gln genotype accounts for 34%, Gln/Glu 56% and Glu/Glu 10%. There was no significant difference in the allele frequency of /"asthmatics"/ compared with healthy group. The frequency of genotype /"beta 2-AR"/ 164 loci in /"asthmatics"/: Thr/Thr genotype accounts for 10%, Thr/Ile 83% and Ile/Ile 7%. There was no significant difference in the frequency of Ile/Ile genotype in /"asthmatics"/ compared with healthy group, and in the allele frequency of /"asthmatics"/ compared with healthy group. In addition, our study reveals that /"beta 2-AR"/ 16 locus genetic polymorphism is in association with /"asthmatic"/ severity. CONCLUSIONS: These results suggest that /"beta 2-AR"/ 16 locus genetic polymorphism is correlated with asthma severity in the people of the Han nationality of northern China. | [
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11793481 | Sanfilippo syndrome in Turkey: Identification of novel mutations in subtypes A and B. | Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the degradation of heparan sulfate, with sulfamidase (SGSH) being deficient in MPS IIIA and a-N-acetylglucosaminidase (NAGLU) deficient in MPS IIIB. Mutation screening using SSCP/heteroduplex analysis on genomic DNA fragments was performed in five Turkish MPS IIIA and eight Turkish MPS IIIB patients. In this study two mutations of SGSH were identified in MPS IIIA patients: R74C and the novel mutation P288S, and one polymorphism (IVS1+23 C>G). Five different mutations of NAGLU were identified in MPS IIIB patients: L682R, H248R, E153K, g.17703 A>G (novel), and T437I (novel). The clinical data of all patients are reported in detail. A high degree of genetic heterogeneity was observed in the Turkish MPS IIIA and MPS IIIB patients. | /"Sanfilippo syndrome"/ in Turkey: Identification of novel mutations in subtypes A and B. | /"Sanfilippo syndrome"/ (/"mucopolysaccharidosis type III"/, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the degradation of heparan sulfate, with sulfamidase (/"SGSH"/) being /"deficient in MPS IIIA"/ and a-N-acetylglucosaminidase (NAGLU) /"deficient in MPS IIIB"/. Mutation screening using SSCP/heteroduplex analysis on genomic DNA fragments was performed in five Turkish /"MPS IIIA"/ and eight Turkish /"MPS IIIB"/ patients. In this study two mutations of /"SGSH"/ were identified in /"MPS IIIA"/ patients: R74C and the novel mutation P288S, and one polymorphism (IVS1+23 C>G). Five different mutations of NAGLU were identified in /"MPS IIIB"/ patients: L682R, H248R, E153K, g.17703 A>G (novel), and T437I (novel). The clinical data of all patients are reported in detail. A high degree of genetic heterogeneity was observed in the Turkish /"MPS IIIA"/ and /"MPS IIIB"/ patients. | [
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11793481 | Sanfilippo syndrome in Turkey: Identification of novel mutations in subtypes A and B. | Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the degradation of heparan sulfate, with sulfamidase (SGSH) being deficient in MPS IIIA and a-N-acetylglucosaminidase (NAGLU) deficient in MPS IIIB. Mutation screening using SSCP/heteroduplex analysis on genomic DNA fragments was performed in five Turkish MPS IIIA and eight Turkish MPS IIIB patients. In this study two mutations of SGSH were identified in MPS IIIA patients: R74C and the novel mutation P288S, and one polymorphism (IVS1+23 C>G). Five different mutations of NAGLU were identified in MPS IIIB patients: L682R, H248R, E153K, g.17703 A>G (novel), and T437I (novel). The clinical data of all patients are reported in detail. A high degree of genetic heterogeneity was observed in the Turkish MPS IIIA and MPS IIIB patients. | /"Sanfilippo syndrome"/ in Turkey: Identification of novel mutations in subtypes A and B. | /"Sanfilippo syndrome"/ (/"mucopolysaccharidosis type III"/, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the degradation of heparan sulfate, with sulfamidase (SGSH) being /"deficient in MPS IIIA"/ and /"a-N-acetylglucosaminidase"/ (/"NAGLU"/) /"deficient in MPS IIIB"/IB"/. Mutation screening using SSCP/heteroduplex analysis on genomic DNA fragments was performed in five Turkish /"MPS IIIA"/ and eight Turkish /"MPS IIIB"/IB"/ patients. In this study two mutations of SGSH were identified in /"MPS IIIA"/ patients: R74C and the novel mutation P288S, and one polymorphism (IVS1+23 C>G). Five different mutations of /"NAGLU"/ were identified in /"MPS IIIB"/IB"/ patients: L682R, H248R, E153K, g.17703 A>G (novel), and T437I (novel). The clinical data of all patients are reported in detail. A high degree of genetic heterogeneity was observed in the Turkish /"MPS IIIA"/ and /"MPS IIIB"/IB"/ patients. | [
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11793481 | Sanfilippo syndrome in Turkey: Identification of novel mutations in subtypes A and B. | Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the degradation of heparan sulfate, with sulfamidase (SGSH) being deficient in MPS IIIA and a-N-acetylglucosaminidase (NAGLU) deficient in MPS IIIB. Mutation screening using SSCP/heteroduplex analysis on genomic DNA fragments was performed in five Turkish MPS IIIA and eight Turkish MPS IIIB patients. In this study two mutations of SGSH were identified in MPS IIIA patients: R74C and the novel mutation P288S, and one polymorphism (IVS1+23 C>G). Five different mutations of NAGLU were identified in MPS IIIB patients: L682R, H248R, E153K, g.17703 A>G (novel), and T437I (novel). The clinical data of all patients are reported in detail. A high degree of genetic heterogeneity was observed in the Turkish MPS IIIA and MPS IIIB patients. | Sanfilippo syndrome in Turkey: Identification of novel mutations in subtypes A and B. | Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild /"somatic disease"/. MPS III results from a deficiency in one of the four enzymes involved in the degradation of heparan sulfate, with sulfamidase (SGSH) being deficient in MPS IIIA and /"a-N-acetylglucosaminidase"/ (/"NAGLU"/) deficient in /"MPS IIIB"/. Mutation screening using SSCP/heteroduplex analysis on genomic DNA fragments was performed in five Turkish MPS IIIA and eight Turkish /"MPS IIIB"/ patients. In this study two mutations of SGSH were identified in MPS IIIA patients: R74C and the novel mutation P288S, and one polymorphism (IVS1+23 C>G). Five different mutations of /"NAGLU"/ were identified in /"MPS IIIB"/ patients: L682R, H248R, E153K, g.17703 A>G (novel), and T437I (novel). The clinical data of all patients are reported in detail. A high degree of genetic heterogeneity was observed in the Turkish MPS IIIA and /"MPS IIIB"/ patients. | [
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11793481 | Sanfilippo syndrome in Turkey: Identification of novel mutations in subtypes A and B. | Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the degradation of heparan sulfate, with sulfamidase (SGSH) being deficient in MPS IIIA and a-N-acetylglucosaminidase (NAGLU) deficient in MPS IIIB. Mutation screening using SSCP/heteroduplex analysis on genomic DNA fragments was performed in five Turkish MPS IIIA and eight Turkish MPS IIIB patients. In this study two mutations of SGSH were identified in MPS IIIA patients: R74C and the novel mutation P288S, and one polymorphism (IVS1+23 C>G). Five different mutations of NAGLU were identified in MPS IIIB patients: L682R, H248R, E153K, g.17703 A>G (novel), and T437I (novel). The clinical data of all patients are reported in detail. A high degree of genetic heterogeneity was observed in the Turkish MPS IIIA and MPS IIIB patients. | Sanfilippo syndrome in Turkey: Identification of novel mutations in subtypes A and B. | Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild /"somatic disease"/. MPS III results from a deficiency in one of the four enzymes involved in the degradation of heparan sulfate, with sulfamidase (SGSH) being deficient in MPS IIIA and /"a-N-acetylglucosaminidase"/ (/"NAGLU"/) deficient in /"MPS IIIB"/. Mutation screening using SSCP/heteroduplex analysis on genomic DNA fragments was performed in five Turkish MPS IIIA and eight Turkish /"MPS IIIB"/ patients. In this study two mutations of SGSH were identified in MPS IIIA patients: R74C and the novel mutation P288S, and one polymorphism (IVS1+23 C>G). Five different mutations of /"NAGLU"/ were identified in /"MPS IIIB"/ patients: L682R, H248R, E153K, g.17703 A>G (novel), and T437I (novel). The clinical data of all patients are reported in detail. A high degree of genetic heterogeneity was observed in the Turkish MPS IIIA and /"MPS IIIB"/ patients. | [
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11793483 | Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency. | Ornithine transcarbamylase (OTC) deficiency, a X-linked disorder, is the most frequent inborn error of the urea cycle. Point mutations and small deletions/insertions in the OTC gene are responsible for the majority of the cases and have a "private" character with little recurrence. We report on eleven pathological changes in the OTC gene sequence detected in three males with mild clinical presentations, and in eight symptomatic females. All of these mutations are novel. Only one mutation affects a CpG mutational hot spot, whereas all but one of the mutations caused an abnormal SSCP of the corresponding PCR-amplified exon. Two mutations occurring in females involved one or two base deletions in codons 196 and 330, respectively, causing frameshift changes and premature termination. Another two mutations in a female and a male affected acceptor splice sites at bases -1 and -3 of the intron 6/exon 7 and intron 9/exon 10 junctions, respectively. All other mutations were point changes causing the simple amino acid substitutions (M1I, I160S, L191F, M206I, L301F, P305H and L341P), although the mutation M1I may abolish translation of the OTC polypeptide. This mutation coexisted in a female patient with the change T333A that appears to be a previously unreported polymorphism. The three male patients but only four of the eight female patients inherited the mutation. | Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for /"ornithine transcarbamylase"/ (/"OTC"/) in patients with /"OTC deficiency"/. | /"Ornithine transcarbamylase (OTC) deficiency"/ency, a X-linked disorder, is the most frequent inborn error of the urea cycle. Point mutations and small deletions/insertions in the /"OTC"/ gene are responsible for the majority of the cases and have a "private" character with little recurrence. We report on eleven pathological changes in the /"OTC"/ gene sequence detected in three males with mild clinical presentations, and in eight symptomatic females. All of these mutations are novel. Only one mutation affects a CpG mutational hot spot, whereas all but one of the mutations caused an abnormal SSCP of the corresponding PCR-amplified exon. Two mutations occurring in females involved one or two base deletions in codons 196 and 330, respectively, causing frameshift changes and premature termination. Another two mutations in a female and a male affected acceptor splice sites at bases -1 and -3 of the intron 6/exon 7 and intron 9/exon 10 junctions, respectively. All other mutations were point changes causing the simple amino acid substitutions (M1I, I160S, L191F, M206I, L301F, P305H and L341P), although the mutation M1I may abolish translation of the /"OTC"/ polypeptide. This mutation coexisted in a female patient with the change T333A that appears to be a previously unreported polymorphism. The three male patients but only four of the eight female patients inherited the mutation. | [
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11793483 | Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency. | Ornithine transcarbamylase (OTC) deficiency, a X-linked disorder, is the most frequent inborn error of the urea cycle. Point mutations and small deletions/insertions in the OTC gene are responsible for the majority of the cases and have a "private" character with little recurrence. We report on eleven pathological changes in the OTC gene sequence detected in three males with mild clinical presentations, and in eight symptomatic females. All of these mutations are novel. Only one mutation affects a CpG mutational hot spot, whereas all but one of the mutations caused an abnormal SSCP of the corresponding PCR-amplified exon. Two mutations occurring in females involved one or two base deletions in codons 196 and 330, respectively, causing frameshift changes and premature termination. Another two mutations in a female and a male affected acceptor splice sites at bases -1 and -3 of the intron 6/exon 7 and intron 9/exon 10 junctions, respectively. All other mutations were point changes causing the simple amino acid substitutions (M1I, I160S, L191F, M206I, L301F, P305H and L341P), although the mutation M1I may abolish translation of the OTC polypeptide. This mutation coexisted in a female patient with the change T333A that appears to be a previously unreported polymorphism. The three male patients but only four of the eight female patients inherited the mutation. | Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for /"ornithine transcarbamylase"/ (/"OTC"/) in patients with OTC deficiency. | Ornithine transcarbamylase (/"OTC"/) deficiency, a /"X-linked disorder"/, is the most frequent inborn error of the urea cycle. Point mutations and small deletions/insertions in the /"OTC"/ gene are responsible for the majority of the cases and have a "private" character with little recurrence. We report on eleven pathological changes in the /"OTC"/ gene sequence detected in three males with mild clinical presentations, and in eight symptomatic females. All of these mutations are novel. Only one mutation affects a CpG mutational hot spot, whereas all but one of the mutations caused an abnormal SSCP of the corresponding PCR-amplified exon. Two mutations occurring in females involved one or two base deletions in codons 196 and 330, respectively, causing frameshift changes and premature termination. Another two mutations in a female and a male affected acceptor splice sites at bases -1 and -3 of the intron 6/exon 7 and intron 9/exon 10 junctions, respectively. All other mutations were point changes causing the simple amino acid substitutions (M1I, I160S, L191F, M206I, L301F, P305H and L341P), although the mutation M1I may abolish translation of the /"OTC"/ polypeptide. This mutation coexisted in a female patient with the change T333A that appears to be a previously unreported polymorphism. The three male patients but only four of the eight female patients inherited the mutation. | [
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11799476 | CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. | Recent investigations identified heterozygous CFC1 mutations in subjects with heterotaxy syndrome, all of whom had congenital cardiac malformations, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of congenital heart disease---namely, transposition of the great arteries and double-outlet right ventricle, in the absence of laterality defects---would also have CFC1 mutations. Our analysis of the CFC1 gene in patients with these cardiac disorders identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these cardiac malformations and indicates that some cases of transposition of the great arteries and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving CFC1 plays a critical role in normal and abnormal cardiovascular development. | /"CFC1"/ mutations in patients with /"transposition of the great arteries"/ and double-outlet right ventricle. | Recent investigations identified heterozygous /"CFC1"/ mutations in subjects with heterotaxy syndrome, all of whom had congenital cardiac malformations, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of congenital heart disease---namely, /"transposition of the great arteries"/ and double-outlet right ventricle, in the absence of laterality defects---would also have /"CFC1"/ mutations. Our analysis of the /"CFC1"/ gene in patients with these cardiac disorders identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these cardiac malformations and indicates that some cases of /"transposition of the great arteries"/ and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving /"CFC1"/ plays a critical role in normal and abnormal cardiovascular development. | [
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11799476 | CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. | Recent investigations identified heterozygous CFC1 mutations in subjects with heterotaxy syndrome, all of whom had congenital cardiac malformations, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of congenital heart disease---namely, transposition of the great arteries and double-outlet right ventricle, in the absence of laterality defects---would also have CFC1 mutations. Our analysis of the CFC1 gene in patients with these cardiac disorders identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these cardiac malformations and indicates that some cases of transposition of the great arteries and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving CFC1 plays a critical role in normal and abnormal cardiovascular development. | /"CFC1"/ mutations in patients with transposition of the great arteries and /"double-outlet"/ right ventricle. | Recent investigations identified heterozygous /"CFC1"/ mutations in subjects with heterotaxy syndrome, all of whom had congenital cardiac malformations, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of congenital heart disease---namely, transposition of the great arteries and /"double-outlet"/ right ventricle, in the absence of laterality defects---would also have /"CFC1"/ mutations. Our analysis of the /"CFC1"/ gene in patients with these cardiac disorders identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these cardiac malformations and indicates that some cases of transposition of the great arteries and /"double-outlet"/ right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving /"CFC1"/ plays a critical role in normal and abnormal cardiovascular development. | [
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11799476 | CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. | Recent investigations identified heterozygous CFC1 mutations in subjects with heterotaxy syndrome, all of whom had congenital cardiac malformations, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of congenital heart disease---namely, transposition of the great arteries and double-outlet right ventricle, in the absence of laterality defects---would also have CFC1 mutations. Our analysis of the CFC1 gene in patients with these cardiac disorders identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these cardiac malformations and indicates that some cases of transposition of the great arteries and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving CFC1 plays a critical role in normal and abnormal cardiovascular development. | /"CFC1"/ mutations in patients with transposition of the great arteries and double-outlet right ventricle. | Recent investigations identified heterozygous /"CFC1"/ mutations in subjects with heterotaxy syndrome, all of whom had /"congenital cardiac malformations"/, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of /"congenital heart disease"/---namely, transposition of the great arteries and double-outlet right ventricle, in the absence of laterality defects---would also have /"CFC1"/ mutations. Our analysis of the /"CFC1"/ gene in patients with these /"cardiac disorders"/ identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these /"cardiac malformations"/ and indicates that some cases of transposition of the great arteries and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving /"CFC1"/ plays a critical role in normal and abnormal cardiovascular development. | [
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} | No |
11799476 | CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. | Recent investigations identified heterozygous CFC1 mutations in subjects with heterotaxy syndrome, all of whom had congenital cardiac malformations, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of congenital heart disease---namely, transposition of the great arteries and double-outlet right ventricle, in the absence of laterality defects---would also have CFC1 mutations. Our analysis of the CFC1 gene in patients with these cardiac disorders identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these cardiac malformations and indicates that some cases of transposition of the great arteries and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving CFC1 plays a critical role in normal and abnormal cardiovascular development. | /"CFC1"/ mutations in patients with transposition of the great arteries and double-outlet right ventricle. | Recent investigations identified heterozygous /"CFC1"/ mutations in subjects with heterotaxy syndrome, all of whom had /"congenital cardiac malformations"/, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of /"congenital heart disease"/---namely, transposition of the great arteries and double-outlet right ventricle, in the absence of laterality defects---would also have /"CFC1"/ mutations. Our analysis of the /"CFC1"/ gene in patients with these /"cardiac disorders"/ identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these /"cardiac malformations"/ and indicates that some cases of transposition of the great arteries and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving /"CFC1"/ plays a critical role in normal and abnormal cardiovascular development. | [
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} | No |
11802810 | Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma. | This is the first report to show that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of therapy. We investigated the hypothesis that ATP7B, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain breast carcinomas. To test this hypothesis, ATP7B expression and protein level were examined in 41 breast carcinomas using RT-PCR and immunohistochemistry. ATP7B gene / protein could be detected in 22.0% (9 / 41) of breast carcinomas and ATP7B gene expression was correlated well with the protein expression. In nine ATP7B-positive tumors, adjacent normal breast tissue was similarly analyzed, revealing that ATP7B is upregulated in breast carcinoma. ATP7B gene expression in poorly differentiated carcinoma was significantly higher than that in well- / moderately differentiated carcinoma (P = 0.012). Furthermore, we found no association between the ATP7B gene / protein expression and that of MDR1, MRP1, LRP and BCRP. These findings suggested that ATP7B gene expression might be a chemoresistance marker for cisplatin in patients with poorly differentiated breast carcinoma. | Copper-transporting P-type adenosine triphosphatase (/"ATP7B"/) is expressed in human /"breast carcinoma"/. | This is the first report to show that a copper-transporting P-type adenosine triphosphatase, /"ATP7B"/, is expressed in certain /"breast carcinomas"/, and a priori knowledge of its expression is important for the choice of therapy. We investigated the hypothesis that /"ATP7B"/, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain /"breast carcinomas"/. To test this hypothesis, /"ATP7B"/ expression and protein level were examined in 41 /"breast carcinomas"/ using RT-PCR and immunohistochemistry. /"ATP7B"/ gene / protein could be detected in 22.0% (9 / 41) of /"breast carcinomas"/ and /"ATP7B"/ gene expression was correlated well with the protein expression. In nine /"ATP7B"/-positive tumors, adjacent normal breast tissue was similarly analyzed, revealing that /"ATP7B"/ is upregulated in /"breast carcinoma"/. /"ATP7B"/ gene expression in poorly differentiated carcinoma was significantly higher than that in well- / moderately differentiated carcinoma (P = 0.012). Furthermore, we found no association between the /"ATP7B"/ gene / protein expression and that of MDR1, MRP1, LRP and BCRP. These findings suggested that /"ATP7B"/ gene expression might be a chemoresistance marker for cisplatin in patients with poorly differentiated /"breast carcinoma"/. | [
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}
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} | {
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"entity_id": "D001943",
"entity_type": "Disease",
"text_name": "breast carcinomas"
} | Yes |
11802810 | Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma. | This is the first report to show that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of therapy. We investigated the hypothesis that ATP7B, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain breast carcinomas. To test this hypothesis, ATP7B expression and protein level were examined in 41 breast carcinomas using RT-PCR and immunohistochemistry. ATP7B gene / protein could be detected in 22.0% (9 / 41) of breast carcinomas and ATP7B gene expression was correlated well with the protein expression. In nine ATP7B-positive tumors, adjacent normal breast tissue was similarly analyzed, revealing that ATP7B is upregulated in breast carcinoma. ATP7B gene expression in poorly differentiated carcinoma was significantly higher than that in well- / moderately differentiated carcinoma (P = 0.012). Furthermore, we found no association between the ATP7B gene / protein expression and that of MDR1, MRP1, LRP and BCRP. These findings suggested that ATP7B gene expression might be a chemoresistance marker for cisplatin in patients with poorly differentiated breast carcinoma. | Copper-transporting P-type adenosine triphosphatase (/"ATP7B"/) is expressed in human breast carcinoma. | This is the first report to show that a copper-transporting P-type adenosine triphosphatase, /"ATP7B"/, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of therapy. We investigated the hypothesis that /"ATP7B"/, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain breast carcinomas. To test this hypothesis, /"ATP7B"/ expression and protein level were examined in 41 breast carcinomas using RT-PCR and immunohistochemistry. /"ATP7B"/ gene / protein could be detected in 22.0% (9 / 41) of breast carcinomas and /"ATP7B"/ gene expression was correlated well with the protein expression. In nine /"ATP7B"/-positive /"tumors"/, adjacent normal breast tissue was similarly analyzed, revealing that /"ATP7B"/ is upregulated in breast carcinoma. /"ATP7B"/ gene expression in poorly differentiated carcinoma was significantly higher than that in well- / moderately differentiated carcinoma (P = 0.012). Furthermore, we found no association between the /"ATP7B"/ gene / protein expression and that of MDR1, MRP1, LRP and BCRP. These findings suggested that /"ATP7B"/ gene expression might be a chemoresistance marker for cisplatin in patients with poorly differentiated breast carcinoma. | [
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"entity_type": "Gene",
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},
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"text_name": "ATP7B"
},
{
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"end_idx": "1180",
"entity_id": "644079",
"entity_type": "Gene",
"text_name": "BCRP"
}
] | {
"begin_idx": "1112",
"end_idx": "1117",
"entity_id": "540",
"entity_type": "Gene",
"text_name": "ATP7B"
} | {
"begin_idx": "792",
"end_idx": "798",
"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "tumors"
} | No |
11843659 | Toenail dystrophy with COL7A1 glycine substitution mutations segregates as an autosomal dominant trait in 2 families with dystrophic epidermolysis bullosa. | /"Toenail dystrophy"/ with /"COL7A1"/ glycine substitution mutations segregates as an autosomal dominant trait in 2 families with dystrophic epidermolysis bullosa. | [
{
"begin_idx": "0",
"end_idx": "17",
"entity_id": "C564384",
"entity_type": "Disease",
"text_name": "Toenail dystrophy"
},
{
"begin_idx": "122",
"end_idx": "154",
"entity_id": "D016108",
"entity_type": "Disease",
"text_name": "dystrophic epidermolysis bullosa"
},
{
"begin_idx": "23",
"end_idx": "29",
"entity_id": "1294",
"entity_type": "Gene",
"text_name": "COL7A1"
}
] | {
"begin_idx": "23",
"end_idx": "29",
"entity_id": "1294",
"entity_type": "Gene",
"text_name": "COL7A1"
} | {
"begin_idx": "0",
"end_idx": "17",
"entity_id": "C564384",
"entity_type": "Disease",
"text_name": "Toenail dystrophy"
} | Yes |
||
11843659 | Toenail dystrophy with COL7A1 glycine substitution mutations segregates as an autosomal dominant trait in 2 families with dystrophic epidermolysis bullosa. | Toenail dystrophy with /"COL7A1"/ glycine substitution mutations segregates as an autosomal dominant trait in 2 families with /"dystrophic epidermolysis bullosa"/. | [
{
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"end_idx": "17",
"entity_id": "C564384",
"entity_type": "Disease",
"text_name": "Toenail dystrophy"
},
{
"begin_idx": "122",
"end_idx": "154",
"entity_id": "D016108",
"entity_type": "Disease",
"text_name": "dystrophic epidermolysis bullosa"
},
{
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"text_name": "COL7A1"
}
] | {
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"text_name": "COL7A1"
} | {
"begin_idx": "122",
"end_idx": "154",
"entity_id": "D016108",
"entity_type": "Disease",
"text_name": "dystrophic epidermolysis bullosa"
} | No |
||
11857544 | Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. | Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS1 polypeptides with partial function. Together, these results suggest an allelic genotype-phenotype relationship among the various clinical forms of CHS. | Apparent genotype-phenotype correlation in childhood, adolescent, and adult /"Chediak-Higashi syndrome"/. | /"Chediak-Higashi syndrome"/ (/"CHS"/) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent /"CHS"/ phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the /"CHS1"/ gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of /"CHS"/. In patients with severe childhood /"CHS"/, we found only functionally null mutant /"CHS1"/ alleles, whereas in patients with the adolescent and adult forms of /"CHS"/ we also found missense mutant alleles that likely encode /"CHS1"/ polypeptides with partial function. Together, these results suggest an allelic genotype-phenotype relationship among the various clinical forms of /"CHS"/. | [
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},
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"text_name": "infections"
},
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"text_name": "neurological dysfunction"
},
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"text_name": "neurological dysfunction"
},
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"text_name": "reduced pigmentation"
},
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"text_name": "autosomal recessive disorder"
},
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} | {
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"text_name": "Chediak-Higashi syndrome"
} | Yes |
11857544 | Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. | Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS1 polypeptides with partial function. Together, these results suggest an allelic genotype-phenotype relationship among the various clinical forms of CHS. | Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. | Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, /"bleeding"/ tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the /"CHS1"/ gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant /"CHS1"/ alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode /"CHS1"/ polypeptides with partial function. Together, these results suggest an allelic genotype-phenotype relationship among the various clinical forms of CHS. | [
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] | {
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} | {
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"entity_id": "D006470",
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"text_name": "bleeding"
} | No |
11859714 | [Glutathione-S-transferase M1 genotype in patients with hepatocellular carcinoma]. | OBJECTIVE: To study the glutathione-S-tranterase M1 (GSTM1) genotype in patients with hepatocellular carcinoma (HCC) with aflatoxin B1(AFB1) in a high risk region in Guangxi. METHODS: Specific GSTM1 primers and PCR technique were used for the detection of GSTM1 genotype using the peripheral leukocytes. A total of 379 samples was examined including 162 HCC patients whose lesions had been confirmed by pathology, 177 adults of local residents without cancer and 40 young men coming from other places with incidence of HCC. RESULTS: The frequency of GSTM1-null genotype in HCC patients was 102/162(63%), in local residents it was 92/177(52%) and in young men from outside it was 13/40(33%), which were significantly different. CONCLUSION: GSTM1 is one of the pivotal phase II detoxicated enzymes for AFB1. GSTM1 genetic deletion predisposes the individuals to HCC. However, the development of a HCC not only requires a genetic susceptibility, but also a AFB1 highly contaminated environment. The synergism of carcinogenic viruses such as HBV and HCV is also needed. These, when happen to be present together in an area in Guangxi, would lead to a high incidence of HCC. | [Glutathione-S-transferase M1 genotype in patients with /"hepatocellular carcinoma"/]. | OBJECTIVE: To study the /"glutathione-S-tranterase M1"/ (/"GSTM1"/) genotype in patients with /"hepatocellular carcinoma"/ (/"HCC"/) with aflatoxin B1(AFB1) in a high risk region in Guangxi. METHODS: Specific /"GSTM1"/ primers and PCR technique were used for the detection of /"GSTM1"/ genotype using the peripheral leukocytes. A total of 379 samples was examined including 162 /"HCC"/ patients whose lesions had been confirmed by pathology, 177 adults of local residents without cancer and 40 young men coming from other places with incidence of /"HCC"/. RESULTS: The frequency of /"GSTM1"/-null genotype in /"HCC"/ patients was 102/162(63%), in local residents it was 92/177(52%) and in young men from outside it was 13/40(33%), which were significantly different. CONCLUSION: /"GSTM1"/ is one of the pivotal phase II detoxicated enzymes for AFB1. /"GSTM1"/ genetic deletion predisposes the individuals to /"HCC"/. However, the development of a /"HCC"/ not only requires a genetic susceptibility, but also a AFB1 highly contaminated environment. The synergism of carcinogenic viruses such as HBV and HCV is also needed. These, when happen to be present together in an area in Guangxi, would lead to a high incidence of /"HCC"/. | [
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"text_name": "hepatocellular carcinoma"
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"text_name": "cancer"
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},
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},
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},
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},
{
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}
] | {
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} | {
"begin_idx": "56",
"end_idx": "80",
"entity_id": "D006528",
"entity_type": "Disease",
"text_name": "hepatocellular carcinoma"
} | Yes |
11859714 | [Glutathione-S-transferase M1 genotype in patients with hepatocellular carcinoma]. | OBJECTIVE: To study the glutathione-S-tranterase M1 (GSTM1) genotype in patients with hepatocellular carcinoma (HCC) with aflatoxin B1(AFB1) in a high risk region in Guangxi. METHODS: Specific GSTM1 primers and PCR technique were used for the detection of GSTM1 genotype using the peripheral leukocytes. A total of 379 samples was examined including 162 HCC patients whose lesions had been confirmed by pathology, 177 adults of local residents without cancer and 40 young men coming from other places with incidence of HCC. RESULTS: The frequency of GSTM1-null genotype in HCC patients was 102/162(63%), in local residents it was 92/177(52%) and in young men from outside it was 13/40(33%), which were significantly different. CONCLUSION: GSTM1 is one of the pivotal phase II detoxicated enzymes for AFB1. GSTM1 genetic deletion predisposes the individuals to HCC. However, the development of a HCC not only requires a genetic susceptibility, but also a AFB1 highly contaminated environment. The synergism of carcinogenic viruses such as HBV and HCV is also needed. These, when happen to be present together in an area in Guangxi, would lead to a high incidence of HCC. | [Glutathione-S-transferase M1 genotype in patients with hepatocellular carcinoma]. | OBJECTIVE: To study the /"glutathione-S-tranterase M1"/ (/"GSTM1"/) genotype in patients with hepatocellular carcinoma (HCC) with aflatoxin B1(AFB1) in a high risk region in Guangxi. METHODS: Specific /"GSTM1"/ primers and PCR technique were used for the detection of /"GSTM1"/ genotype using the peripheral leukocytes. A total of 379 samples was examined including 162 HCC patients whose lesions had been confirmed by pathology, 177 adults of local residents without /"cancer"/ and 40 young men coming from other places with incidence of HCC. RESULTS: The frequency of /"GSTM1"/-null genotype in HCC patients was 102/162(63%), in local residents it was 92/177(52%) and in young men from outside it was 13/40(33%), which were significantly different. CONCLUSION: /"GSTM1"/ is one of the pivotal phase II detoxicated enzymes for AFB1. /"GSTM1"/ genetic deletion predisposes the individuals to HCC. However, the development of a HCC not only requires a genetic susceptibility, but also a AFB1 highly contaminated environment. The synergism of carcinogenic viruses such as HBV and HCV is also needed. These, when happen to be present together in an area in Guangxi, would lead to a high incidence of HCC. | [
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} | {
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"entity_id": "D009369",
"entity_type": "Disease",
"text_name": "cancer"
} | No |
11891618 | Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the calpain-10 locus. | Recently, a positional cloning study proposed that haplotypes at the calpain-10 locus (CAPN10) are associated with increased risk of type 2 diabetes, or non-insulin-dependent diabetes mellitus, in Mexican Americans, Finns, and Germans. To inform the interpretation of the original mapping results and to look for evidence for the action of natural selection on CAPN10, we undertook a population-based genotyping survey of the candidate susceptibility variants. First, we genotyped sites 43, 19, and 63 (the haplotype-defining variants previously proposed) and four closely linked SNPs, in 561 individuals from 11 populations from five continents, and we examined the linkage disequilibrium among them. We then examined the ancestral state of these sites by sequencing orthologous portions of CAPN10 in chimpanzee and orangutan (the identity of sites 43 and 19 was further investigated in a limited sample of other great apes and Old World and New World monkeys). Our survey suggests larger-than-expected differences in the distribution of CAPN10 susceptibility variants between African and non-African populations, with common, derived haplotypes in European and Asian samples (including one of two proposed risk haplotypes) being rare or absent in African samples. These results suggest a history of positive natural selection at the locus, resulting in significant geographic differences in polymorphism frequencies. The relationship of these differences to disease risk is discussed. | Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the /"calpain-10"/ locus. | Recently, a positional cloning study proposed that haplotypes at the /"calpain-10"/ locus (/"CAPN10"/) are associated with increased risk of type 2 diabetes, or /"non-insulin-dependent diabetes mellitus"/, in Mexican Americans, Finns, and Germans. To inform the interpretation of the original mapping results and to look for evidence for the action of natural selection on /"CAPN10"/, we undertook a population-based genotyping survey of the candidate susceptibility variants. First, we genotyped sites 43, 19, and 63 (the haplotype-defining variants previously proposed) and four closely linked SNPs, in 561 individuals from 11 populations from five continents, and we examined the linkage disequilibrium among them. We then examined the ancestral state of these sites by sequencing orthologous portions of /"CAPN10"/ in chimpanzee and orangutan (the identity of sites 43 and 19 was further investigated in a limited sample of other great apes and Old World and New World monkeys). Our survey suggests larger-than-expected differences in the distribution of /"CAPN10"/ susceptibility variants between African and non-African populations, with common, derived haplotypes in European and Asian samples (including one of two proposed risk haplotypes) being rare or absent in African samples. These results suggest a history of positive natural selection at the locus, resulting in significant geographic differences in polymorphism frequencies. The relationship of these differences to disease risk is discussed. | [
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} | Yes |
11891618 | Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the calpain-10 locus. | Recently, a positional cloning study proposed that haplotypes at the calpain-10 locus (CAPN10) are associated with increased risk of type 2 diabetes, or non-insulin-dependent diabetes mellitus, in Mexican Americans, Finns, and Germans. To inform the interpretation of the original mapping results and to look for evidence for the action of natural selection on CAPN10, we undertook a population-based genotyping survey of the candidate susceptibility variants. First, we genotyped sites 43, 19, and 63 (the haplotype-defining variants previously proposed) and four closely linked SNPs, in 561 individuals from 11 populations from five continents, and we examined the linkage disequilibrium among them. We then examined the ancestral state of these sites by sequencing orthologous portions of CAPN10 in chimpanzee and orangutan (the identity of sites 43 and 19 was further investigated in a limited sample of other great apes and Old World and New World monkeys). Our survey suggests larger-than-expected differences in the distribution of CAPN10 susceptibility variants between African and non-African populations, with common, derived haplotypes in European and Asian samples (including one of two proposed risk haplotypes) being rare or absent in African samples. These results suggest a history of positive natural selection at the locus, resulting in significant geographic differences in polymorphism frequencies. The relationship of these differences to disease risk is discussed. | Geographic and haplotype structure of candidate type 2 /"diabetes"/ susceptibility variants at the /"calpain-10"/ locus. | Recently, a positional cloning study proposed that haplotypes at the /"calpain-10"/ locus (/"CAPN10"/) are associated with increased risk of type 2 /"diabetes"/, or non-insulin-dependent diabetes mellitus, in Mexican Americans, Finns, and Germans. To inform the interpretation of the original mapping results and to look for evidence for the action of natural selection on /"CAPN10"/, we undertook a population-based genotyping survey of the candidate susceptibility variants. First, we genotyped sites 43, 19, and 63 (the haplotype-defining variants previously proposed) and four closely linked SNPs, in 561 individuals from 11 populations from five continents, and we examined the linkage disequilibrium among them. We then examined the ancestral state of these sites by sequencing orthologous portions of /"CAPN10"/ in chimpanzee and orangutan (the identity of sites 43 and 19 was further investigated in a limited sample of other great apes and Old World and New World monkeys). Our survey suggests larger-than-expected differences in the distribution of /"CAPN10"/ susceptibility variants between African and non-African populations, with common, derived haplotypes in European and Asian samples (including one of two proposed risk haplotypes) being rare or absent in African samples. These results suggest a history of positive natural selection at the locus, resulting in significant geographic differences in polymorphism frequencies. The relationship of these differences to disease risk is discussed. | [
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11895223 | HLA-DRB3*0101 is associated with Graves' disease in Jamaicans. | OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians. | HLA-DRB3*0101 is associated with /"Graves' disease"/ in Jamaicans. | OBJECTIVES: /"Graves' disease"/ is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with /"Graves' disease"/ in Jamaicans. PATIENTS: One hundred and six Jamaicans with /"Graves' disease"/ and 104 controls. DESIGN: Oligotyping for /"HLA-DRB1"/, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for /"Graves' disease"/ were /"DRB1"/ *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), /"DRB1"/*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of /"Graves' disease"/, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with /"Graves' disease"/ share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype /"DRB1"/ *0301, DRB3*0101, DQA1*0501 with Caucasians. | [
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11895223 | HLA-DRB3*0101 is associated with Graves' disease in Jamaicans. | OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians. | HLA-DRB3*0101 is associated with /"Graves' disease"/ in Jamaicans. | OBJECTIVES: /"Graves' disease"/ is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with /"Graves' disease"/ in Jamaicans. PATIENTS: One hundred and six Jamaicans with /"Graves' disease"/ and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, /"DQA1"/ and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for /"Graves' disease"/ were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of /"Graves' disease"/, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with /"Graves' disease"/ share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, /"DQA1"/*0501 with Caucasians. | [
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11895223 | HLA-DRB3*0101 is associated with Graves' disease in Jamaicans. | OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians. | HLA-DRB3*0101 is associated with /"Graves' disease"/ in Jamaicans. | OBJECTIVES: /"Graves' disease"/ is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with /"Graves' disease"/ in Jamaicans. PATIENTS: One hundred and six Jamaicans with /"Graves' disease"/ and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and /"DQB1"/ alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for /"Graves' disease"/ were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of /"Graves' disease"/, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with /"Graves' disease"/ share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians. | [
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} | {
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} | Yes |
11895223 | HLA-DRB3*0101 is associated with Graves' disease in Jamaicans. | OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians. | /"HLA-DRB3"/*0101 is associated with /"Graves' disease"/ in Jamaicans. | OBJECTIVES: /"Graves' disease"/ is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with /"Graves' disease"/ in Jamaicans. PATIENTS: One hundred and six Jamaicans with /"Graves' disease"/ and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of /"HLA-DRB3"/ *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for /"Graves' disease"/ were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of /"Graves' disease"/, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with /"Graves' disease"/ share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians. | [
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11895223 | HLA-DRB3*0101 is associated with Graves' disease in Jamaicans. | OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians. | HLA-DRB3*0101 is associated with /"Graves' disease"/ in Jamaicans. | OBJECTIVES: /"Graves' disease"/ is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with /"Graves' disease"/ in Jamaicans. PATIENTS: One hundred and six Jamaicans with /"Graves' disease"/ and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for /"Graves' disease"/ were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and /"DRB4"/ *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of /"Graves' disease"/, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with /"Graves' disease"/ share the DRB3 *0101 susceptible allele and the /"DRB4"/ *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians. | [
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11895223 | HLA-DRB3*0101 is associated with Graves' disease in Jamaicans. | OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians. | HLA-DRB3*0101 is associated with Graves' disease in Jamaicans. | OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for /"HLA-DRB1"/, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were /"DRB1"/ *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), /"DRB1"/*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated /"autoimmune diseases"/ were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype /"DRB1"/ *0301, DRB3*0101, DQA1*0501 with Caucasians. | [
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11895872 | A polymorphism in the CYP17 gene and risk of prostate cancer. | Steroid hormones are important in the etiology and progression of prostate cancer, and expression of genes involved in hormone production may alter susceptibility. One such gene is CYP17, which encodes the cytochrome P450c17a enzyme responsible for the biosynthesis of testosterone. A T to C transition (A2 allele) in the 5' promoter region of the gene is hypothesized to increase the rate of gene transcription, increase androgen production, and thereby increase risk of prostate cancer. To test this hypothesis, germ-line DNA samples from a large population-based study of incident prostate cancer cases (n = 590) and controls (n = 538) of similar age without the disease were genotyped. The frequency of the A2 allele was similar in cases and controls. Compared with men with the A1/A1 genotype, the adjusted odds ratio was 0.81 for the A1/A2 and 0.87 for the A2/A2 genotype. Risk estimates did not vary substantially by age or race. However, stratification by family history of prostate cancer revealed that among white men with an affected first-degree relative, homozygotes for the A2 allele had a significant elevation in risk (odds ratio = 19.2; 95% confidence interval, 2.2-157.4) compared with men who were homozygous for the A1 allele (interaction P = 0.0005). These results suggest that the CYP17 A2/A2 genotype predicts susceptibility to prostate cancer in white men with a family history of the disease. It is also possible that CYP17 interacts with other genes that influence risk of familial prostate cancer. | A polymorphism in the /"CYP17"/ gene and risk of /"prostate cancer"/. | Steroid hormones are important in the etiology and progression of /"prostate cancer"/, and expression of genes involved in hormone production may alter susceptibility. One such gene is /"CYP17"/, which encodes the /"cytochrome P450c17"/a enzyme responsible for the biosynthesis of testosterone. A T to C transition (A2 allele) in the 5' promoter region of the gene is hypothesized to increase the rate of gene transcription, increase androgen production, and thereby increase risk of /"prostate cancer"/. To test this hypothesis, germ-line DNA samples from a large population-based study of incident /"prostate cancer"/ cases (n = 590) and controls (n = 538) of similar age without the disease were genotyped. The frequency of the A2 allele was similar in cases and controls. Compared with men with the A1/A1 genotype, the adjusted odds ratio was 0.81 for the A1/A2 and 0.87 for the A2/A2 genotype. Risk estimates did not vary substantially by age or race. However, stratification by family history of /"prostate cancer"/ revealed that among white men with an affected first-degree relative, homozygotes for the A2 allele had a significant elevation in risk (odds ratio = 19.2; 95% confidence interval, 2.2-157.4) compared with men who were homozygous for the A1 allele (interaction P = 0.0005). These results suggest that the /"CYP17"/ A2/A2 genotype predicts susceptibility to /"prostate cancer"/ in white men with a family history of the disease. It is also possible that /"CYP17"/ interacts with other genes that influence risk of /"familial prostate cancer"/. | [
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11895872 | A polymorphism in the CYP17 gene and risk of prostate cancer. | Steroid hormones are important in the etiology and progression of prostate cancer, and expression of genes involved in hormone production may alter susceptibility. One such gene is CYP17, which encodes the cytochrome P450c17a enzyme responsible for the biosynthesis of testosterone. A T to C transition (A2 allele) in the 5' promoter region of the gene is hypothesized to increase the rate of gene transcription, increase androgen production, and thereby increase risk of prostate cancer. To test this hypothesis, germ-line DNA samples from a large population-based study of incident prostate cancer cases (n = 590) and controls (n = 538) of similar age without the disease were genotyped. The frequency of the A2 allele was similar in cases and controls. Compared with men with the A1/A1 genotype, the adjusted odds ratio was 0.81 for the A1/A2 and 0.87 for the A2/A2 genotype. Risk estimates did not vary substantially by age or race. However, stratification by family history of prostate cancer revealed that among white men with an affected first-degree relative, homozygotes for the A2 allele had a significant elevation in risk (odds ratio = 19.2; 95% confidence interval, 2.2-157.4) compared with men who were homozygous for the A1 allele (interaction P = 0.0005). These results suggest that the CYP17 A2/A2 genotype predicts susceptibility to prostate cancer in white men with a family history of the disease. It is also possible that CYP17 interacts with other genes that influence risk of familial prostate cancer. | A polymorphism in the CYP17 gene and risk of /"prostate cancer"/. | Steroid hormones are important in the etiology and progression of /"prostate cancer"/, and expression of genes involved in hormone production may alter susceptibility. One such gene is CYP17, which encodes the cytochrome P450c17a enzyme responsible for the biosynthesis of testosterone. A T to C transition (A2 allele) in the 5' promoter region of the gene is hypothesized to increase the rate of gene transcription, increase androgen production, and thereby increase risk of /"prostate cancer"/. To test this hypothesis, germ-line DNA samples from a large population-based study of incident /"prostate cancer"/ cases (n = 590) and controls (n = 538) of similar age without the disease were genotyped. The frequency of the A2 allele was similar in cases and controls. Compared with men with the A1/A1 genotype, the adjusted odds ratio was 0.81 for the /"A1/A2 and 0"/.87 for the A2/A2 genotype. Risk estimates did not vary substantially by age or race. However, stratification by family history of /"prostate cancer"/ revealed that among white men with an affected first-degree relative, homozygotes for the A2 allele had a significant elevation in risk (odds ratio = 19.2; 95% confidence interval, 2.2-157.4) compared with men who were homozygous for the A1 allele (interaction P = 0.0005). These results suggest that the CYP17 A2/A2 genotype predicts susceptibility to /"prostate cancer"/ in white men with a family history of the disease. It is also possible that CYP17 interacts with other genes that influence risk of /"familial prostate cancer"/. | [
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11930987 | Physical activity does not mitigate G-protein-related genetic risk for obesity in individuals of African descent. | The G-protein beta3 subunit 825 TT genotype has been associated with obesity and hypertension. We examined the interaction between the G-protein TT genotype, physical activity and body mass index (BMI) in a cross-sectional study of African immigrants and African Americans. The genotype frequencies were 6.3% CC, 37.7% CT, and 56% TT. After adjusting for potential confounders, BMI was found to be significantly higher in the sedentary than in the physically active participants (p=0.045). There was no statistically significant effect for genotype (p=0.215) or the interaction between genotype and the level of physical activity (p=0.219). However, the individuals with the CC or CT genotype who were physically active had substantially lower BMIs (M+/-SE) (i.e., 25.74+/-2.02) than any of the other groups: sedentary CC + CT (30.58+/-1.03), sedentary TT (30.65+/-1.00) or active TT (29.43+/-1.65). Because of the low statistical power of this study, further research is needed to confirm these findings and to explore potential gene-environment/lifestyle interactions. | Physical activity does not mitigate G-protein-related genetic risk for /"obesity"/ in individuals of African descent. | The /"G-protein beta3"/ subunit 825 TT genotype has been associated with /"obesity"/ and hypertension. We examined the interaction between the G-protein TT genotype, physical activity and body mass index (BMI) in a cross-sectional study of African immigrants and African Americans. The genotype frequencies were 6.3% CC, 37.7% CT, and 56% TT. After adjusting for potential confounders, BMI was found to be significantly higher in the sedentary than in the physically active participants (p=0.045). There was no statistically significant effect for genotype (p=0.215) or the interaction between genotype and the level of physical activity (p=0.219). However, the individuals with the CC or CT genotype who were physically active had substantially lower BMIs (M+/-SE) (i.e., 25.74+/-2.02) than any of the other groups: sedentary CC + CT (30.58+/-1.03), sedentary TT (30.65+/-1.00) or active TT (29.43+/-1.65). Because of the low statistical power of this study, further research is needed to confirm these findings and to explore potential gene-environment/lifestyle interactions. | [
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11930987 | Physical activity does not mitigate G-protein-related genetic risk for obesity in individuals of African descent. | The G-protein beta3 subunit 825 TT genotype has been associated with obesity and hypertension. We examined the interaction between the G-protein TT genotype, physical activity and body mass index (BMI) in a cross-sectional study of African immigrants and African Americans. The genotype frequencies were 6.3% CC, 37.7% CT, and 56% TT. After adjusting for potential confounders, BMI was found to be significantly higher in the sedentary than in the physically active participants (p=0.045). There was no statistically significant effect for genotype (p=0.215) or the interaction between genotype and the level of physical activity (p=0.219). However, the individuals with the CC or CT genotype who were physically active had substantially lower BMIs (M+/-SE) (i.e., 25.74+/-2.02) than any of the other groups: sedentary CC + CT (30.58+/-1.03), sedentary TT (30.65+/-1.00) or active TT (29.43+/-1.65). Because of the low statistical power of this study, further research is needed to confirm these findings and to explore potential gene-environment/lifestyle interactions. | Physical activity does not mitigate G-protein-related genetic risk for obesity in individuals of African descent. | The /"G-protein beta3"/ subunit 825 TT genotype has been associated with obesity and /"hypertension"/. We examined the interaction between the G-protein TT genotype, physical activity and body mass index (BMI) in a cross-sectional study of African immigrants and African Americans. The genotype frequencies were 6.3% CC, 37.7% CT, and 56% TT. After adjusting for potential confounders, BMI was found to be significantly higher in the sedentary than in the physically active participants (p=0.045). There was no statistically significant effect for genotype (p=0.215) or the interaction between genotype and the level of physical activity (p=0.219). However, the individuals with the CC or CT genotype who were physically active had substantially lower BMIs (M+/-SE) (i.e., 25.74+/-2.02) than any of the other groups: sedentary CC + CT (30.58+/-1.03), sedentary TT (30.65+/-1.00) or active TT (29.43+/-1.65). Because of the low statistical power of this study, further research is needed to confirm these findings and to explore potential gene-environment/lifestyle interactions. | [
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11933203 | An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus. | Osteopontin (SPP1) is a soluble ligand with pleomorphic immunologic activities including activation of macrophage chemotaxis, promotion of Th1 responses, and activation of B1 B cells. It has been implicated in the development of murine lupus and is overexpressed in humans with systemic lupus erythematosus (SLE). We examined a polymorphism of osteopontin for an association with lupus in humans in an effort to determine whether there is any evidence that a genetic predisposition to altered osteopontin expression might explain the overexpression seen in human SLE patients. A silent polymorphism (707C>T, rs1126616) of osteopontin was significantly associated with SLE. Additional associations with renal disease and opportunisitic infections were suggested. This is the first phenotypic association with a polymorphic variant of osteopontin. | An /"osteopontin"/ (/"SPP1"/) polymorphism is associated with /"systemic lupus erythematosus"/. | /"Osteopontin"/ (/"SPP1"/) is a soluble ligand with pleomorphic immunologic activities including activation of macrophage chemotaxis, promotion of Th1 responses, and activation of B1 B cells. It has been implicated in the development of murine lupus and is overexpressed in humans with /"systemic lupus erythematosus"/ (/"SLE"/). We examined a polymorphism of /"osteopontin"/ for an association with lupus in humans in an effort to determine whether there is any evidence that a genetic predisposition to altered /"osteopontin"/ expression might explain the overexpression seen in human /"SLE"/ patients. A silent polymorphism (707C>T, rs1126616) of /"osteopontin"/ was significantly associated with /"SLE"/. Additional associations with renal disease and opportunisitic infections were suggested. This is the first phenotypic association with a polymorphic variant of /"osteopontin"/. | [
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11933203 | An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus. | Osteopontin (SPP1) is a soluble ligand with pleomorphic immunologic activities including activation of macrophage chemotaxis, promotion of Th1 responses, and activation of B1 B cells. It has been implicated in the development of murine lupus and is overexpressed in humans with systemic lupus erythematosus (SLE). We examined a polymorphism of osteopontin for an association with lupus in humans in an effort to determine whether there is any evidence that a genetic predisposition to altered osteopontin expression might explain the overexpression seen in human SLE patients. A silent polymorphism (707C>T, rs1126616) of osteopontin was significantly associated with SLE. Additional associations with renal disease and opportunisitic infections were suggested. This is the first phenotypic association with a polymorphic variant of osteopontin. | An osteopontin (SPP1) polymorphism is associated with /"systemic lupus erythematosus"/. | Osteopontin (SPP1) is a soluble ligand with pleomorphic immunologic activities including activation of macrophage chemotaxis, promotion of /"Th1"/ responses, and activation of B1 B cells. It has been implicated in the development of murine lupus and is overexpressed in humans with /"systemic lupus erythematosus"/ (/"SLE"/). We examined a polymorphism of osteopontin for an association with lupus in humans in an effort to determine whether there is any evidence that a genetic predisposition to altered osteopontin expression might explain the overexpression seen in human /"SLE"/ patients. A silent polymorphism (707C>T, rs1126616) of osteopontin was significantly associated with /"SLE"/. Additional associations with renal disease and opportunisitic infections were suggested. This is the first phenotypic association with a polymorphic variant of osteopontin. | [
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11935341 | Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. | Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an inherited neurologic disorder with macrocephaly before the age of one and slowly progressive deterioration of motor functions. Magnetic resonance imaging shows diffusely abnormal and swollen white matter of the cerebral hemispheres and the presence of subcortical cysts in the anterior-temporal region and often also in the frontoparietal region. Mutations in the MLC1 gene, encoding a putative membrane protein, have been recently identified as a cause for MLC. Here, we describe 14 new mutations in 18 patients. Two identified polymorphisms lead to alterations of amino acid residues. The role, suggested by others, of a mutation in the MLC1gene in catatonic schizophrenia and the possible function of the MLC1 protein as a cation channel are discussed. | Identification of novel mutations in /"MLC1"/ responsible for /"Megalencephalic leukoencephalopathy with subcortical cysts"/. | /"Megalencephalic leukoencephalopathy with subcortical cysts"/ (/"MLC"/LC"/) is an inherited neurologic disorder with macrocephaly before the age of one and slowly progressive deterioration of motor functions. Magnetic resonance imaging shows diffusely abnormal and swollen white matter of the cerebral hemispheres and the presence of subcortical cysts in the anterior-temporal region and often also in the frontoparietal region. Mutations in the /"MLC1"/ gene, encoding a putative membrane protein, have been recently identified as a cause for /"MLC"/LC"/. Here, we describe 14 new mutations in 18 patients. Two identified polymorphisms lead to alterations of amino acid residues. The role, suggested by others, of a mutation in the /"MLC1"/gene in catatonic schizophrenia and the possible function of the /"MLC1"/ protein as a cation channel are discussed. | [
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11935341 | Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. | Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an inherited neurologic disorder with macrocephaly before the age of one and slowly progressive deterioration of motor functions. Magnetic resonance imaging shows diffusely abnormal and swollen white matter of the cerebral hemispheres and the presence of subcortical cysts in the anterior-temporal region and often also in the frontoparietal region. Mutations in the MLC1 gene, encoding a putative membrane protein, have been recently identified as a cause for MLC. Here, we describe 14 new mutations in 18 patients. Two identified polymorphisms lead to alterations of amino acid residues. The role, suggested by others, of a mutation in the MLC1gene in catatonic schizophrenia and the possible function of the MLC1 protein as a cation channel are discussed. | Identification of novel mutations in /"MLC1"/ responsible for megalencephalic leukoencephalopathy with subcortical cysts. | Megalencephalic leukoencephalopathy with subcortical cysts (/"MLC"/) is an inherited /"neurologic disorder"/ with macrocephaly before the age of one and slowly progressive deterioration of motor functions. Magnetic resonance imaging shows diffusely abnormal and swollen white matter of the cerebral hemispheres and the presence of subcortical cysts in the anterior-temporal region and often also in the frontoparietal region. Mutations in the /"MLC1"/ gene, encoding a putative membrane protein, have been recently identified as a cause for /"MLC"/. Here, we describe 14 new mutations in 18 patients. Two identified polymorphisms lead to alterations of amino acid residues. The role, suggested by others, of a mutation in the /"MLC1"/gene in catatonic schizophrenia and the possible function of the /"MLC1"/ protein as a cation channel are discussed. | [
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} | No |
11939812 | Is the loose anagen hair syndrome a keratin disorder? A clinical and molecular study. | OBJECTIVES: To report the clinical features of the loose anagen hair syndrome and to test the hypothesis that the typical gap between the hair and the inner root sheath may result from hereditary defects in the inner root sheath or the apposed companion layer. DESIGN: Case series. SETTING: A pediatric dermatology unit (referral center). PATIENTS: A consecutive sample of 17 children (13 girls). For 9 of them and their first-degree relatives, molecular analyses were performed in the K6HF gene with 50 appropriate controls. INTERVENTION: Minoxidil therapy (5% lotion) in 11 patients for 1 to 12 months. MAIN OUTCOME MEASURES: Clinical and follow-up features and determination of mutations in the K6HF gene. RESULTS: Most patients had easily pluckable hair with no sign of scalp inflammation or scarring. Ten patients seldom cut their hair, and 4 had unmanageable hair. One patient had hypodontia. Two patients had an additional clinical phenotype of diffuse partial woolly hair. The family history was positive for loose anagen hair syndrome in 5 patients. Marked improvement was noted after treatment with 5% minoxidil lotion in 7 of the 11 patients treated. Polymerase chain reaction analysis of the gene segments encoding the alpha-helical 1A and 2B subdomains of K6hf, the type II cytokeratin exclusively expressed in the companion layer, was performed in 9 families. In 3 of these 9 families, a heterozygous glutamic acid and lysine mutation, E337K, was identified in the L2 linker region of K6HF. CONCLUSIONS: Diffuse partial woolly hair can be associated with loose anagen hair syndrome. A keratin mutation, E337K in K6HF, was possibly causative in 3 of the 9 families studied. Another keratin, and possibly the type I partner of K6hf, could be responsible for loose anagen hair syndrome in other patients, or the gene involved may be a minor gene. | Is the /"loose anagen hair syndrome"/ a keratin disorder? A clinical and molecular study. | OBJECTIVES: To report the clinical features of the /"loose anagen hair syndrome"/ and to test the hypothesis that the typical gap between the hair and the inner root sheath may result from hereditary defects in the inner root sheath or the apposed companion layer. DESIGN: Case series. SETTING: A pediatric dermatology unit (referral center). PATIENTS: A consecutive sample of 17 children (13 girls). For 9 of them and their first-degree relatives, molecular analyses were performed in the /"K6HF"/ gene with 50 appropriate controls. INTERVENTION: Minoxidil therapy (5% lotion) in 11 patients for 1 to 12 months. MAIN OUTCOME MEASURES: Clinical and follow-up features and determination of mutations in the /"K6HF"/ gene. RESULTS: Most patients had easily pluckable hair with no sign of scalp inflammation or scarring. Ten patients seldom cut their hair, and 4 had unmanageable hair. One patient had hypodontia. Two patients had an additional clinical phenotype of diffuse partial woolly hair. The family history was positive for /"loose anagen hair syndrome"/ in 5 patients. Marked improvement was noted after treatment with 5% minoxidil lotion in 7 of the 11 patients treated. Polymerase chain reaction analysis of the gene segments encoding the alpha-helical 1A and 2B subdomains of /"K6hf"/, the type II cytokeratin exclusively expressed in the companion layer, was performed in 9 families. In 3 of these 9 families, a heterozygous glutamic acid and lysine mutation, E337K, was identified in the L2 linker region of /"K6HF"/. CONCLUSIONS: Diffuse partial woolly hair can be associated with /"loose anagen hair syndrome"/. A keratin mutation, E337K in /"K6HF"/, was possibly causative in 3 of the 9 families studied. Another keratin, and possibly the type I partner of /"K6hf"/, could be responsible for /"loose anagen hair syndrome"/ in other patients, or the gene involved may be a minor gene. | [
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11939812 | Is the loose anagen hair syndrome a keratin disorder? A clinical and molecular study. | OBJECTIVES: To report the clinical features of the loose anagen hair syndrome and to test the hypothesis that the typical gap between the hair and the inner root sheath may result from hereditary defects in the inner root sheath or the apposed companion layer. DESIGN: Case series. SETTING: A pediatric dermatology unit (referral center). PATIENTS: A consecutive sample of 17 children (13 girls). For 9 of them and their first-degree relatives, molecular analyses were performed in the K6HF gene with 50 appropriate controls. INTERVENTION: Minoxidil therapy (5% lotion) in 11 patients for 1 to 12 months. MAIN OUTCOME MEASURES: Clinical and follow-up features and determination of mutations in the K6HF gene. RESULTS: Most patients had easily pluckable hair with no sign of scalp inflammation or scarring. Ten patients seldom cut their hair, and 4 had unmanageable hair. One patient had hypodontia. Two patients had an additional clinical phenotype of diffuse partial woolly hair. The family history was positive for loose anagen hair syndrome in 5 patients. Marked improvement was noted after treatment with 5% minoxidil lotion in 7 of the 11 patients treated. Polymerase chain reaction analysis of the gene segments encoding the alpha-helical 1A and 2B subdomains of K6hf, the type II cytokeratin exclusively expressed in the companion layer, was performed in 9 families. In 3 of these 9 families, a heterozygous glutamic acid and lysine mutation, E337K, was identified in the L2 linker region of K6HF. CONCLUSIONS: Diffuse partial woolly hair can be associated with loose anagen hair syndrome. A keratin mutation, E337K in K6HF, was possibly causative in 3 of the 9 families studied. Another keratin, and possibly the type I partner of K6hf, could be responsible for loose anagen hair syndrome in other patients, or the gene involved may be a minor gene. | Is the loose anagen hair syndrome a /"keratin disorder"/? A clinical and molecular study. | OBJECTIVES: To report the clinical features of the loose anagen hair syndrome and to test the hypothesis that the typical gap between the hair and the inner root sheath may result from /"hereditary defects"/ in the inner root sheath or the apposed companion layer. DESIGN: Case series. SETTING: A pediatric dermatology unit (referral center). PATIENTS: A consecutive sample of 17 children (13 girls). For 9 of them and their first-degree relatives, molecular analyses were performed in the /"K6HF"/ gene with 50 appropriate controls. INTERVENTION: Minoxidil therapy (5% lotion) in 11 patients for 1 to 12 months. MAIN OUTCOME MEASURES: Clinical and follow-up features and determination of mutations in the /"K6HF"/ gene. RESULTS: Most patients had easily pluckable hair with no sign of scalp inflammation or scarring. Ten patients seldom cut their hair, and 4 had unmanageable hair. One patient had hypodontia. Two patients had an additional clinical phenotype of diffuse partial woolly hair. The family history was positive for loose anagen hair syndrome in 5 patients. Marked improvement was noted after treatment with 5% minoxidil lotion in 7 of the 11 patients treated. Polymerase chain reaction analysis of the gene segments encoding the alpha-helical 1A and 2B subdomains of /"K6hf"/, the type II cytokeratin exclusively expressed in the companion layer, was performed in 9 families. In 3 of these 9 families, a heterozygous glutamic acid and lysine mutation, E337K, was identified in the L2 linker region of /"K6HF"/. CONCLUSIONS: Diffuse partial woolly hair can be associated with loose anagen hair syndrome. A keratin mutation, E337K in /"K6HF"/, was possibly causative in 3 of the 9 families studied. Another keratin, and possibly the type I partner of /"K6hf"/, could be responsible for loose anagen hair syndrome in other patients, or the gene involved may be a minor gene. | [
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11942593 | Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. | INTRODUCTION: Sympathetic activation is a trigger for life-threatening arrhythmias in many patients with the congenital long QT syndrome (LQTS), and an increase in heart rate has been reported just prior to torsades de pointes in patients with drug-associated (acquired) LQTS (aLQTS). We compared the frequencies of five recognized nonsynonymous coding region polymorphisms in genes encoding the beta1-adrenergic and beta2-adrenergic receptors (AR) in 93 patients with aLQTS and 3 control groups: an ethically diverse set of individuals from middle Tennessee (n = 71), a subset of the Polymorphism Discovery Resource obtained from National Human Genome Research Institute (n = 89), and patients who tolerated QT-prolonging drugs without aLQTS (non-aLQTS group; n = 66). METHODS AND RESULTS: Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly and Gly389Arg (beta1-AR) and Thr164Ile (beta2-AR). For Arg16Gly and Gln27Glu, polymorphic sites 33 nucleotides apart in the beta2-AR, single-stranded conformational polymorphism was used to distinguish among the 4 possible haplotypes and 10 possible genotypes. Allele frequencies were similar among the 4 groups at the 2 beta1-AR sites. The uncommon Ile164 variant in beta2-AR was slightly more frequent in patients (3.2%) than in any of the 3 control groups (0.6% to 2.3%). At the 16-27 neighboring sites in the beta2-AR, one haplotype (Arg16/Glu27) was not detected, as in previous studies; hence, only 6 genotypes were present. There were fewer Gly16/Gln27 homozygotes in the non-aLQTS group (1.5%) than in two other control groups or the aLQTS group (8.5% to 10%). CONCLUSION: None of the five common nonsynonymous coding region polymorphisms in the beta-AR genes predict drug-associated torsades de pointes, although the Gly16/Gln27 haplotype may be a risk factor. | Polymorphisms in beta-adrenergic receptor genes in the acquired /"long QT syndrome"/. | INTRODUCTION: Sympathetic activation is a trigger for life-threatening arrhythmias in many patients with the /"congenital long QT syndrome"/ (/"LQTS"/), and an increase in heart rate has been reported just prior to torsades de pointes in patients with drug-associated (acquired) /"LQTS"/ (aLQTS). We compared the frequencies of five recognized nonsynonymous coding region polymorphisms in genes encoding the beta1-adrenergic and beta2-adrenergic receptors (AR) in 93 patients with aLQTS and 3 control groups: an ethically diverse set of individuals from middle Tennessee (n = 71), a subset of the Polymorphism Discovery Resource obtained from National Human Genome Research Institute (n = 89), and patients who tolerated QT-prolonging drugs without aLQTS (non-aLQTS group; n = 66). METHODS AND RESULTS: Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly and Gly389Arg (/"beta1-AR"/) and Thr164Ile (beta2-AR). For Arg16Gly and Gln27Glu, polymorphic sites 33 nucleotides apart in the beta2-AR, single-stranded conformational polymorphism was used to distinguish among the 4 possible haplotypes and 10 possible genotypes. Allele frequencies were similar among the 4 groups at the 2 /"beta1-AR"/ sites. The uncommon Ile164 variant in beta2-AR was slightly more frequent in patients (3.2%) than in any of the 3 control groups (0.6% to 2.3%). At the 16-27 neighboring sites in the beta2-AR, one haplotype (Arg16/Glu27) was not detected, as in previous studies; hence, only 6 genotypes were present. There were fewer Gly16/Gln27 homozygotes in the non-aLQTS group (1.5%) than in two other control groups or the aLQTS group (8.5% to 10%). CONCLUSION: None of the five common nonsynonymous coding region polymorphisms in the beta-AR genes predict drug-associated torsades de pointes, although the Gly16/Gln27 haplotype may be a risk factor. | [
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11942593 | Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. | INTRODUCTION: Sympathetic activation is a trigger for life-threatening arrhythmias in many patients with the congenital long QT syndrome (LQTS), and an increase in heart rate has been reported just prior to torsades de pointes in patients with drug-associated (acquired) LQTS (aLQTS). We compared the frequencies of five recognized nonsynonymous coding region polymorphisms in genes encoding the beta1-adrenergic and beta2-adrenergic receptors (AR) in 93 patients with aLQTS and 3 control groups: an ethically diverse set of individuals from middle Tennessee (n = 71), a subset of the Polymorphism Discovery Resource obtained from National Human Genome Research Institute (n = 89), and patients who tolerated QT-prolonging drugs without aLQTS (non-aLQTS group; n = 66). METHODS AND RESULTS: Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly and Gly389Arg (beta1-AR) and Thr164Ile (beta2-AR). For Arg16Gly and Gln27Glu, polymorphic sites 33 nucleotides apart in the beta2-AR, single-stranded conformational polymorphism was used to distinguish among the 4 possible haplotypes and 10 possible genotypes. Allele frequencies were similar among the 4 groups at the 2 beta1-AR sites. The uncommon Ile164 variant in beta2-AR was slightly more frequent in patients (3.2%) than in any of the 3 control groups (0.6% to 2.3%). At the 16-27 neighboring sites in the beta2-AR, one haplotype (Arg16/Glu27) was not detected, as in previous studies; hence, only 6 genotypes were present. There were fewer Gly16/Gln27 homozygotes in the non-aLQTS group (1.5%) than in two other control groups or the aLQTS group (8.5% to 10%). CONCLUSION: None of the five common nonsynonymous coding region polymorphisms in the beta-AR genes predict drug-associated torsades de pointes, although the Gly16/Gln27 haplotype may be a risk factor. | Polymorphisms in beta-adrenergic receptor genes in the acquired /"long QT syndrome"/. | INTRODUCTION: Sympathetic activation is a trigger for life-threatening arrhythmias in many patients with the /"congenital long QT syndrome"/ (/"LQTS"/), and an increase in heart rate has been reported just prior to torsades de pointes in patients with drug-associated (acquired) /"LQTS"/ (aLQTS). We compared the frequencies of five recognized nonsynonymous coding region polymorphisms in genes encoding the beta1-adrenergic and beta2-adrenergic receptors (AR) in 93 patients with aLQTS and 3 control groups: an ethically diverse set of individuals from middle Tennessee (n = 71), a subset of the Polymorphism Discovery Resource obtained from National Human Genome Research Institute (n = 89), and patients who tolerated QT-prolonging drugs without aLQTS (non-aLQTS group; n = 66). METHODS AND RESULTS: Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly and Gly389Arg (beta1-AR) and Thr164Ile (/"beta2-AR"/). For Arg16Gly and Gln27Glu, polymorphic sites 33 nucleotides apart in the /"beta2-AR"/, single-stranded conformational polymorphism was used to distinguish among the 4 possible haplotypes and 10 possible genotypes. Allele frequencies were similar among the 4 groups at the 2 beta1-AR sites. The uncommon Ile164 variant in /"beta2-AR"/ was slightly more frequent in patients (3.2%) than in any of the 3 control groups (0.6% to 2.3%). At the 16-27 neighboring sites in the /"beta2-AR"/, one haplotype (Arg16/Glu27) was not detected, as in previous studies; hence, only 6 genotypes were present. There were fewer Gly16/Gln27 homozygotes in the non-aLQTS group (1.5%) than in two other control groups or the aLQTS group (8.5% to 10%). CONCLUSION: None of the five common nonsynonymous coding region polymorphisms in the beta-AR genes predict drug-associated torsades de pointes, although the Gly16/Gln27 haplotype may be a risk factor. | [
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11942593 | Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. | INTRODUCTION: Sympathetic activation is a trigger for life-threatening arrhythmias in many patients with the congenital long QT syndrome (LQTS), and an increase in heart rate has been reported just prior to torsades de pointes in patients with drug-associated (acquired) LQTS (aLQTS). We compared the frequencies of five recognized nonsynonymous coding region polymorphisms in genes encoding the beta1-adrenergic and beta2-adrenergic receptors (AR) in 93 patients with aLQTS and 3 control groups: an ethically diverse set of individuals from middle Tennessee (n = 71), a subset of the Polymorphism Discovery Resource obtained from National Human Genome Research Institute (n = 89), and patients who tolerated QT-prolonging drugs without aLQTS (non-aLQTS group; n = 66). METHODS AND RESULTS: Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly and Gly389Arg (beta1-AR) and Thr164Ile (beta2-AR). For Arg16Gly and Gln27Glu, polymorphic sites 33 nucleotides apart in the beta2-AR, single-stranded conformational polymorphism was used to distinguish among the 4 possible haplotypes and 10 possible genotypes. Allele frequencies were similar among the 4 groups at the 2 beta1-AR sites. The uncommon Ile164 variant in beta2-AR was slightly more frequent in patients (3.2%) than in any of the 3 control groups (0.6% to 2.3%). At the 16-27 neighboring sites in the beta2-AR, one haplotype (Arg16/Glu27) was not detected, as in previous studies; hence, only 6 genotypes were present. There were fewer Gly16/Gln27 homozygotes in the non-aLQTS group (1.5%) than in two other control groups or the aLQTS group (8.5% to 10%). CONCLUSION: None of the five common nonsynonymous coding region polymorphisms in the beta-AR genes predict drug-associated torsades de pointes, although the Gly16/Gln27 haplotype may be a risk factor. | Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. | INTRODUCTION: Sympathetic activation is a trigger for life-threatening arrhythmias in many patients with the congenital long QT syndrome (LQTS), and an increase in heart rate has been reported just prior to /"torsades de pointes"/ in patients with drug-associated (acquired) LQTS (aLQTS). We compared the frequencies of five recognized nonsynonymous coding region polymorphisms in genes encoding the beta1-adrenergic and beta2-adrenergic receptors (AR) in 93 patients with aLQTS and 3 control groups: an ethically diverse set of individuals from middle Tennessee (n = 71), a subset of the Polymorphism Discovery Resource obtained from National Human Genome Research Institute (n = 89), and patients who tolerated QT-prolonging drugs without aLQTS (non-aLQTS group; n = 66). METHODS AND RESULTS: Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly and Gly389Arg (beta1-AR) and Thr164Ile (/"beta2-AR"/). For Arg16Gly and Gln27Glu, polymorphic sites 33 nucleotides apart in the /"beta2-AR"/, single-stranded conformational polymorphism was used to distinguish among the 4 possible haplotypes and 10 possible genotypes. Allele frequencies were similar among the 4 groups at the 2 beta1-AR sites. The uncommon Ile164 variant in /"beta2-AR"/ was slightly more frequent in patients (3.2%) than in any of the 3 control groups (0.6% to 2.3%). At the 16-27 neighboring sites in the /"beta2-AR"/, one haplotype (Arg16/Glu27) was not detected, as in previous studies; hence, only 6 genotypes were present. There were fewer Gly16/Gln27 homozygotes in the non-aLQTS group (1.5%) than in two other control groups or the aLQTS group (8.5% to 10%). CONCLUSION: None of the five common nonsynonymous coding region polymorphisms in the beta-AR genes predict drug-associated /"torsades de pointes"/, although the Gly16/Gln27 haplotype may be a risk factor. | [
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11942593 | Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. | INTRODUCTION: Sympathetic activation is a trigger for life-threatening arrhythmias in many patients with the congenital long QT syndrome (LQTS), and an increase in heart rate has been reported just prior to torsades de pointes in patients with drug-associated (acquired) LQTS (aLQTS). We compared the frequencies of five recognized nonsynonymous coding region polymorphisms in genes encoding the beta1-adrenergic and beta2-adrenergic receptors (AR) in 93 patients with aLQTS and 3 control groups: an ethically diverse set of individuals from middle Tennessee (n = 71), a subset of the Polymorphism Discovery Resource obtained from National Human Genome Research Institute (n = 89), and patients who tolerated QT-prolonging drugs without aLQTS (non-aLQTS group; n = 66). METHODS AND RESULTS: Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly and Gly389Arg (beta1-AR) and Thr164Ile (beta2-AR). For Arg16Gly and Gln27Glu, polymorphic sites 33 nucleotides apart in the beta2-AR, single-stranded conformational polymorphism was used to distinguish among the 4 possible haplotypes and 10 possible genotypes. Allele frequencies were similar among the 4 groups at the 2 beta1-AR sites. The uncommon Ile164 variant in beta2-AR was slightly more frequent in patients (3.2%) than in any of the 3 control groups (0.6% to 2.3%). At the 16-27 neighboring sites in the beta2-AR, one haplotype (Arg16/Glu27) was not detected, as in previous studies; hence, only 6 genotypes were present. There were fewer Gly16/Gln27 homozygotes in the non-aLQTS group (1.5%) than in two other control groups or the aLQTS group (8.5% to 10%). CONCLUSION: None of the five common nonsynonymous coding region polymorphisms in the beta-AR genes predict drug-associated torsades de pointes, although the Gly16/Gln27 haplotype may be a risk factor. | Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. | INTRODUCTION: Sympathetic activation is a trigger for life-threatening /"arrhythmias"/ in many patients with the congenital long QT syndrome (LQTS), and an increase in heart rate has been reported just prior to torsades de pointes in patients with drug-associated (acquired) LQTS (aLQTS). We compared the frequencies of five recognized nonsynonymous coding region polymorphisms in genes encoding the beta1-adrenergic and beta2-adrenergic receptors (AR) in 93 patients with aLQTS and 3 control groups: an ethically diverse set of individuals from middle Tennessee (n = 71), a subset of the Polymorphism Discovery Resource obtained from National Human Genome Research Institute (n = 89), and patients who tolerated QT-prolonging drugs without aLQTS (non-aLQTS group; n = 66). METHODS AND RESULTS: Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly and Gly389Arg (beta1-AR) and Thr164Ile (/"beta2-AR"/). For Arg16Gly and Gln27Glu, polymorphic sites 33 nucleotides apart in the /"beta2-AR"/, single-stranded conformational polymorphism was used to distinguish among the 4 possible haplotypes and 10 possible genotypes. Allele frequencies were similar among the 4 groups at the 2 beta1-AR sites. The uncommon Ile164 variant in /"beta2-AR"/ was slightly more frequent in patients (3.2%) than in any of the 3 control groups (0.6% to 2.3%). At the 16-27 neighboring sites in the /"beta2-AR"/, one haplotype (Arg16/Glu27) was not detected, as in previous studies; hence, only 6 genotypes were present. There were fewer Gly16/Gln27 homozygotes in the non-aLQTS group (1.5%) than in two other control groups or the aLQTS group (8.5% to 10%). CONCLUSION: None of the five common nonsynonymous coding region polymorphisms in the beta-AR genes predict drug-associated torsades de pointes, although the Gly16/Gln27 haplotype may be a risk factor. | [
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11948460 | Germline mutations in E-cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer. | Somatic mutations in the E-cadherin (CDH1) gene have frequently been reported in cases with diffuse gastric and lobular breast cancers. Recently, germline mutations have been identified in families with diffuse gastric cancers. In families with hereditary prostate cancer (HPC), a significant association of prostate cancer, gastric and/or breast cancer has been observed in epidemiological studies. The aim of this study was to investigate if germline mutations in CDH1 could explain the risk for cancer in HPC families with an excess of gastric and breast cancer. In total, 17 members from 13 HPC families and 3 members from 3 families with hereditary gastric cancer (HGC) were screened for germline CDH1 sequence alterations using PCR/Denaturing HPLC for initial screening of nucleotide variants followed by confirmatory direct sequencing analysis. The frequency of identified novel germline mutations were tested for in 136 cases with hereditary prostate cancer and 215 cases of sporadic prostate cancer with 422 age matched controls in an allelic discrimination assay. In total, 8 sequence variants were detected in 20 samples tested. In the HPC families, we found 2 missense mutations, A592T in exon 12 and a novel D777N in exon 15 and a mutation in intron 5, 687+92T>A. A previously known polymorphism in exon 13 and 3 sequence variations in introns and untranslated regions were also found, of which the significance is unknown. In HGC-023 with early onset diffuse gastric cancer a truncating mutation, R335X, was identified in exon 7. None of the missense mutations or 687+92T>A were found in the extended HPC material or in the sporadic prostate cancer cases with age-matched controls in the allelic discrimination assay. We found several germline mutations of unknown clinical significance in the CDH1 gene that probably do not explain the association of prostate, gastric and/or breast cancers in the HPC-families. Two missense mutations and a mutation in intron 5 were identified that do not influence the risk of hereditary or sporadic prostate cancer in general and are considered to be pedigree specific. In a family with hereditary gastric cancer of the diffuse type, we identified the first truncating germline mutation in a Scandinavian family. | Germline mutations in /"E-cadherin"/ do not explain association of /"hereditary prostate cancer"/, gastric cancer and breast cancer. | Somatic mutations in the /"E-cadherin"/ (/"CDH1"/) gene have frequently been reported in cases with diffuse gastric and lobular breast cancers. Recently, germline mutations have been identified in families with diffuse gastric cancers. In families with /"hereditary prostate cancer"/ (/"HPC"/), a significant association of /"prostate cancer"/, gastric and/or breast cancer has been observed in epidemiological studies. The aim of this study was to investigate if germline mutations in /"CDH1"/ could explain the risk for cancer in /"HPC"/ families with an excess of gastric and breast cancer. In total, 17 members from 13 /"HPC"/ families and 3 members from 3 families with hereditary gastric cancer (HGC) were screened for germline /"CDH1"/ sequence alterations using PCR/Denaturing HPLC for initial screening of nucleotide variants followed by confirmatory direct sequencing analysis. The frequency of identified novel germline mutations were tested for in 136 cases with /"hereditary prostate cancer"/ and 215 cases of /"sporadic prostate cancer"/ with 422 age matched controls in an allelic discrimination assay. In total, 8 sequence variants were detected in 20 samples tested. In the /"HPC"/ families, we found 2 missense mutations, A592T in exon 12 and a novel D777N in exon 15 and a mutation in intron 5, 687+92T>A. A previously known polymorphism in exon 13 and 3 sequence variations in introns and untranslated regions were also found, of which the significance is unknown. In HGC-023 with early onset diffuse gastric cancer a truncating mutation, R335X, was identified in exon 7. None of the missense mutations or 687+92T>A were found in the extended /"HPC"/ material or in the /"sporadic prostate cancer"/ cases with age-matched controls in the allelic discrimination assay. We found several germline mutations of unknown clinical significance in the /"CDH1"/ gene that probably do not explain the association of prostate, gastric and/or breast cancers in the /"HPC"/-families. Two missense mutations and a mutation in intron 5 were identified that do not influence the risk of /"hereditary or sporadic prostate cancer"/ in general and are considered to be pedigree specific. In a family with hereditary gastric cancer of the diffuse type, we identified the first truncating germline mutation in a Scandinavian family. | [
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11948460 | Germline mutations in E-cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer. | Somatic mutations in the E-cadherin (CDH1) gene have frequently been reported in cases with diffuse gastric and lobular breast cancers. Recently, germline mutations have been identified in families with diffuse gastric cancers. In families with hereditary prostate cancer (HPC), a significant association of prostate cancer, gastric and/or breast cancer has been observed in epidemiological studies. The aim of this study was to investigate if germline mutations in CDH1 could explain the risk for cancer in HPC families with an excess of gastric and breast cancer. In total, 17 members from 13 HPC families and 3 members from 3 families with hereditary gastric cancer (HGC) were screened for germline CDH1 sequence alterations using PCR/Denaturing HPLC for initial screening of nucleotide variants followed by confirmatory direct sequencing analysis. The frequency of identified novel germline mutations were tested for in 136 cases with hereditary prostate cancer and 215 cases of sporadic prostate cancer with 422 age matched controls in an allelic discrimination assay. In total, 8 sequence variants were detected in 20 samples tested. In the HPC families, we found 2 missense mutations, A592T in exon 12 and a novel D777N in exon 15 and a mutation in intron 5, 687+92T>A. A previously known polymorphism in exon 13 and 3 sequence variations in introns and untranslated regions were also found, of which the significance is unknown. In HGC-023 with early onset diffuse gastric cancer a truncating mutation, R335X, was identified in exon 7. None of the missense mutations or 687+92T>A were found in the extended HPC material or in the sporadic prostate cancer cases with age-matched controls in the allelic discrimination assay. We found several germline mutations of unknown clinical significance in the CDH1 gene that probably do not explain the association of prostate, gastric and/or breast cancers in the HPC-families. Two missense mutations and a mutation in intron 5 were identified that do not influence the risk of hereditary or sporadic prostate cancer in general and are considered to be pedigree specific. In a family with hereditary gastric cancer of the diffuse type, we identified the first truncating germline mutation in a Scandinavian family. | Germline mutations in /"E-cadherin"/ do not explain association of hereditary prostate cancer, gastric cancer and /"breast cancer"/. | Somatic mutations in the /"E-cadherin"/ (/"CDH1"/) gene have frequently been reported in cases with diffuse gastric and lobular breast cancers. Recently, germline mutations have been identified in families with diffuse gastric cancers. In families with hereditary prostate cancer (HPC), a significant association of prostate cancer, /"gastric and/or breast cancer"/ has been observed in epidemiological studies. The aim of this study was to investigate if germline mutations in /"CDH1"/ could explain the risk for cancer in HPC families with an excess of /"gastric and breast cancer"/. In total, 17 members from 13 HPC families and 3 members from 3 families with hereditary gastric cancer (HGC) were screened for germline /"CDH1"/ sequence alterations using PCR/Denaturing HPLC for initial screening of nucleotide variants followed by confirmatory direct sequencing analysis. The frequency of identified novel germline mutations were tested for in 136 cases with hereditary prostate cancer and 215 cases of sporadic prostate cancer with 422 age matched controls in an allelic discrimination assay. In total, 8 sequence variants were detected in 20 samples tested. In the HPC families, we found 2 missense mutations, A592T in exon 12 and a novel D777N in exon 15 and a mutation in intron 5, 687+92T>A. A previously known polymorphism in exon 13 and 3 sequence variations in introns and untranslated regions were also found, of which the significance is unknown. In HGC-023 with early onset diffuse gastric cancer a truncating mutation, R335X, was identified in exon 7. None of the missense mutations or 687+92T>A were found in the extended HPC material or in the sporadic prostate cancer cases with age-matched controls in the allelic discrimination assay. We found several germline mutations of unknown clinical significance in the /"CDH1"/ gene that probably do not explain the association of prostate, /"gastric and/or breast cancers"/ in the HPC-families. Two missense mutations and a mutation in intron 5 were identified that do not influence the risk of hereditary or sporadic prostate cancer in general and are considered to be pedigree specific. In a family with hereditary gastric cancer of the diffuse type, we identified the first truncating germline mutation in a Scandinavian family. | [
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11951178 | Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene. | Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) gene are found in approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate modifier gene in FALS with mutations in the SOD-1 gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a modifier gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model. | Early onset of severe /"familial amyotrophic lateral sclerosis"/ with a SOD-1 mutation: potential impact of /"CNTF"/ as a candidate modifier gene. | Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) gene are found in approximately 20% of patients with /"familial amyotrophic lateral sclerosis"/ (/"FALS"/), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from /"FALS"/ after a rapid disease course of 11 mo. Sequencing of the SOD-1 gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the /"CNTF"/ gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with /"CNTF"/(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that /"CNTF"/ acts as a candidate modifier gene in /"FALS"/ with mutations in the SOD-1 gene. Such hSOD-1G93A//"CNTF"/-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A//"CNTF"/-wild-type mice. Linkage analysis revealed that the SOD-1 gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the /"CNTF"/ locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous /"CNTF"/ gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that /"CNTF"/ acts as a modifier gene that leads to early onset of disease in patients with /"FALS"/ who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model. | [
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11951178 | Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene. | Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) gene are found in approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate modifier gene in FALS with mutations in the SOD-1 gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a modifier gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model. | Early onset of severe /"familial amyotrophic lateral sclerosis"/ with a /"SOD-1"/ mutation: potential impact of CNTF as a candidate modifier gene. | Mutations in the copper/zinc superoxide dismutase 1 (/"SOD-1"/) gene are found in approximately 20% of patients with /"familial amyotrophic lateral sclerosis"/ (/"FALS"/), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from /"FALS"/ after a rapid disease course of 11 mo. Sequencing of the /"SOD-1"/ gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate modifier gene in /"FALS"/ with mutations in the /"SOD-1"/ gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the /"SOD-1"/ gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a modifier gene that leads to early onset of disease in patients with /"FALS"/ who have /"SOD-1"/ mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model. | [
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11951178 | Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene. | Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) gene are found in approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate modifier gene in FALS with mutations in the SOD-1 gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a modifier gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model. | Early onset of severe familial amyotrophic lateral sclerosis with a /"SOD-1"/ mutation: potential impact of CNTF as a candidate modifier gene. | Mutations in the copper/zinc superoxide dismutase 1 (/"SOD-1"/) gene are found in approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS), or /"amyotrophic lateral sclerosis"/ 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the /"SOD-1"/ gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate modifier gene in FALS with mutations in the /"SOD-1"/ gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the /"SOD-1"/ gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic /"amyotrophic lateral sclerosis"/ who had a homozygous CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a modifier gene that leads to early onset of disease in patients with FALS who have /"SOD-1"/ mutations, in patients with sporadic /"amyotrophic lateral sclerosis"/, and in the hSOD-1G93A mouse model. | [
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11951178 | Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene. | Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) gene are found in approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate modifier gene in FALS with mutations in the SOD-1 gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a modifier gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model. | Early onset of severe familial amyotrophic lateral sclerosis with a /"SOD-1"/ mutation: potential impact of CNTF as a candidate modifier gene. | Mutations in the copper/zinc superoxide dismutase 1 (/"SOD-1"/) gene are found in approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the /"SOD-1"/ gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate modifier gene in FALS with mutations in the /"SOD-1"/ gene. Such hSOD-1G93A/CNTF-deficient mice develop /"motoneuron disease"/ at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the /"SOD-1"/ gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a modifier gene that leads to early onset of disease in patients with FALS who have /"SOD-1"/ mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model. | [
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} | No |
11976977 | Occurrence of factor V Leiden mutation (Arg506Gln) and anticardiolipin antibodies in migraine patients. | The occurrences of factor V Leiden mutation (Arg506Gln) and antiphospholipid antibodies (APA) in migraine patients have been reported, but the findings are controversial. We investigated the presence of factor V Leiden and the serum level of anticardiolipin antibodies (aCL) in a consecutive series of 70 migraine patients (47 women; mean age, 34.1 years). Of these, 40 patients had migraine with aura. A matched sample of 70 healthy people was considered as the control group. Heterozygous genotype for factor V Leiden mutation was detected in 4 (5.7%) migraine patients (of which 2 had migraine with aura) and in 2 (2.8%) subjects of the control group. Although proportionally more migraine patients harbored the factor V Leiden mutation, this difference was not statistically significant, perhaps due to the small number of patients involved. We found normal serum levels of aCL in all migraine patients. Further studies and a long-term follow-up are warranted to determine the significance of this genetic abnormality in migraine. | Occurrence of /"factor V Leiden"/ mutation (Arg506Gln) and anticardiolipin antibodies in /"migraine"/ patients. | The occurrences of /"factor V Leiden"/ mutation (Arg506Gln) and antiphospholipid antibodies (APA) in /"migraine"/ patients have been reported, but the findings are controversial. We investigated the presence of /"factor V Leiden"/ and the serum level of anticardiolipin antibodies (aCL) in a consecutive series of 70 /"migraine"/ patients (47 women; mean age, 34.1 years). Of these, 40 patients had migraine with aura. A matched sample of 70 healthy people was considered as the control group. Heterozygous genotype for /"factor V Leiden"/ mutation was detected in 4 (5.7%) /"migraine"/ patients (of which 2 had migraine with aura) and in 2 (2.8%) subjects of the control group. Although proportionally more /"migraine"/ patients harbored the /"factor V Leiden"/ mutation, this difference was not statistically significant, perhaps due to the small number of patients involved. We found normal serum levels of aCL in all /"migraine"/ patients. Further studies and a long-term follow-up are warranted to determine the significance of this genetic abnormality in /"migraine"/. | [
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11976977 | Occurrence of factor V Leiden mutation (Arg506Gln) and anticardiolipin antibodies in migraine patients. | The occurrences of factor V Leiden mutation (Arg506Gln) and antiphospholipid antibodies (APA) in migraine patients have been reported, but the findings are controversial. We investigated the presence of factor V Leiden and the serum level of anticardiolipin antibodies (aCL) in a consecutive series of 70 migraine patients (47 women; mean age, 34.1 years). Of these, 40 patients had migraine with aura. A matched sample of 70 healthy people was considered as the control group. Heterozygous genotype for factor V Leiden mutation was detected in 4 (5.7%) migraine patients (of which 2 had migraine with aura) and in 2 (2.8%) subjects of the control group. Although proportionally more migraine patients harbored the factor V Leiden mutation, this difference was not statistically significant, perhaps due to the small number of patients involved. We found normal serum levels of aCL in all migraine patients. Further studies and a long-term follow-up are warranted to determine the significance of this genetic abnormality in migraine. | Occurrence of /"factor V Leiden"/ mutation (Arg506Gln) and anticardiolipin antibodies in migraine patients. | The occurrences of /"factor V Leiden"/ mutation (Arg506Gln) and antiphospholipid antibodies (APA) in migraine patients have been reported, but the findings are controversial. We investigated the presence of /"factor V Leiden"/ and the serum level of anticardiolipin antibodies (aCL) in a consecutive series of 70 migraine patients (47 women; mean age, 34.1 years). Of these, 40 patients had /"migraine with aura"/. A matched sample of 70 healthy people was considered as the control group. Heterozygous genotype for /"factor V Leiden"/ mutation was detected in 4 (5.7%) migraine patients (of which 2 had /"migraine with aura"/) and in 2 (2.8%) subjects of the control group. Although proportionally more migraine patients harbored the /"factor V Leiden"/ mutation, this difference was not statistically significant, perhaps due to the small number of patients involved. We found normal serum levels of aCL in all migraine patients. Further studies and a long-term follow-up are warranted to determine the significance of this genetic abnormality in migraine. | [
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11992567 | Effect of IL-6 polymorphism on risk of Alzheimer disease: genotype-phenotype association study in Japanese cases. | Interleukin-6 (IL-6), an inflammatory cytokine might be involved in the pathophysiology of Alzheimer disease (AD); several studies have reported that the "C allele of IL-6 variable number of tandem repeat polymorphism" (IL-6vntr) delayed initial onset of AD and also decreased its risk per se. Another polymorphism, G/C allele of IL-6 gene promoter region (IL-6prom), is also a candidate because it has an influence on the regulation of plasma IL-6 concentration. We examined these IL-6 polymorphisms in 128 Japanese AD cases and 83 control cases using a PCR-RFLP method. The results showed the frequency of the IL-6prom G allele was significantly increased in AD, although IL-6vntr polymorphism was not. Plasma IL-6 concentration of the AD cases was also significantly higher than that of the control cases. Moreover, the IL-6prom G allele-positive AD patients showed a tendency to have higher IL-6 concentration in the AD group. These findings suggest that the IL-6prom G allele which may affect plasma IL-6 concentration might be a risk factor for sporadic AD in Japanese. | Effect of /"IL-6"/ polymorphism on risk of /"Alzheimer disease"/: genotype-phenotype association study in Japanese cases. | /"Interleukin-6"/ (/"IL-6"/), an inflammatory cytokine might be involved in the pathophysiology of /"Alzheimer disease"/ (/"AD"/); several studies have reported that the "C allele of /"IL-6"/ variable number of tandem repeat polymorphism" (IL-6vntr) delayed initial onset of /"AD"/ and also decreased its risk per se. Another polymorphism, G/C allele of /"IL-6"/ gene promoter region (IL-6prom), is also a candidate because it has an influence on the regulation of plasma /"IL-6"/ concentration. We examined these /"IL-6"/ polymorphisms in 128 Japanese /"AD"/ cases and 83 control cases using a PCR-RFLP method. The results showed the frequency of the /"IL-6"/prom G allele was significantly increased in /"AD"/, although /"IL-6"/vntr polymorphism was not. Plasma /"IL-6"/ concentration of the /"AD"/ cases was also significantly higher than that of the control cases. Moreover, the /"IL-6"/prom G allele-positive /"AD"/ patients showed a tendency to have higher /"IL-6"/ concentration in the /"AD"/ group. These findings suggest that the /"IL-6"/prom G allele which may affect plasma /"IL-6"/ concentration might be a risk factor for sporadic /"AD"/ in Japanese. | [
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11992568 | No association between DCP1 genotype and late-onset Alzheimer disease. | In a study of 261 patients with Alzheimer disease (AD) and 306 cognitively normal control subjects from Germany, Switzerland, and Italy, we found no association between genotype counts or allelic frequencies of DCP1, the gene encoding angiotensin-converting enzyme. In accordance with several other studies, our data could not confirm previous association findings. Critical review about all studies available on DCP1 genotyping and AD, age-associated cognitive decline, longevity, and other conditions revealed remarkable inconsistencies. Several studies showed significant deviations of genotype counts from Hardy Weinberg equilibrium (HWE). Deviations from HWE may limit the comparability of study results and require clarification before drawing conclusions with respect to disease risk, health conditions, or longevity in association with DCP1 genotype. | No association between /"DCP1"/ genotype and late-onset /"Alzheimer disease"/. | In a study of 261 patients with /"Alzheimer disease"/ (/"AD"/) and 306 cognitively normal control subjects from Germany, Switzerland, and Italy, we found no association between genotype counts or allelic frequencies of /"DCP1"/, the gene encoding /"angiotensin-converting enzyme"/. In accordance with several other studies, our data could not confirm previous association findings. Critical review about all studies available on /"DCP1"/ genotyping and /"AD"/, age-associated cognitive decline, longevity, and other conditions revealed remarkable inconsistencies. Several studies showed significant deviations of genotype counts from Hardy Weinberg equilibrium (HWE). Deviations from HWE may limit the comparability of study results and require clarification before drawing conclusions with respect to disease risk, health conditions, or longevity in association with /"DCP1"/ genotype. | [
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11992568 | No association between DCP1 genotype and late-onset Alzheimer disease. | In a study of 261 patients with Alzheimer disease (AD) and 306 cognitively normal control subjects from Germany, Switzerland, and Italy, we found no association between genotype counts or allelic frequencies of DCP1, the gene encoding angiotensin-converting enzyme. In accordance with several other studies, our data could not confirm previous association findings. Critical review about all studies available on DCP1 genotyping and AD, age-associated cognitive decline, longevity, and other conditions revealed remarkable inconsistencies. Several studies showed significant deviations of genotype counts from Hardy Weinberg equilibrium (HWE). Deviations from HWE may limit the comparability of study results and require clarification before drawing conclusions with respect to disease risk, health conditions, or longevity in association with DCP1 genotype. | No association between /"DCP1"/ genotype and late-onset Alzheimer disease. | In a study of 261 patients with Alzheimer disease (AD) and 306 cognitively normal control subjects from Germany, Switzerland, and Italy, we found no association between genotype counts or allelic frequencies of /"DCP1"/, the gene encoding /"angiotensin-converting enzyme"/. In accordance with several other studies, our data could not confirm previous association findings. Critical review about all studies available on /"DCP1"/ genotyping and AD, age-associated /"cognitive decline"/, longevity, and other conditions revealed remarkable inconsistencies. Several studies showed significant deviations of genotype counts from Hardy Weinberg equilibrium (HWE). Deviations from HWE may limit the comparability of study results and require clarification before drawing conclusions with respect to disease risk, health conditions, or longevity in association with /"DCP1"/ genotype. | [
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12000493 | Thromboxane A2 receptor gene polymorphism is associated with the serum concentration of cat-specific immunoglobulin E as well as the development and severity of asthma in Chinese children. | Thromboxane A2 and its receptor (TBXA2R) are involved in the constriction of vascular and respiratory smooth muscles. The T924C polymorphism in the TBXA2R gene was recently found to be associated with asthma in Japanese adults but not in children. Its relationship with atopy or asthma severity in children has not been defined. To investigate this further, we first assessed the severity of asthma in Chinese children using a standardized questionnaire modified from the Disease Severity Score and spirometric evaluation. Then, peripheral blood was analyzed for serum total and aeroallergen-specific immunoglobulin E (IgE) levels, and TBXA2R T924C genotypes were determined by restriction fragment length polymorphism (RFLP) analysis. One-hundred and fifty three asthmatic patients and 57 control children were recruited, of respective mean ages 9.9 and 11.0 years (p = 0.07). The mean logarithmic serum total IgE concentration was 2.57 and 2.09, respectively, for the asthmatic group and control group (p < 0.0001). Atopy was detected in 132 (86%) asthmatics and 33 (58%) controls. A significant association was observed between T924C and the diagnosis of atopic asthma (p = 0.044; odds ratio: 1.84). In addition, those asthmatics homozygous for the mutant allele in T924C had a lower forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (p = 0.032 and 0.002, respectively). Among our asthmatic patients, the TBXA2R T924C polymorphism correlated with the concentration of cat-specific IgE in serum (p = 0.046). Nonetheless, this gene marker did not show an association with the serum total IgE concentration or any clinical indicator of asthma severity. In conclusion, our results suggest that the T924C marker in the TBXA2R gene is associated, in Chinese children, with an increased susceptibility of developing atopic asthma. This marker is also associated with the extent of allergic sensitization to cat, as well as with reduced FEV1 and FVC values. | Thromboxane A2 receptor gene polymorphism is associated with the serum concentration of cat-specific immunoglobulin E as well as the development and severity of /"asthma"/ in Chinese children. | Thromboxane A2 and its receptor (/"TBXA2R"/) are involved in the constriction of vascular and respiratory smooth muscles. The T924C polymorphism in the /"TBXA2R"/ gene was recently found to be associated with /"asthma"/ in Japanese adults but not in children. Its relationship with atopy or /"asthma"/ severity in children has not been defined. To investigate this further, we first assessed the severity of /"asthma"/ in Chinese children using a standardized questionnaire modified from the Disease Severity Score and spirometric evaluation. Then, peripheral blood was analyzed for serum total and aeroallergen-specific immunoglobulin E (IgE) levels, and /"TBXA2R"/ T924C genotypes were determined by restriction fragment length polymorphism (RFLP) analysis. One-hundred and fifty three asthmatic patients and 57 control children were recruited, of respective mean ages 9.9 and 11.0 years (p = 0.07). The mean logarithmic serum total IgE concentration was 2.57 and 2.09, respectively, for the asthmatic group and control group (p < 0.0001). Atopy was detected in 132 (86%) asthmatics and 33 (58%) controls. A significant association was observed between T924C and the diagnosis of atopic asthma (p = 0.044; odds ratio: 1.84). In addition, those asthmatics homozygous for the mutant allele in T924C had a lower forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (p = 0.032 and 0.002, respectively). Among our asthmatic patients, the /"TBXA2R"/ T924C polymorphism correlated with the concentration of cat-specific IgE in serum (p = 0.046). Nonetheless, this gene marker did not show an association with the serum total IgE concentration or any clinical indicator of /"asthma"/ severity. In conclusion, our results suggest that the T924C marker in the /"TBXA2R"/ gene is associated, in Chinese children, with an increased susceptibility of developing atopic asthma. This marker is also associated with the extent of allergic sensitization to cat, as well as with reduced FEV1 and FVC values. | [
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12000493 | Thromboxane A2 receptor gene polymorphism is associated with the serum concentration of cat-specific immunoglobulin E as well as the development and severity of asthma in Chinese children. | Thromboxane A2 and its receptor (TBXA2R) are involved in the constriction of vascular and respiratory smooth muscles. The T924C polymorphism in the TBXA2R gene was recently found to be associated with asthma in Japanese adults but not in children. Its relationship with atopy or asthma severity in children has not been defined. To investigate this further, we first assessed the severity of asthma in Chinese children using a standardized questionnaire modified from the Disease Severity Score and spirometric evaluation. Then, peripheral blood was analyzed for serum total and aeroallergen-specific immunoglobulin E (IgE) levels, and TBXA2R T924C genotypes were determined by restriction fragment length polymorphism (RFLP) analysis. One-hundred and fifty three asthmatic patients and 57 control children were recruited, of respective mean ages 9.9 and 11.0 years (p = 0.07). The mean logarithmic serum total IgE concentration was 2.57 and 2.09, respectively, for the asthmatic group and control group (p < 0.0001). Atopy was detected in 132 (86%) asthmatics and 33 (58%) controls. A significant association was observed between T924C and the diagnosis of atopic asthma (p = 0.044; odds ratio: 1.84). In addition, those asthmatics homozygous for the mutant allele in T924C had a lower forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (p = 0.032 and 0.002, respectively). Among our asthmatic patients, the TBXA2R T924C polymorphism correlated with the concentration of cat-specific IgE in serum (p = 0.046). Nonetheless, this gene marker did not show an association with the serum total IgE concentration or any clinical indicator of asthma severity. In conclusion, our results suggest that the T924C marker in the TBXA2R gene is associated, in Chinese children, with an increased susceptibility of developing atopic asthma. This marker is also associated with the extent of allergic sensitization to cat, as well as with reduced FEV1 and FVC values. | Thromboxane A2 receptor gene polymorphism is associated with the serum concentration of cat-specific immunoglobulin E as well as the development and severity of asthma in Chinese children. | Thromboxane A2 and its receptor (/"TBXA2R"/) are involved in the constriction of vascular and respiratory smooth muscles. The T924C polymorphism in the /"TBXA2R"/ gene was recently found to be associated with asthma in Japanese adults but not in children. Its relationship with atopy or asthma severity in children has not been defined. To investigate this further, we first assessed the severity of asthma in Chinese children using a standardized questionnaire modified from the Disease Severity Score and spirometric evaluation. Then, peripheral blood was analyzed for serum total and aeroallergen-specific immunoglobulin E (IgE) levels, and /"TBXA2R"/ T924C genotypes were determined by restriction fragment length polymorphism (RFLP) analysis. One-hundred and fifty three /"asthmatic"/ patients and 57 control children were recruited, of respective mean ages 9.9 and 11.0 years (p = 0.07). The mean logarithmic serum total IgE concentration was 2.57 and 2.09, respectively, for the /"asthmatic"/ group and control group (p < 0.0001). Atopy was detected in 132 (86%) asthmatics and 33 (58%) controls. A significant association was observed between T924C and the diagnosis of atopic asthma (p = 0.044; odds ratio: 1.84). In addition, those asthmatics homozygous for the mutant allele in T924C had a lower forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (p = 0.032 and 0.002, respectively). Among our /"asthmatic"/ patients, the /"TBXA2R"/ T924C polymorphism correlated with the concentration of cat-specific IgE in serum (p = 0.046). Nonetheless, this gene marker did not show an association with the serum total IgE concentration or any clinical indicator of asthma severity. In conclusion, our results suggest that the T924C marker in the /"TBXA2R"/ gene is associated, in Chinese children, with an increased susceptibility of developing atopic asthma. This marker is also associated with the extent of allergic sensitization to cat, as well as with reduced FEV1 and FVC values. | [
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12006918 | Hepatic lipase gene -514 C/T polymorphism and premature coronary heart disease. | BACKGROUND: A common polymorphism in the hepatic lipase (HL) gene promoter, -514C/T, affecting enzyme activity, has been associated with alterations in plasma lipoprotein levels. However a relationship with coronary heart disease (CHD) is less well documented. DESIGN AND METHODS: We studied HL -514 C/T in 562 Caucasian CHD patients aged under 50 years and in 642 Caucasian community recruited subjects without historical evidence of CHD. RESULTS: Male CHD subjects (n = 490) had a 41% carrier rate for the C to T substitution, compared with 33% in corresponding controls (n = 330), [OR = 1.42 (95% CI:1.06-1.90), P < 0.02], T allele frequencies being 0.231 and 0.177 respectively [OR = 1.39 (1.08-1.78), P < 0.01]. In male CHD subjects, the T allele was associated with higher HDL-cholesterol (HDL-C) (CC: 0.95 +/- 0.24 (SD); CT: 1.04 +/- 0.41; TT: 1.01 +/- 0.20 mmol/l, P = 0.02, ANOVA) but the trend was not significant in females. In male CHD patients the T allele was more frequently encountered in those with high (> 4.5 mmol/l) than in those with low triglycerides [68% vs. 39%, OR = 3.13 (1.54-6.67), P = 0.001]. In community control subjects, the T allele was associated with a trend to higher HDL-C levels, the significance varying between subgroups while, in males, serum total and LDL-cholesterol were significantly lower in T homozygotes than in the other two genotypes (LDL-C: 2.73 +/- 0.63 vs. 3.56 +/- 0.95 mmol/l; P = 0.01). During the course of this study, a previously unreported promoter region polymorphism was found exclusively on -514C chromosomes (-592A/G, A allele frequency 0.108, 95% CI 0.09 - 0.126). It can lead to mistyping of C as T alleles in C/T heterozygotes, resulting in overestimation of -514 T homozygotes. CONCLUSIONS: The T allele of the hepatic lipase -514 C/T polymorphism is associated with changes in plasma lipids. The superficially paradoxical predisposition to CHD in males is attributable to impairment of TG rich lipoprotein metabolism and reverse cholesterol transport. | /"Hepatic lipase"/ gene -514 C/T polymorphism and premature /"coronary heart disease"/. | BACKGROUND: A common polymorphism in the /"hepatic lipase"/ (/"HL"/) gene promoter, -514C/T, affecting enzyme activity, has been associated with alterations in plasma lipoprotein levels. However a relationship with /"coronary heart disease"/ (/"CHD"/) is less well documented. DESIGN AND METHODS: We studied /"HL"/ -514 C/T in 562 Caucasian /"CHD"/ patients aged under 50 years and in 642 Caucasian community recruited subjects without historical evidence of /"CHD"/. RESULTS: Male /"CHD"/ subjects (n = 490) had a 41% carrier rate for the C to T substitution, compared with 33% in corresponding controls (n = 330), [OR = 1.42 (95% CI:1.06-1.90), P < 0.02], T allele frequencies being 0.231 and 0.177 respectively [OR = 1.39 (1.08-1.78), P < 0.01]. In male /"CHD"/ subjects, the T allele was associated with higher HDL-cholesterol (HDL-C) (CC: 0.95 +/- 0.24 (SD); CT: 1.04 +/- 0.41; TT: 1.01 +/- 0.20 mmol/l, P = 0.02, ANOVA) but the trend was not significant in females. In male /"CHD"/ patients the T allele was more frequently encountered in those with high (> 4.5 mmol/l) than in those with low triglycerides [68% vs. 39%, OR = 3.13 (1.54-6.67), P = 0.001]. In community control subjects, the T allele was associated with a trend to higher HDL-C levels, the significance varying between subgroups while, in males, serum total and LDL-cholesterol were significantly lower in T homozygotes than in the other two genotypes (LDL-C: 2.73 +/- 0.63 vs. 3.56 +/- 0.95 mmol/l; P = 0.01). During the course of this study, a previously unreported promoter region polymorphism was found exclusively on -514C chromosomes (-592A/G, A allele frequency 0.108, 95% CI 0.09 - 0.126). It can lead to mistyping of C as T alleles in C/T heterozygotes, resulting in overestimation of -514 T homozygotes. CONCLUSIONS: The T allele of the /"hepatic lipase"/ -514 C/T polymorphism is associated with changes in plasma lipids. The superficially paradoxical predisposition to /"CHD"/ in males is attributable to impairment of TG rich lipoprotein metabolism and reverse cholesterol transport. | [
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12007670 | ApoE genotype influences the biological effect of donepezil on APP metabolism in Alzheimer disease: evidence from a peripheral model. | Three major amyloid precursor protein (APP) forms with apparent molecular weight ranging from 106 to 130 kDa are present in human platelets. Alzheimer disease (AD) is associated with a decreased APP forms ratio (APPr) between the three major forms. A total of 25 mild to moderate AD patients were investigated. Platelet APPr was studied before and after 30 days of acetylcholinesterase-inhibitor treatment (donepezil, 5 mg daily). Patients were grouped into non-epsilon4 carriers and epsilon4 carriers according to apolipoprotein E (ApoE) genotype. At baseline, all patients showed low APPr levels and no significant difference was found between the two ApoE subgroups. After treatment, although a marked improvement in APPr was observed in most patients, non-epsilon4 carriers displayed a higher increase compared to epsilon4 carriers (P<0.0001). The present study provides evidence that donepezil influences APP metabolism in platelets, and suggests that ApoE genotype might be an important modulating factor for drug responsiveness in AD. | /"ApoE"/ genotype influences the biological effect of donepezil on APP metabolism in /"Alzheimer disease"/: evidence from a peripheral model. | Three major amyloid precursor protein (APP) forms with apparent molecular weight ranging from 106 to 130 kDa are present in human platelets. /"Alzheimer disease"/ (/"AD"/) is associated with a decreased APP forms ratio (APPr) between the three major forms. A total of 25 mild to moderate /"AD"/ patients were investigated. Platelet APPr was studied before and after 30 days of acetylcholinesterase-inhibitor treatment (donepezil, 5 mg daily). Patients were grouped into non-epsilon4 carriers and epsilon4 carriers according to /"apolipoprotein E"/ (/"ApoE"/) genotype. At baseline, all patients showed low APPr levels and no significant difference was found between the two /"ApoE"/ subgroups. After treatment, although a marked improvement in APPr was observed in most patients, non-epsilon4 carriers displayed a higher increase compared to epsilon4 carriers (P<0.0001). The present study provides evidence that donepezil influences APP metabolism in platelets, and suggests that /"ApoE"/ genotype might be an important modulating factor for drug responsiveness in /"AD"/. | [
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"text_name": "Alzheimer disease"
} | Yes |
12010932 | Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298-->Asp polymorphism) to the presence, extent, and severity of coronary artery disease. | BACKGROUND: Genetic variants of endothelial nitric oxide synthase (eNOS) could influence individual susceptibility to coronary artery disease. OBJECTIVE: To assess whether Glu298-->Asp polymorphism of the eNOS gene is associated with the occurrence and severity of angiographically defined coronary artery disease in the Italian population. METHODS: Polymerase chain reaction/restriction fragment length polymorphism analysis was done to detect the Glu298-->Asp variant of the eNOS gene in 201 patients with coronary artery disease and 114 controls. The severity of coronary artery disease was expressed by the number of affected vessels and by the Duke scoring system. RESULTS: The frequencies of the eNOS Glu/Glu, Glu/Asp, and Asp/Asp genotypes in the coronary artery disease group were significantly different from those of controls (45.3%, 38.8%, and 15.9% v 42.1%, 51.8%, and 6.1%, respectively; chi2 = 8.589, p = 0.0136). In comparison with subjects who had a Glu298 allele in the eNOS gene, the risk of coronary artery disease was increased among Asp/Asp carriers (odds ratio 2.9, 95% confidence interval 1.2 to 6.8, p = 0.01) and was independent of the other common risk factors (p = 0.04). There was a significant association between the eNOS Glu298-->Asp variant and both the number of stenosed vessels (mean (SEM), 2.3 (0.1) for Asp/Asp v 1.9 (0.1) and 1.8 (0.1) for Glu/Glu and Glu/Asp, respectively; p = 0.01) and the Duke score (56.1 (3.1) for Asp/Asp v 46.7 (2.0) and 46.1 (1.9) for Glu/Glu and Glu/Asp, respectively; p = 0.02). CONCLUSIONS: Glu298-->Asp polymorphism of the eNOS gene appears to be associated with the presence, extent, and severity of angiographically assessed coronary artery disease. | Evidence for association of a common variant of the /"endothelial nitric oxide synthase"/ gene (Glu298-->Asp polymorphism) to the presence, extent, and severity of /"coronary artery disease"/. | BACKGROUND: Genetic variants of /"endothelial nitric oxide synthase"/ (/"eNOS"/) could influence individual susceptibility to /"coronary artery disease"/. OBJECTIVE: To assess whether Glu298-->Asp polymorphism of the /"eNOS"/ gene is associated with the occurrence and severity of angiographically defined /"coronary artery disease"/ in the Italian population. METHODS: Polymerase chain reaction/restriction fragment length polymorphism analysis was done to detect the Glu298-->Asp variant of the /"eNOS"/ gene in 201 patients with /"coronary artery disease"/ and 114 controls. The severity of /"coronary artery disease"/ was expressed by the number of affected vessels and by the Duke scoring system. RESULTS: The frequencies of the /"eNOS"/ Glu/Glu, Glu/Asp, and Asp/Asp genotypes in the /"coronary artery disease"/ group were significantly different from those of controls (45.3%, 38.8%, and 15.9% v 42.1%, 51.8%, and 6.1%, respectively; chi2 = 8.589, p = 0.0136). In comparison with subjects who had a Glu298 allele in the /"eNOS"/ gene, the risk of /"coronary artery disease"/ was increased among Asp/Asp carriers (odds ratio 2.9, 95% confidence interval 1.2 to 6.8, p = 0.01) and was independent of the other common risk factors (p = 0.04). There was a significant association between the /"eNOS"/ Glu298-->Asp variant and both the number of stenosed vessels (mean (SEM), 2.3 (0.1) for Asp/Asp v 1.9 (0.1) and 1.8 (0.1) for Glu/Glu and Glu/Asp, respectively; p = 0.01) and the Duke score (56.1 (3.1) for Asp/Asp v 46.7 (2.0) and 46.1 (1.9) for Glu/Glu and Glu/Asp, respectively; p = 0.02). CONCLUSIONS: Glu298-->Asp polymorphism of the /"eNOS"/ gene appears to be associated with the presence, extent, and severity of angiographically assessed /"coronary artery disease"/. | [
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12028996 | Multiplex minisequencing of the 21-hydroxylase gene as a rapid strategy to confirm congenital adrenal hyperplasia. | BACKGROUND: Congenital adrenal hyperplasia (CAH) is a frequent autosomal recessive disease, with a wide range of clinical manifestations, most commonly attributable to mutations in the 21-hydroxylase gene (CYP21). Large gene deletions, large gene conversions, a small 8-basepair deletion, and eight point mutations in CYP21 account for approximately 95% of all enzyme deficiencies. We developed a new strategy for a rapid CYP21 analysis. METHODS: DNA samples from 40 CAH patients previously genotyped by direct DNA sequencing were reanalyzed by allele-specific amplification of the functional CYP21 gene followed by a multiplex minisequencing reaction using 13 primers. In addition, a second PCR that amplified a part of exon 3 was used to demonstrate the presence or absence of at least one functional gene. RESULTS: The assay detected the P453S mutation and nine of the most common mutations (P30L, intron 2 splice, Delta 8bp, I172N, exon 6 cluster, V281L, F306+t, Q318X, and R356W) caused by microconversions from the CYP21P pseudogene. The concordance was 100% for detecting these mutations, including gene deletions and large gene conversions. The 40 patient DNA samples were analyzed in 1.5 working days by one technician (actual hands-on time, 3.5 h). The material cost for analyzing one sample was approximately 10.00 Euros (US 9.00). CONCLUSIONS: This novel mutation screening strategy rapidly detects 90-95% of all mutations associated with CAH and appears applicable as a tool for confirmation of increased 17-hydroxyprogesterone found in neonatal CAH screening. | Multiplex minisequencing of the 21-hydroxylase gene as a rapid strategy to confirm /"congenital adrenal hyperplasia"/. | BACKGROUND: /"Congenital adrenal hyperplasia"/ (/"CAH"/) is a frequent autosomal recessive disease, with a wide range of clinical manifestations, most commonly attributable to mutations in the 21-hydroxylase gene (/"CYP21"/). Large gene deletions, large gene conversions, a small 8-basepair deletion, and eight point mutations in /"CYP21"/ account for approximately 95% of all enzyme deficiencies. We developed a new strategy for a rapid /"CYP21"/ analysis. METHODS: DNA samples from 40 /"CAH"/ patients previously genotyped by direct DNA sequencing were reanalyzed by allele-specific amplification of the functional /"CYP21"/ gene followed by a multiplex minisequencing reaction using 13 primers. In addition, a second PCR that amplified a part of exon 3 was used to demonstrate the presence or absence of at least one functional gene. RESULTS: The assay detected the P453S mutation and nine of the most common mutations (P30L, intron 2 splice, Delta 8bp, I172N, exon 6 cluster, V281L, F306+t, Q318X, and R356W) caused by microconversions from the CYP21P pseudogene. The concordance was 100% for detecting these mutations, including gene deletions and large gene conversions. The 40 patient DNA samples were analyzed in 1.5 working days by one technician (actual hands-on time, 3.5 h). The material cost for analyzing one sample was approximately 10.00 Euros (US 9.00). CONCLUSIONS: This novel mutation screening strategy rapidly detects 90-95% of all mutations associated with /"CAH"/ and appears applicable as a tool for confirmation of increased 17-hydroxyprogesterone found in neonatal /"CAH"/ screening. | [
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12028996 | Multiplex minisequencing of the 21-hydroxylase gene as a rapid strategy to confirm congenital adrenal hyperplasia. | BACKGROUND: Congenital adrenal hyperplasia (CAH) is a frequent autosomal recessive disease, with a wide range of clinical manifestations, most commonly attributable to mutations in the 21-hydroxylase gene (CYP21). Large gene deletions, large gene conversions, a small 8-basepair deletion, and eight point mutations in CYP21 account for approximately 95% of all enzyme deficiencies. We developed a new strategy for a rapid CYP21 analysis. METHODS: DNA samples from 40 CAH patients previously genotyped by direct DNA sequencing were reanalyzed by allele-specific amplification of the functional CYP21 gene followed by a multiplex minisequencing reaction using 13 primers. In addition, a second PCR that amplified a part of exon 3 was used to demonstrate the presence or absence of at least one functional gene. RESULTS: The assay detected the P453S mutation and nine of the most common mutations (P30L, intron 2 splice, Delta 8bp, I172N, exon 6 cluster, V281L, F306+t, Q318X, and R356W) caused by microconversions from the CYP21P pseudogene. The concordance was 100% for detecting these mutations, including gene deletions and large gene conversions. The 40 patient DNA samples were analyzed in 1.5 working days by one technician (actual hands-on time, 3.5 h). The material cost for analyzing one sample was approximately 10.00 Euros (US 9.00). CONCLUSIONS: This novel mutation screening strategy rapidly detects 90-95% of all mutations associated with CAH and appears applicable as a tool for confirmation of increased 17-hydroxyprogesterone found in neonatal CAH screening. | Multiplex minisequencing of the 21-hydroxylase gene as a rapid strategy to confirm congenital adrenal hyperplasia. | BACKGROUND: Congenital adrenal hyperplasia (CAH) is a frequent /"autosomal recessive disease"/, with a wide range of clinical manifestations, most commonly attributable to mutations in the 21-hydroxylase gene (/"CYP21"/). Large gene deletions, large gene conversions, a small 8-basepair deletion, and eight point mutations in /"CYP21"/ account for approximately 95% of all enzyme deficiencies. We developed a new strategy for a rapid /"CYP21"/ analysis. METHODS: DNA samples from 40 CAH patients previously genotyped by direct DNA sequencing were reanalyzed by allele-specific amplification of the functional /"CYP21"/ gene followed by a multiplex minisequencing reaction using 13 primers. In addition, a second PCR that amplified a part of exon 3 was used to demonstrate the presence or absence of at least one functional gene. RESULTS: The assay detected the P453S mutation and nine of the most common mutations (P30L, intron 2 splice, Delta 8bp, I172N, exon 6 cluster, V281L, F306+t, Q318X, and R356W) caused by microconversions from the CYP21P pseudogene. The concordance was 100% for detecting these mutations, including gene deletions and large gene conversions. The 40 patient DNA samples were analyzed in 1.5 working days by one technician (actual hands-on time, 3.5 h). The material cost for analyzing one sample was approximately 10.00 Euros (US 9.00). CONCLUSIONS: This novel mutation screening strategy rapidly detects 90-95% of all mutations associated with CAH and appears applicable as a tool for confirmation of increased 17-hydroxyprogesterone found in neonatal CAH screening. | [
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12032588 | Identification of lamin A/C ( LMNA) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B. | Mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found to cause at least four different kinds of genetic disorders: autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; MIM 181350); limb-girdle muscular dystrophy type 1B (LGMD1B; MIM 159001); dilated cardiomyopathy type 1A (CMD1A; MIM 115200); and familial partial lipodystrophy (FPLD; MIM 151660). Recently, we have studied two Korean patients with atrioventricular conduction defects. They had variable extents of muscular dystrophy; one patient was diagnosed with EDMD2 and the other with LGMD1B. We performed a mutation analysis of the LMNA gene by direct sequencing and found two different missense mutations: R249Q and R377L, in the EDMD2 and LGMD1B patient, respectively. The R249Q mutation is located within the central rod domain of the LMNA gene, and has been described in at least five unrelated sporadic EDMD2 patients. On the other hand, the R377L mutation, also located within the rod domain, is a novel mutation, although a histidine substitution instead of leucine (R377H) has been reported previously in an LGMD1B patient. To our knowledge, this is the first report of LMNA gene mutations in Korean patients with EDMD2 and LGMD1B. | Identification of /"lamin A/C"/ ( /"LMNA"/) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and /"limb-girdle muscular dystrophy"/ 1B. | Mutations in the /"LMNA"/ gene encoding lamins A and C by alternative splicing have been found to cause at least four different kinds of genetic disorders: autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; MIM 181350); limb-girdle muscular dystrophy type 1B (LGMD1B; MIM 159001); dilated cardiomyopathy type 1A (/"CMD1A"/; MIM 115200); and familial partial lipodystrophy (FPLD; MIM 151660). Recently, we have studied two Korean patients with atrioventricular conduction defects. They had variable extents of muscular dystrophy; one patient was diagnosed with EDMD2 and the other with LGMD1B. We performed a mutation analysis of the /"LMNA"/ gene by direct sequencing and found two different missense mutations: R249Q and R377L, in the EDMD2 and LGMD1B patient, respectively. The R249Q mutation is located within the central rod domain of the /"LMNA"/ gene, and has been described in at least five unrelated sporadic EDMD2 patients. On the other hand, the R377L mutation, also located within the rod domain, is a novel mutation, although a histidine substitution instead of leucine (R377H) has been reported previously in an LGMD1B patient. To our knowledge, this is the first report of /"LMNA"/ gene mutations in Korean patients with EDMD2 and LGMD1B. | [
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12032588 | Identification of lamin A/C ( LMNA) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B. | Mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found to cause at least four different kinds of genetic disorders: autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; MIM 181350); limb-girdle muscular dystrophy type 1B (LGMD1B; MIM 159001); dilated cardiomyopathy type 1A (CMD1A; MIM 115200); and familial partial lipodystrophy (FPLD; MIM 151660). Recently, we have studied two Korean patients with atrioventricular conduction defects. They had variable extents of muscular dystrophy; one patient was diagnosed with EDMD2 and the other with LGMD1B. We performed a mutation analysis of the LMNA gene by direct sequencing and found two different missense mutations: R249Q and R377L, in the EDMD2 and LGMD1B patient, respectively. The R249Q mutation is located within the central rod domain of the LMNA gene, and has been described in at least five unrelated sporadic EDMD2 patients. On the other hand, the R377L mutation, also located within the rod domain, is a novel mutation, although a histidine substitution instead of leucine (R377H) has been reported previously in an LGMD1B patient. To our knowledge, this is the first report of LMNA gene mutations in Korean patients with EDMD2 and LGMD1B. | Identification of /"lamin A/C"/ ( /"LMNA"/) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B. | Mutations in the /"LMNA"/ gene encoding lamins A and C by alternative splicing have been found to cause at least four different kinds of genetic disorders: autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; MIM 181350); limb-girdle muscular dystrophy type 1B (LGMD1B; MIM 159001); dilated cardiomyopathy type 1A (/"CMD1A"/; MIM 115200); and /"familial partial lipodystrophy"/ (/"FPLD"/; MIM 151660). Recently, we have studied two Korean patients with atrioventricular conduction defects. They had variable extents of muscular dystrophy; one patient was diagnosed with EDMD2 and the other with LGMD1B. We performed a mutation analysis of the /"LMNA"/ gene by direct sequencing and found two different missense mutations: R249Q and R377L, in the EDMD2 and LGMD1B patient, respectively. The R249Q mutation is located within the central rod domain of the /"LMNA"/ gene, and has been described in at least five unrelated sporadic EDMD2 patients. On the other hand, the R377L mutation, also located within the rod domain, is a novel mutation, although a histidine substitution instead of leucine (R377H) has been reported previously in an LGMD1B patient. To our knowledge, this is the first report of /"LMNA"/ gene mutations in Korean patients with EDMD2 and LGMD1B. | [
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12034804 | Are interleukin-1 gene polymorphisms risk factors or disease modifiers in AD? | Polymorphisms in the interleukin-1 genes, IL-1A and IL-1B, have been associated with AD, but not in all studies. The authors genotyped the IL-1A(-889) and IL-1B(-511) polymorphisms in large independent cohorts of 503 control individuals and 395 patients with AD, and a further 100 with brain Abeta load. No evidence was found of risk for AD with these variants, nor of an effect on age at onset. However, an impact of IL-1B(-511) on Abeta(40) load (p < 0.05) was detected. | Are interleukin-1 gene polymorphisms risk factors or disease modifiers in /"AD"/? | Polymorphisms in the interleukin-1 genes, IL-1A and /"IL-1B"/, have been associated with /"AD"/, but not in all studies. The authors genotyped the IL-1A(-889) and /"IL-1B"/(-511) polymorphisms in large independent cohorts of 503 control individuals and 395 patients with /"AD"/, and a further 100 with brain Abeta load. No evidence was found of risk for /"AD"/ with these variants, nor of an effect on age at onset. However, an impact of /"IL-1B"/(-511) on Abeta(40) load (p < 0.05) was detected. | [
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12034804 | Are interleukin-1 gene polymorphisms risk factors or disease modifiers in AD? | Polymorphisms in the interleukin-1 genes, IL-1A and IL-1B, have been associated with AD, but not in all studies. The authors genotyped the IL-1A(-889) and IL-1B(-511) polymorphisms in large independent cohorts of 503 control individuals and 395 patients with AD, and a further 100 with brain Abeta load. No evidence was found of risk for AD with these variants, nor of an effect on age at onset. However, an impact of IL-1B(-511) on Abeta(40) load (p < 0.05) was detected. | Are /"interleukin-1"/ gene polymorphisms risk factors or disease modifiers in /"AD"/? | Polymorphisms in the /"interleukin-1"/ genes, /"IL-1A"/ and IL-1B, have been associated with /"AD"/, but not in all studies. The authors genotyped the /"IL-1A"/(-889) and IL-1B(-511) polymorphisms in large independent cohorts of 503 control individuals and 395 patients with /"AD"/, and a further 100 with brain Abeta load. No evidence was found of risk for /"AD"/ with these variants, nor of an effect on age at onset. However, an impact of IL-1B(-511) on Abeta(40) load (p < 0.05) was detected. | [
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12058348 | Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. | Multiple-lentigines (ML)/LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition--characterized by lentigines and caf au lait spots, facial anomalies, cardiac defects--that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple caf au lait spots, for mutations in the NS gene, PTPN11, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the NS PTPN11 mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS. | Grouping of /"multiple-lentigines/LEOPARD and Noonan syndromes"/ on the /"PTPN11"/ gene. | /"Multiple-lentigines"/ (/"ML"/)/LEOPARD (/"multiple lentigines"/, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition--characterized by lentigines and caf au lait spots, facial anomalies, cardiac defects--that shares several clinical features with Noonan syndrome (NS). We screened nine patients with /"ML/LEOPARD syndrome"/ (including a mother-daughter pair) and two children with NS who had multiple caf au lait spots, for mutations in the NS gene, /"PTPN11"/, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the /"PTPN11"/ phosphotyrosine phosphatase domain, which is involved in <30% of the NS /"PTPN11"/ mutations. The study demonstrates that /"ML/LEOPARD syndrome"/ and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the /"ML"///"LEOPARD-syndrome subtype of NS"/. | [
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12058348 | Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. | Multiple-lentigines (ML)/LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition--characterized by lentigines and caf au lait spots, facial anomalies, cardiac defects--that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple caf au lait spots, for mutations in the NS gene, PTPN11, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the NS PTPN11 mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS. | Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the /"PTPN11"/ gene. | Multiple-lentigines (ML)/LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, /"pulmonary stenosis"/, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition--characterized by lentigines and caf au lait spots, facial anomalies, cardiac defects--that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple caf au lait spots, for mutations in the NS gene, /"PTPN11"/, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the /"PTPN11"/ phosphotyrosine phosphatase domain, which is involved in <30% of the NS /"PTPN11"/ mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS. | [
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12059121 | Prevalence of hemochromatosis-related symptoms among individuals with mutations in the HFE gene. | OBJECTIVE: To determine the prevalence of hemochromatosis-related symptoms in homozygotes for the HFE mutation C282Y compared with controls without HFE mutations identified through a large screening program of subjects attending a health appraisal center. SUBJECTS AND METHODS: Presence of symptoms commonly associated with clinical hemochromatosis was ascertained by self-report on a written questionnaire among C282Y homozygotes and HFE wild-type subjects of white or Hispanic ethnicity identified from screening 41,599 adult subjects between March 1999 and August 2001. A subset of C282Y homozygotes and wild-type subjects identified from 12,756 subjects attending the center in the final year of the study completed a standardized double-blind interview with a physician regarding the presence, duration, and severity of a larger set of symptoms. Prevalence of symptoms among C282Y homozygotes and wild-type controls ascertained by written questionnaire and interview were compared by chi2 analysis or Fisher exact test. Symptoms among subjects with other combinations of the C282Y and H63D HFE mutations were also assessed by questionnaire. RESULTS: The 124 C282Y homozygotes who filled out the written questionnaire and the 17 C282Y homozygotes who completed the physician double-blind interview reported no significantly higher rates of arthritis or joint pain, abdominal pain, arrhythmias, darkening of skin, or other symptoms traditionally associated with hemochromatosis compared with the 22,429 wild-type controls who filled out the written questionnaire and 29 wild-type controls who completed the double-blind interview. The only symptom reported more frequently by C282Y homozygotes was loss of body hair, reported by 5 C282Y/C282Y female subjects compared with 1 wild-type male subject (P=.02) in the physician interview. Symptoms among subjects with other HFE genotypes were similar to symptoms of wild-type subjects. CONCLUSIONS: Results of this study indicate that many of the symptoms associated with hemochromatosis are common among HFE wild types and that clinical penetrance of the C282Y/C282Y genotype in regard to these symptoms is low. | Prevalence of /"hemochromatosis"/-related symptoms among individuals with mutations in the /"HFE"/ gene. | OBJECTIVE: To determine the prevalence of /"hemochromatosis"/-related symptoms in homozygotes for the /"HFE"/ mutation C282Y compared with controls without /"HFE"/ mutations identified through a large screening program of subjects attending a health appraisal center. SUBJECTS AND METHODS: Presence of symptoms commonly associated with clinical /"hemochromatosis"/ was ascertained by self-report on a written questionnaire among C282Y homozygotes and /"HFE"/ wild-type subjects of white or Hispanic ethnicity identified from screening 41,599 adult subjects between March 1999 and August 2001. A subset of C282Y homozygotes and wild-type subjects identified from 12,756 subjects attending the center in the final year of the study completed a standardized double-blind interview with a physician regarding the presence, duration, and severity of a larger set of symptoms. Prevalence of symptoms among C282Y homozygotes and wild-type controls ascertained by written questionnaire and interview were compared by chi2 analysis or Fisher exact test. Symptoms among subjects with other combinations of the C282Y and H63D /"HFE"/ mutations were also assessed by questionnaire. RESULTS: The 124 C282Y homozygotes who filled out the written questionnaire and the 17 C282Y homozygotes who completed the physician double-blind interview reported no significantly higher rates of arthritis or joint pain, abdominal pain, arrhythmias, darkening of skin, or other symptoms traditionally associated with /"hemochromatosis"/ compared with the 22,429 wild-type controls who filled out the written questionnaire and 29 wild-type controls who completed the double-blind interview. The only symptom reported more frequently by C282Y homozygotes was loss of body hair, reported by 5 C282Y/C282Y female subjects compared with 1 wild-type male subject (P=.02) in the physician interview. Symptoms among subjects with other /"HFE"/ genotypes were similar to symptoms of wild-type subjects. CONCLUSIONS: Results of this study indicate that many of the symptoms associated with /"hemochromatosis"/ are common among /"HFE"/ wild types and that clinical penetrance of the C282Y/C282Y genotype in regard to these symptoms is low. | [
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12059121 | Prevalence of hemochromatosis-related symptoms among individuals with mutations in the HFE gene. | OBJECTIVE: To determine the prevalence of hemochromatosis-related symptoms in homozygotes for the HFE mutation C282Y compared with controls without HFE mutations identified through a large screening program of subjects attending a health appraisal center. SUBJECTS AND METHODS: Presence of symptoms commonly associated with clinical hemochromatosis was ascertained by self-report on a written questionnaire among C282Y homozygotes and HFE wild-type subjects of white or Hispanic ethnicity identified from screening 41,599 adult subjects between March 1999 and August 2001. A subset of C282Y homozygotes and wild-type subjects identified from 12,756 subjects attending the center in the final year of the study completed a standardized double-blind interview with a physician regarding the presence, duration, and severity of a larger set of symptoms. Prevalence of symptoms among C282Y homozygotes and wild-type controls ascertained by written questionnaire and interview were compared by chi2 analysis or Fisher exact test. Symptoms among subjects with other combinations of the C282Y and H63D HFE mutations were also assessed by questionnaire. RESULTS: The 124 C282Y homozygotes who filled out the written questionnaire and the 17 C282Y homozygotes who completed the physician double-blind interview reported no significantly higher rates of arthritis or joint pain, abdominal pain, arrhythmias, darkening of skin, or other symptoms traditionally associated with hemochromatosis compared with the 22,429 wild-type controls who filled out the written questionnaire and 29 wild-type controls who completed the double-blind interview. The only symptom reported more frequently by C282Y homozygotes was loss of body hair, reported by 5 C282Y/C282Y female subjects compared with 1 wild-type male subject (P=.02) in the physician interview. Symptoms among subjects with other HFE genotypes were similar to symptoms of wild-type subjects. CONCLUSIONS: Results of this study indicate that many of the symptoms associated with hemochromatosis are common among HFE wild types and that clinical penetrance of the C282Y/C282Y genotype in regard to these symptoms is low. | Prevalence of hemochromatosis-related symptoms among individuals with mutations in the /"HFE"/ gene. | OBJECTIVE: To determine the prevalence of hemochromatosis-related symptoms in homozygotes for the /"HFE"/ mutation C282Y compared with controls without /"HFE"/ mutations identified through a large screening program of subjects attending a health appraisal center. SUBJECTS AND METHODS: Presence of symptoms commonly associated with clinical hemochromatosis was ascertained by self-report on a written questionnaire among C282Y homozygotes and /"HFE"/ wild-type subjects of white or Hispanic ethnicity identified from screening 41,599 adult subjects between March 1999 and August 2001. A subset of C282Y homozygotes and wild-type subjects identified from 12,756 subjects attending the center in the final year of the study completed a standardized double-blind interview with a physician regarding the presence, duration, and severity of a larger set of symptoms. Prevalence of symptoms among C282Y homozygotes and wild-type controls ascertained by written questionnaire and interview were compared by chi2 analysis or Fisher exact test. Symptoms among subjects with other combinations of the C282Y and H63D /"HFE"/ mutations were also assessed by questionnaire. RESULTS: The 124 C282Y homozygotes who filled out the written questionnaire and the 17 C282Y homozygotes who completed the physician double-blind interview reported no significantly higher rates of arthritis or joint pain, abdominal pain, /"arrhythmias"/, darkening of skin, or other symptoms traditionally associated with hemochromatosis compared with the 22,429 wild-type controls who filled out the written questionnaire and 29 wild-type controls who completed the double-blind interview. The only symptom reported more frequently by C282Y homozygotes was loss of body hair, reported by 5 C282Y/C282Y female subjects compared with 1 wild-type male subject (P=.02) in the physician interview. Symptoms among subjects with other /"HFE"/ genotypes were similar to symptoms of wild-type subjects. CONCLUSIONS: Results of this study indicate that many of the symptoms associated with hemochromatosis are common among /"HFE"/ wild types and that clinical penetrance of the C282Y/C282Y genotype in regard to these symptoms is low. | [
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12078789 | Lactic acidosis after cardiac surgery is associated with polymorphisms in tumor necrosis factor and interleukin 10 genes. | BACKGROUND: Lactic acidosis after cardiac surgery is a manifestation of excess cytokine production. Cytokine-related genetic polymorphisms account for variability in cytokine response and may predispose to the development of lactic acidosis after cardiac surgery. METHODS: Routine postoperative cardiac surgery patients were studied. Lactic acid levels were greater than 4 mmol/L in study patients and less than 4 mmol/L in controls. Polymerase chain reaction-based techniques were used to examine carriage of tumor necrosis factor beta (TNF-beta), TNF G-308A, and interleukin 10 (IL-10) G-1082A alleles. RESULTS: Demographic characteristics and details of surgery were similar for 30 control and 21 study patients. Lactic acid levels after intensive care admission changed over time and were related to both TNF-beta and IL-10 G-1082A polymorphisms. All 4 study patients homozygous for TNF-beta1 and carrying an IL-10-1082A allele developed lactic acidosis (p = 0.02). There was no relation between the rate of epinephrine infusion or duration of cardiopulmonary bypass and lactic acid levels. CONCLUSIONS: Genetic factors have a role in the development of lactic acidosis after cardiac surgery. | /"Lactic acidosis"/ after cardiac surgery is associated with polymorphisms in tumor necrosis factor and /"interleukin 10"/ genes. | BACKGROUND: /"Lactic acidosis"/ after cardiac surgery is a manifestation of excess cytokine production. Cytokine-related genetic polymorphisms account for variability in cytokine response and may predispose to the development of /"lactic acidosis"/ after cardiac surgery. METHODS: Routine postoperative cardiac surgery patients were studied. Lactic acid levels were greater than 4 mmol/L in study patients and less than 4 mmol/L in controls. Polymerase chain reaction-based techniques were used to examine carriage of tumor necrosis factor beta (TNF-beta), TNF G-308A, and /"interleukin 10"/ (/"IL-10"/) G-1082A alleles. RESULTS: Demographic characteristics and details of surgery were similar for 30 control and 21 study patients. Lactic acid levels after intensive care admission changed over time and were related to both TNF-beta and /"IL-10"/ G-1082A polymorphisms. All 4 study patients homozygous for TNF-beta1 and carrying an /"IL-10"/-1082A allele developed /"lactic acidosis"/ (p = 0.02). There was no relation between the rate of epinephrine infusion or duration of cardiopulmonary bypass and lactic acid levels. CONCLUSIONS: Genetic factors have a role in the development of /"lactic acidosis"/ after cardiac surgery. | [
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} | Yes |
12078789 | Lactic acidosis after cardiac surgery is associated with polymorphisms in tumor necrosis factor and interleukin 10 genes. | BACKGROUND: Lactic acidosis after cardiac surgery is a manifestation of excess cytokine production. Cytokine-related genetic polymorphisms account for variability in cytokine response and may predispose to the development of lactic acidosis after cardiac surgery. METHODS: Routine postoperative cardiac surgery patients were studied. Lactic acid levels were greater than 4 mmol/L in study patients and less than 4 mmol/L in controls. Polymerase chain reaction-based techniques were used to examine carriage of tumor necrosis factor beta (TNF-beta), TNF G-308A, and interleukin 10 (IL-10) G-1082A alleles. RESULTS: Demographic characteristics and details of surgery were similar for 30 control and 21 study patients. Lactic acid levels after intensive care admission changed over time and were related to both TNF-beta and IL-10 G-1082A polymorphisms. All 4 study patients homozygous for TNF-beta1 and carrying an IL-10-1082A allele developed lactic acidosis (p = 0.02). There was no relation between the rate of epinephrine infusion or duration of cardiopulmonary bypass and lactic acid levels. CONCLUSIONS: Genetic factors have a role in the development of lactic acidosis after cardiac surgery. | /"Lactic acidosis"/ after cardiac surgery is associated with polymorphisms in tumor necrosis factor and interleukin 10 genes. | BACKGROUND: /"Lactic acidosis"/ after cardiac surgery is a manifestation of excess cytokine production. Cytokine-related genetic polymorphisms account for variability in cytokine response and may predispose to the development of /"lactic acidosis"/ after cardiac surgery. METHODS: Routine postoperative cardiac surgery patients were studied. Lactic acid levels were greater than 4 mmol/L in study patients and less than 4 mmol/L in controls. Polymerase chain reaction-based techniques were used to examine carriage of /"tumor necrosis factor beta"/ (/"TNF-beta"/), TNF G-308A, and interleukin 10 (IL-10) G-1082A alleles. RESULTS: Demographic characteristics and details of surgery were similar for 30 control and 21 study patients. Lactic acid levels after intensive care admission changed over time and were related to both /"TNF-beta"/ and IL-10 G-1082A polymorphisms. All 4 study patients homozygous for TNF-beta1 and carrying an IL-10-1082A allele developed /"lactic acidosis"/ (p = 0.02). There was no relation between the rate of epinephrine infusion or duration of cardiopulmonary bypass and lactic acid levels. CONCLUSIONS: Genetic factors have a role in the development of /"lactic acidosis"/ after cardiac surgery. | [
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} | No |
12080485 | Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. | Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as "Nasu-Hakola disease," is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype. | Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. | /"Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy"/ (/"PLOSL"/), also known as "/"Nasu-Hakola disease"/," is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified /"PLOSL"/ mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in /"PLOSL"/, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of /"PLOSL"/ by identifying /"TREM2"/ as the second /"PLOSL"/ gene. /"TREM2"/ forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with /"PLOSL"/ have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype. | [
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12080485 | Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. | Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as "Nasu-Hakola disease," is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype. | Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. | /"Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy"/ (/"PLOSL"/), also known as "/"Nasu-Hakola disease"/," is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified /"PLOSL"/ mutations in /"TYROBP"/ (/"DAP12"/), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in /"PLOSL"/, with some patients carrying no mutations in /"TYROBP"/. Here we complete the molecular pathology of /"PLOSL"/ by identifying TREM2 as the second /"PLOSL"/ gene. TREM2 forms a receptor signaling complex with /"TYROBP"/ and triggers activation of the immune responses in macrophages and dendritic cells. Patients with /"PLOSL"/ have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive /"TYROBP"/-mediated activation pathway. Our data imply that the /"TYROBP"/-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype. | [
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} | No |
12081984 | Serotonin transporter gene polymorphism and myocardial infarction: Etude Cas-T moins de l'Infarctus du Myocarde (ECTIM). | BACKGROUND: Depression is a risk factor for myocardial infarction (MI). Selective serotonin reuptake inhibitors reduce this risk. The site of action is the serotonin transporter (SLC6A4), which is expressed in brain and blood cells. A functional polymorphism in the promoter region of the SLC6A4 gene has been described. This polymorphism may be associated with the risk of MI. METHODS AND RESULTS: The SLC6A4 polymorphism has been investigated by polymerase chain reaction in 671 male patients with MI and in 688 controls from the Etude Cas-T moins de l'Infarctus du Myocarde (ECTIM) multicentric study. Percentages for LL, LS, and SS genotypes were 35.5%, 45.4%, and 19.1%, respectively, for cases versus 28.1%, 49.1%, and 22.8%, respectively, for controls. S allele frequency was 41.8% and 47.4% for cases and controls, respectively. After adjustment for age and center by using multivariable logistic regression, the odds ratio for MI associated with the LL genotype was 1.40 (95% CI 1.11 to 1.76, P=0.0047). CONCLUSIONS: The LL genotype of the SLC6A4 polymorphism is associated with a higher risk of MI. This could be attributable to the effect of the polymorphism on serotonin-mediated platelet activation or smooth muscle cell proliferation or on other risk factors, such as depression or response to stress. | /"Serotonin transporter"/ gene polymorphism and /"myocardial infarction"/: Etude Cas-T moins de l'Infarctus du Myocarde (ECTIM). | BACKGROUND: Depression is a risk factor for /"myocardial infarction"/ (/"MI"/). Selective serotonin reuptake inhibitors reduce this risk. The site of action is the /"serotonin transporter"/ (/"SLC6A4"/), which is expressed in brain and blood cells. A functional polymorphism in the promoter region of the /"SLC6A4"/ gene has been described. This polymorphism may be associated with the risk of /"MI"/. METHODS AND RESULTS: The /"SLC6A4"/ polymorphism has been investigated by polymerase chain reaction in 671 male patients with /"MI"/ and in 688 controls from the Etude Cas-T moins de l'Infarctus du Myocarde (ECTIM) multicentric study. Percentages for LL, LS, and SS genotypes were 35.5%, 45.4%, and 19.1%, respectively, for cases versus 28.1%, 49.1%, and 22.8%, respectively, for controls. S allele frequency was 41.8% and 47.4% for cases and controls, respectively. After adjustment for age and center by using multivariable logistic regression, the odds ratio for /"MI"/ associated with the LL genotype was 1.40 (95% CI 1.11 to 1.76, P=0.0047). CONCLUSIONS: The LL genotype of the /"SLC6A4"/ polymorphism is associated with a higher risk of /"MI"/. This could be attributable to the effect of the polymorphism on serotonin-mediated platelet activation or smooth muscle cell proliferation or on other risk factors, such as depression or response to stress. | [
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12081984 | Serotonin transporter gene polymorphism and myocardial infarction: Etude Cas-T moins de l'Infarctus du Myocarde (ECTIM). | BACKGROUND: Depression is a risk factor for myocardial infarction (MI). Selective serotonin reuptake inhibitors reduce this risk. The site of action is the serotonin transporter (SLC6A4), which is expressed in brain and blood cells. A functional polymorphism in the promoter region of the SLC6A4 gene has been described. This polymorphism may be associated with the risk of MI. METHODS AND RESULTS: The SLC6A4 polymorphism has been investigated by polymerase chain reaction in 671 male patients with MI and in 688 controls from the Etude Cas-T moins de l'Infarctus du Myocarde (ECTIM) multicentric study. Percentages for LL, LS, and SS genotypes were 35.5%, 45.4%, and 19.1%, respectively, for cases versus 28.1%, 49.1%, and 22.8%, respectively, for controls. S allele frequency was 41.8% and 47.4% for cases and controls, respectively. After adjustment for age and center by using multivariable logistic regression, the odds ratio for MI associated with the LL genotype was 1.40 (95% CI 1.11 to 1.76, P=0.0047). CONCLUSIONS: The LL genotype of the SLC6A4 polymorphism is associated with a higher risk of MI. This could be attributable to the effect of the polymorphism on serotonin-mediated platelet activation or smooth muscle cell proliferation or on other risk factors, such as depression or response to stress. | /"Serotonin transporter"/ gene polymorphism and myocardial infarction: Etude Cas-T moins de l'Infarctus du Myocarde (ECTIM). | BACKGROUND: /"Depression"/ is a risk factor for myocardial infarction (MI). Selective serotonin reuptake inhibitors reduce this risk. The site of action is the /"serotonin transporter"/ (/"SLC6A4"/), which is expressed in brain and blood cells. A functional polymorphism in the promoter region of the /"SLC6A4"/ gene has been described. This polymorphism may be associated with the risk of MI. METHODS AND RESULTS: The /"SLC6A4"/ polymorphism has been investigated by polymerase chain reaction in 671 male patients with MI and in 688 controls from the Etude Cas-T moins de l'Infarctus du Myocarde (ECTIM) multicentric study. Percentages for LL, LS, and SS genotypes were 35.5%, 45.4%, and 19.1%, respectively, for cases versus 28.1%, 49.1%, and 22.8%, respectively, for controls. S allele frequency was 41.8% and 47.4% for cases and controls, respectively. After adjustment for age and center by using multivariable logistic regression, the odds ratio for MI associated with the LL genotype was 1.40 (95% CI 1.11 to 1.76, P=0.0047). CONCLUSIONS: The LL genotype of the /"SLC6A4"/ polymorphism is associated with a higher risk of MI. This could be attributable to the effect of the polymorphism on serotonin-mediated platelet activation or smooth muscle cell proliferation or on other risk factors, such as /"depression"/ or response to stress. | [
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12089173 | Relationship between genetic polymorphisms of alcohol-metabolizing enzymes and changes in risk factors for coronary heart disease associated with alcohol consumption. | BACKGROUND: There are large individual variations in the responses of risk factors for coronary heart disease to alcohol consumption. To clarify the factors responsible for these individual variations, we studied the relationship between blood pressure, serum lipids, and uric acid and the genetic polymorphisms of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 in alcohol drinkers. METHODS: We examined 133 male workers who drank >300 g of alcohol per week. Information regarding lifestyle habits was obtained by questionnaire. The ADH2 genotype was determined by PCR and subsequent digestion with MaeIII. The ALDH2 genotype was determined based on amplified product length polymorphisms. RESULTS: When the workers were divided into three groups: the ADH2(1)/2(1), ADH2(1)/2(2), and ADH2(2)/2(2) groups, the mean triglycerides and gamma-glutamyl transpeptidase concentrations were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In addition, multiple logistic regression analysis showed that the frequencies of individuals whose systolic blood pressure, triglycerides, and uric acid values were in the highest one third were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In contrast, no difference was observed between the ALDH2(1)/2(1) and (ALDH2(1)/2(2) + ALDH2(2)/2(2)) groups with regard to the mean value of any variable and to the frequency of individuals with any variable value in the highest one third. CONCLUSION: Individuals with the ADH2(1)/2(1) genotype might suffer fewer negative effects of drinking. | Relationship between genetic polymorphisms of alcohol-metabolizing enzymes and changes in risk factors for /"coronary heart disease"/ associated with alcohol consumption. | BACKGROUND: There are large individual variations in the responses of risk factors for /"coronary heart disease"/ to alcohol consumption. To clarify the factors responsible for these individual variations, we studied the relationship between blood pressure, serum lipids, and uric acid and the genetic polymorphisms of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 in alcohol drinkers. METHODS: We examined 133 male workers who drank >300 g of alcohol per week. Information regarding lifestyle habits was obtained by questionnaire. The ADH2 genotype was determined by PCR and subsequent digestion with MaeIII. The /"ALDH2"/ genotype was determined based on amplified product length polymorphisms. RESULTS: When the workers were divided into three groups: the ADH2(1)/2(1), ADH2(1)/2(2), and ADH2(2)/2(2) groups, the mean triglycerides and gamma-glutamyl transpeptidase concentrations were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In addition, multiple logistic regression analysis showed that the frequencies of individuals whose systolic blood pressure, triglycerides, and uric acid values were in the highest one third were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In contrast, no difference was observed between the /"ALDH2"/(1)/2(1) and (/"ALDH2"/(1)/2(2) + /"ALDH2"/(2)/2(2)) groups with regard to the mean value of any variable and to the frequency of individuals with any variable value in the highest one third. CONCLUSION: Individuals with the ADH2(1)/2(1) genotype might suffer fewer negative effects of drinking. | [
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12089173 | Relationship between genetic polymorphisms of alcohol-metabolizing enzymes and changes in risk factors for coronary heart disease associated with alcohol consumption. | BACKGROUND: There are large individual variations in the responses of risk factors for coronary heart disease to alcohol consumption. To clarify the factors responsible for these individual variations, we studied the relationship between blood pressure, serum lipids, and uric acid and the genetic polymorphisms of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 in alcohol drinkers. METHODS: We examined 133 male workers who drank >300 g of alcohol per week. Information regarding lifestyle habits was obtained by questionnaire. The ADH2 genotype was determined by PCR and subsequent digestion with MaeIII. The ALDH2 genotype was determined based on amplified product length polymorphisms. RESULTS: When the workers were divided into three groups: the ADH2(1)/2(1), ADH2(1)/2(2), and ADH2(2)/2(2) groups, the mean triglycerides and gamma-glutamyl transpeptidase concentrations were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In addition, multiple logistic regression analysis showed that the frequencies of individuals whose systolic blood pressure, triglycerides, and uric acid values were in the highest one third were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In contrast, no difference was observed between the ALDH2(1)/2(1) and (ALDH2(1)/2(2) + ALDH2(2)/2(2)) groups with regard to the mean value of any variable and to the frequency of individuals with any variable value in the highest one third. CONCLUSION: Individuals with the ADH2(1)/2(1) genotype might suffer fewer negative effects of drinking. | Relationship between genetic polymorphisms of alcohol-metabolizing enzymes and changes in risk factors for /"coronary heart disease"/ associated with alcohol consumption. | BACKGROUND: There are large individual variations in the responses of risk factors for /"coronary heart disease"/ to alcohol consumption. To clarify the factors responsible for these individual variations, we studied the relationship between blood pressure, serum lipids, and uric acid and the genetic polymorphisms of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 in alcohol drinkers. METHODS: We examined 133 male workers who drank >300 g of alcohol per week. Information regarding lifestyle habits was obtained by questionnaire. The /"ADH2"/ genotype was determined by PCR and subsequent digestion with MaeIII. The ALDH2 genotype was determined based on amplified product length polymorphisms. RESULTS: When the workers were divided into three groups: the /"ADH2"/(1)/2(1), /"ADH2"/(1)/2(2), and /"ADH2"/(2)/2(2) groups, the mean triglycerides and gamma-glutamyl transpeptidase concentrations were significantly higher in the /"ADH2"/(2)/2(2) group than in the /"ADH2"/(1)/2(1) group. In addition, multiple logistic regression analysis showed that the frequencies of individuals whose systolic blood pressure, triglycerides, and uric acid values were in the highest one third were significantly higher in the /"ADH2"/(2)/2(2) group than in the /"ADH2"/(1)/2(1) group. In contrast, no difference was observed between the ALDH2(1)/2(1) and (ALDH2(1)/2(2) + ALDH2(2)/2(2)) groups with regard to the mean value of any variable and to the frequency of individuals with any variable value in the highest one third. CONCLUSION: Individuals with the /"ADH2"/(1)/2(1) genotype might suffer fewer negative effects of drinking. | [
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12102452 | The angiotensin-converting enzyme gene I/D polymorphism and heart rate variability following acute myocardial infarction. | AIMS: Heart rate variability (HRV) is a measure of cardiac autonomic control and is therefore subject to regulation by the renin-angiotensin system. The primary objective of this study was to determine the effect of an insertion/deletion polymorphism within the angiotensin-converting enzyme (ACE) gene on HRV in the early stages after a myocardial infarction at a time when cardiac autonomic control is deranged. The secondary objective was to determine whether this polymorphism affected the HRV response to inhibition of ACE. MAJOR FINDINGS: 149 Caucasian subjects were studied 25 +/- 16 h following MI using time and frequency domain measures of HRV derived from two 5-minute ECG recordings. Recordings were repeated at 182 +/- 65 h following MI, when subjects had been stabilised on ramipril 2.5 mg bd. The study included 46 subjects with the DD genotype, 69 with the ID genotype, and 34 with the II genotype. No effect of the I/D polymorphism on short-term recordings of HRV was found. There was no difference in HRV response to the introduction of ramipril according to the genotypes. PRINCIPAL CONCLUSIONS: The I/D polymorphism within the ACE gene does not influence HRV after MI or the HRV response to ACE inhibitor therapy with ramipril. These findings may reflect the relative lack of importance of the I/D polymorphism and ACE activity in determining plasma and tissue angiotensin II concentration after a major stimulus to the renin-angiotensin system as occurs after myocardial infarction. | The angiotensin-converting enzyme gene I/D polymorphism and heart rate variability following acute /"myocardial infarction"/. | AIMS: Heart rate variability (HRV) is a measure of cardiac autonomic control and is therefore subject to regulation by the renin-angiotensin system. The primary objective of this study was to determine the effect of an insertion/deletion polymorphism within the angiotensin-converting enzyme (/"ACE"/) gene on HRV in the early stages after a /"myocardial infarction"/ at a time when cardiac autonomic control is deranged. The secondary objective was to determine whether this polymorphism affected the HRV response to inhibition of /"ACE"/. MAJOR FINDINGS: 149 Caucasian subjects were studied 25 +/- 16 h following MI using time and frequency domain measures of HRV derived from two 5-minute ECG recordings. Recordings were repeated at 182 +/- 65 h following MI, when subjects had been stabilised on ramipril 2.5 mg bd. The study included 46 subjects with the DD genotype, 69 with the ID genotype, and 34 with the II genotype. No effect of the I/D polymorphism on short-term recordings of HRV was found. There was no difference in HRV response to the introduction of ramipril according to the genotypes. PRINCIPAL CONCLUSIONS: The I/D polymorphism within the /"ACE"/ gene does not influence HRV after MI or the HRV response to /"ACE"/ inhibitor therapy with ramipril. These findings may reflect the relative lack of importance of the I/D polymorphism and /"ACE"/ activity in determining plasma and tissue angiotensin II concentration after a major stimulus to the renin-angiotensin system as occurs after /"myocardial infarction"/. | [
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"text_name": "myocardial infarction"
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12102452 | The angiotensin-converting enzyme gene I/D polymorphism and heart rate variability following acute myocardial infarction. | AIMS: Heart rate variability (HRV) is a measure of cardiac autonomic control and is therefore subject to regulation by the renin-angiotensin system. The primary objective of this study was to determine the effect of an insertion/deletion polymorphism within the angiotensin-converting enzyme (ACE) gene on HRV in the early stages after a myocardial infarction at a time when cardiac autonomic control is deranged. The secondary objective was to determine whether this polymorphism affected the HRV response to inhibition of ACE. MAJOR FINDINGS: 149 Caucasian subjects were studied 25 +/- 16 h following MI using time and frequency domain measures of HRV derived from two 5-minute ECG recordings. Recordings were repeated at 182 +/- 65 h following MI, when subjects had been stabilised on ramipril 2.5 mg bd. The study included 46 subjects with the DD genotype, 69 with the ID genotype, and 34 with the II genotype. No effect of the I/D polymorphism on short-term recordings of HRV was found. There was no difference in HRV response to the introduction of ramipril according to the genotypes. PRINCIPAL CONCLUSIONS: The I/D polymorphism within the ACE gene does not influence HRV after MI or the HRV response to ACE inhibitor therapy with ramipril. These findings may reflect the relative lack of importance of the I/D polymorphism and ACE activity in determining plasma and tissue angiotensin II concentration after a major stimulus to the renin-angiotensin system as occurs after myocardial infarction. | The angiotensin-converting enzyme gene I/D polymorphism and heart rate variability following acute /"myocardial infarction"/. | AIMS: Heart rate variability (HRV) is a measure of cardiac autonomic control and is therefore subject to regulation by the renin-angiotensin system. The primary objective of this study was to determine the effect of an insertion/deletion polymorphism within the angiotensin-converting enzyme (ACE) gene on HRV in the early stages after a /"myocardial infarction"/ at a time when cardiac autonomic control is deranged. The secondary objective was to determine whether this polymorphism affected the HRV response to inhibition of ACE. MAJOR FINDINGS: 149 Caucasian subjects were studied 25 +/- 16 h following MI using time and frequency domain measures of HRV derived from two 5-minute ECG recordings. Recordings were repeated at 182 +/- 65 h following MI, when subjects had been stabilised on ramipril 2.5 mg bd. The study included 46 subjects with the DD genotype, 69 with the ID genotype, and 34 with the II genotype. No effect of the I/D polymorphism on short-term recordings of HRV was found. There was no difference in HRV response to the introduction of ramipril according to the genotypes. PRINCIPAL CONCLUSIONS: The I/D polymorphism within the ACE gene does not influence HRV after MI or the HRV response to ACE inhibitor therapy with ramipril. These findings may reflect the relative lack of importance of the I/D polymorphism and ACE activity in determining plasma and tissue /"angiotensin II"/ concentration after a major stimulus to the renin-angiotensin system as occurs after /"myocardial infarction"/. | [
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} | No |
12104085 | CETP gene mutation (D442G) increases low-density lipoprotein particle size in patients with coronary heart disease. | BACKGROUND: Small, dense low-density lipoprotein (LDL) in subjects with the atherogenic pattern B has been established as a risk factor of atherosclerosis. Cholesteryl ester transfer protein (CETP) plays an important role in the transfer and exchange of cholesteryl esters and triglycerides between the lipoprotein classes of human plasma. It has been shown that CETP can also change the particle size of high-density lipoprotein (HDL) and LDL subfractions in vitro. Previous clinical studies about CETP gene mutations mainly focused on abnormalities in HDL, few involved those in LDL. OBJECTIVES: To investigate the effect of the D442G mutation in the CETP gene on major peak size of LDL particles in patients with coronary heart diseases (CHD). METHODS: D442G mutation in the CETP gene was detected using the PCR-RFLP. LDL particles sizes were analyzed by 2-16% nondenaturing polyacrylamide gradient gels in CHD patients with D442G mutation in the CETP gene. RESULTS: Six heterozygotes and one homozygote were found to have the D442G mutation among 200 CHD patients. The frequency of this mutation was 3.5%. The major peak size of LDL in patients with gene mutation (n=7) was significantly larger than that in patients without the mutation (n=40) (26.92 +/- 0.79 nm vs. 25.71 +/- 0.66 nm, respectively; P<0.01). All the patients with the gene mutation expressed pattern A, whereas only about half of the patients without the mutation expressed this pattern. The patients with gene mutation had decreased plasma CETP concentration, while increased concentration of HDL-C and apolipoprotein A-I compared with controls. CONCLUSIONS: CETP gene mutation (D442G) increases LDL particle size. This suggests that CETP play an antiatherogenic role. | /"CETP"/ gene mutation (D442G) increases low-density lipoprotein particle size in patients with /"coronary heart disease"/. | BACKGROUND: Small, dense low-density lipoprotein (LDL) in subjects with the atherogenic pattern B has been established as a risk factor of atherosclerosis. /"Cholesteryl ester transfer protein"/ (/"CETP"/) plays an important role in the transfer and exchange of cholesteryl esters and triglycerides between the lipoprotein classes of human plasma. It has been shown that /"CETP"/ can also change the particle size of high-density lipoprotein (HDL) and LDL subfractions in vitro. Previous clinical studies about /"CETP"/ gene mutations mainly focused on abnormalities in HDL, few involved those in LDL. OBJECTIVES: To investigate the effect of the D442G mutation in the /"CETP"/ gene on major peak size of LDL particles in patients with /"coronary heart diseases"/ (/"CHD"/). METHODS: D442G mutation in the /"CETP"/ gene was detected using the PCR-RFLP. LDL particles sizes were analyzed by 2-16% nondenaturing polyacrylamide gradient gels in /"CHD"/ patients with D442G mutation in the /"CETP"/ gene. RESULTS: Six heterozygotes and one homozygote were found to have the D442G mutation among 200 /"CHD"/ patients. The frequency of this mutation was 3.5%. The major peak size of LDL in patients with gene mutation (n=7) was significantly larger than that in patients without the mutation (n=40) (26.92 +/- 0.79 nm vs. 25.71 +/- 0.66 nm, respectively; P<0.01). All the patients with the gene mutation expressed pattern A, whereas only about half of the patients without the mutation expressed this pattern. The patients with gene mutation had decreased plasma /"CETP"/ concentration, while increased concentration of HDL-C and apolipoprotein A-I compared with controls. CONCLUSIONS: /"CETP"/ gene mutation (D442G) increases LDL particle size. This suggests that /"CETP"/ play an antiatherogenic role. | [
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} | Yes |
12104085 | CETP gene mutation (D442G) increases low-density lipoprotein particle size in patients with coronary heart disease. | BACKGROUND: Small, dense low-density lipoprotein (LDL) in subjects with the atherogenic pattern B has been established as a risk factor of atherosclerosis. Cholesteryl ester transfer protein (CETP) plays an important role in the transfer and exchange of cholesteryl esters and triglycerides between the lipoprotein classes of human plasma. It has been shown that CETP can also change the particle size of high-density lipoprotein (HDL) and LDL subfractions in vitro. Previous clinical studies about CETP gene mutations mainly focused on abnormalities in HDL, few involved those in LDL. OBJECTIVES: To investigate the effect of the D442G mutation in the CETP gene on major peak size of LDL particles in patients with coronary heart diseases (CHD). METHODS: D442G mutation in the CETP gene was detected using the PCR-RFLP. LDL particles sizes were analyzed by 2-16% nondenaturing polyacrylamide gradient gels in CHD patients with D442G mutation in the CETP gene. RESULTS: Six heterozygotes and one homozygote were found to have the D442G mutation among 200 CHD patients. The frequency of this mutation was 3.5%. The major peak size of LDL in patients with gene mutation (n=7) was significantly larger than that in patients without the mutation (n=40) (26.92 +/- 0.79 nm vs. 25.71 +/- 0.66 nm, respectively; P<0.01). All the patients with the gene mutation expressed pattern A, whereas only about half of the patients without the mutation expressed this pattern. The patients with gene mutation had decreased plasma CETP concentration, while increased concentration of HDL-C and apolipoprotein A-I compared with controls. CONCLUSIONS: CETP gene mutation (D442G) increases LDL particle size. This suggests that CETP play an antiatherogenic role. | /"CETP"/ gene mutation (D442G) increases low-density lipoprotein particle size in patients with coronary heart disease. | BACKGROUND: Small, dense low-density lipoprotein (LDL) in subjects with the atherogenic pattern B has been established as a risk factor of /"atherosclerosis"/. /"Cholesteryl ester transfer protein"/ (/"CETP"/) plays an important role in the transfer and exchange of cholesteryl esters and triglycerides between the lipoprotein classes of human plasma. It has been shown that /"CETP"/ can also change the particle size of high-density lipoprotein (HDL) and LDL subfractions in vitro. Previous clinical studies about /"CETP"/ gene mutations mainly focused on abnormalities in HDL, few involved those in LDL. OBJECTIVES: To investigate the effect of the D442G mutation in the /"CETP"/ gene on major peak size of LDL particles in patients with coronary heart diseases (CHD). METHODS: D442G mutation in the /"CETP"/ gene was detected using the PCR-RFLP. LDL particles sizes were analyzed by 2-16% nondenaturing polyacrylamide gradient gels in CHD patients with D442G mutation in the /"CETP"/ gene. RESULTS: Six heterozygotes and one homozygote were found to have the D442G mutation among 200 CHD patients. The frequency of this mutation was 3.5%. The major peak size of LDL in patients with gene mutation (n=7) was significantly larger than that in patients without the mutation (n=40) (26.92 +/- 0.79 nm vs. 25.71 +/- 0.66 nm, respectively; P<0.01). All the patients with the gene mutation expressed pattern A, whereas only about half of the patients without the mutation expressed this pattern. The patients with gene mutation had decreased plasma /"CETP"/ concentration, while increased concentration of HDL-C and apolipoprotein A-I compared with controls. CONCLUSIONS: /"CETP"/ gene mutation (D442G) increases LDL particle size. This suggests that /"CETP"/ play an antiatherogenic role. | [
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} | {
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12135317 | Association of G-33A polymorphism in the thrombomodulin gene with myocardial infarction in Koreans. | Thrombomodulin (TM), a thrombin receptor expressed on the endothelial surface, is known to play an important role in the anti-thrombogenic system in vivo. In this study, we examined the effects of 3 single-nucleotide polymorphisms (SNPs) in the TM gene (G-33A, C1418T and C1922T) on the development of myocardial infarction (MI) in Koreans. We found that G-33A was a common SNP (the minor allele frequency was 0.09) in Koreans. Eighty-five MI patients who had received coronary angiography were enrolled and were divided into 3 groups according to the number of coronary arteries in which stenosis was found angiographically (1-vessel disease (1VD) to 3-vessel disease (3VD)). The criterion of coronary stenosis was 50% or more stenosis on angiography. In addition, 102 controls (CONT) who had no significant stenosis were employed. The number of AA/GA genotypes of G-33A was found to be significantly greater in the 1VD than in the CONT (p=0.004 by chi2-test) while no significant difference was found between the multivessel disease (2-3VD) and the CONT. Multiple logistic analysis showed that G-33A was an independent risk factor for the 1VD with an odds ratio of 4.63 (95% confidence interval; 1.62-13.3). C1418T and C1922T were both in linkage disequilibrium with G-33A; however, they were not independent risks for either the 1VD or the 2-3VD. A reporter gene assay showed that G-33A had a significant effect on the TM promoter activity. These results indicated that G-33A polymorphism in TM might be a genetic risk factor for myocardial infarction. | Association of G-33A polymorphism in the /"thrombomodulin"/ gene with /"myocardial infarction"/ in Koreans. | /"Thrombomodulin"/ (/"TM"/), a thrombin receptor expressed on the endothelial surface, is known to play an important role in the anti-thrombogenic system in vivo. In this study, we examined the effects of 3 single-nucleotide polymorphisms (SNPs) in the /"TM"/ gene (G-33A, C1418T and C1922T) on the development of /"myocardial infarction"/ (/"MI"/) in Koreans. We found that G-33A was a common SNP (the minor allele frequency was 0.09) in Koreans. Eighty-five /"MI"/ patients who had received coronary angiography were enrolled and were divided into 3 groups according to the number of coronary arteries in which stenosis was found angiographically (1-vessel disease (1VD) to 3-vessel disease (3VD)). The criterion of coronary stenosis was 50% or more stenosis on angiography. In addition, 102 controls (CONT) who had no significant stenosis were employed. The number of AA/GA genotypes of G-33A was found to be significantly greater in the 1VD than in the CONT (p=0.004 by chi2-test) while no significant difference was found between the multivessel disease (2-3VD) and the CONT. Multiple logistic analysis showed that G-33A was an independent risk factor for the 1VD with an odds ratio of 4.63 (95% confidence interval; 1.62-13.3). C1418T and C1922T were both in linkage disequilibrium with G-33A; however, they were not independent risks for either the 1VD or the 2-3VD. A reporter gene assay showed that G-33A had a significant effect on the /"TM"/ promoter activity. These results indicated that G-33A polymorphism in /"TM"/ might be a genetic risk factor for /"myocardial infarction"/. | [
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"text_name": "myocardial infarction"
} | Yes |
12135317 | Association of G-33A polymorphism in the thrombomodulin gene with myocardial infarction in Koreans. | Thrombomodulin (TM), a thrombin receptor expressed on the endothelial surface, is known to play an important role in the anti-thrombogenic system in vivo. In this study, we examined the effects of 3 single-nucleotide polymorphisms (SNPs) in the TM gene (G-33A, C1418T and C1922T) on the development of myocardial infarction (MI) in Koreans. We found that G-33A was a common SNP (the minor allele frequency was 0.09) in Koreans. Eighty-five MI patients who had received coronary angiography were enrolled and were divided into 3 groups according to the number of coronary arteries in which stenosis was found angiographically (1-vessel disease (1VD) to 3-vessel disease (3VD)). The criterion of coronary stenosis was 50% or more stenosis on angiography. In addition, 102 controls (CONT) who had no significant stenosis were employed. The number of AA/GA genotypes of G-33A was found to be significantly greater in the 1VD than in the CONT (p=0.004 by chi2-test) while no significant difference was found between the multivessel disease (2-3VD) and the CONT. Multiple logistic analysis showed that G-33A was an independent risk factor for the 1VD with an odds ratio of 4.63 (95% confidence interval; 1.62-13.3). C1418T and C1922T were both in linkage disequilibrium with G-33A; however, they were not independent risks for either the 1VD or the 2-3VD. A reporter gene assay showed that G-33A had a significant effect on the TM promoter activity. These results indicated that G-33A polymorphism in TM might be a genetic risk factor for myocardial infarction. | Association of G-33A polymorphism in the /"thrombomodulin"/ gene with myocardial infarction in Koreans. | /"Thrombomodulin"/ (/"TM"/), a thrombin receptor expressed on the endothelial surface, is known to play an important role in the anti-thrombogenic system in vivo. In this study, we examined the effects of 3 single-nucleotide polymorphisms (SNPs) in the /"TM"/ gene (G-33A, C1418T and C1922T) on the development of myocardial infarction (MI) in Koreans. We found that G-33A was a common SNP (the minor allele frequency was 0.09) in Koreans. Eighty-five MI patients who had received coronary angiography were enrolled and were divided into 3 groups according to the number of coronary arteries in which /"stenosis"/ was found angiographically (1-vessel disease (1VD) to 3-vessel disease (3VD)). The criterion of coronary stenosis was 50% or more /"stenosis"/ on angiography. In addition, 102 controls (CONT) who had no significant /"stenosis"/ were employed. The number of AA/GA genotypes of G-33A was found to be significantly greater in the 1VD than in the CONT (p=0.004 by chi2-test) while no significant difference was found between the multivessel disease (2-3VD) and the CONT. Multiple logistic analysis showed that G-33A was an independent risk factor for the 1VD with an odds ratio of 4.63 (95% confidence interval; 1.62-13.3). C1418T and C1922T were both in linkage disequilibrium with G-33A; however, they were not independent risks for either the 1VD or the 2-3VD. A reporter gene assay showed that G-33A had a significant effect on the /"TM"/ promoter activity. These results indicated that G-33A polymorphism in /"TM"/ might be a genetic risk factor for myocardial infarction. | [
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12136242 | Prevalence of the CCR5Delta32 mutation in Brazilian populations and cell susceptibility to HIV-1 infection. | We investigated the occurrence of the CCR5Delta32 mutation in various regional ethnic groups in Brazil and tested the resistance of mutant peripheral blood mononuclear cells (PBMCs) to infection by HIV-1 in vitro. The heterozygous prevalence was 5.3% in uninfected African descendents and 8.8% in HIV-1-positive individuals (neither population had Delta32/Delta32). German descendents were 11% heterozygous and l% Delta32/Delta32. Amerindians were exclusively CCR5/CCR5. Heterozygous uninfected PBMCs showed partial resistance to R5-HIV-1 strains in vitro, but no resistance to X4 virus. HIV-1-positive CCR5/CCR5 had higher viral loads than did heterozygous cells. | Prevalence of the CCR5Delta32 mutation in Brazilian populations and cell susceptibility to /"HIV-1 infection"/. | We investigated the occurrence of the CCR5Delta32 mutation in various regional ethnic groups in Brazil and tested the resistance of mutant peripheral blood mononuclear cells (PBMCs) to /"infection by HIV-1"/ in vitro. The heterozygous prevalence was 5.3% in uninfected African descendents and 8.8% in HIV-1-positive individuals (neither population had Delta32/Delta32). German descendents were 11% heterozygous and l% Delta32/Delta32. Amerindians were exclusively /"CCR5"///"CCR5"/. Heterozygous uninfected PBMCs showed partial resistance to R5-HIV-1 strains in vitro, but no resistance to X4 virus. HIV-1-positive /"CCR5"///"CCR5"/ had higher viral loads than did heterozygous cells. | [
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"text_name": "infection by HIV-1"
} | Yes |
12140136 | A T2517C polymorphism in the GSTM4 gene is associated with risk of developing lung cancer. | The human Mu class Glutathione S-Transferases is a family of genes encoding phase II detoxifying enzymes thus playing a significant role in the detoxification of potential carcinogens. While there are many contradicting reports on the association of GSTM1 polymorphisms and cancer development, no studies exist to date describing polymorphisms in GSTM4. We have identified a new C-T polymorphism in intron 6 of the GSTM4 gene (T2517C, Genebank sequence accession number X68677) and termed the allele carrying T at this position allele *A and the allele carrying C, allele *B. Screening a population sample in Merseyside, England, revealed 23 carriers of the *B allele out of 156 healthy control individuals but only 12 carriers of the *B allele out of 163 individuals with lung cancer (O.R.=2.23, Fisher's test P=0.026). The polymorphism did not demonstrate any associations with tumour type, gender, and age at presentation. This is the first report on the implication of a polymorphism in the GSTM4 gene in lung cancer risk. Further studies are required to investigate the relation of this polymorphism to cancer risk to substantiate these findings. | A T2517C polymorphism in the /"GSTM4"/ gene is associated with risk of developing /"lung cancer"/. | The human Mu class Glutathione S-Transferases is a family of genes encoding phase II detoxifying enzymes thus playing a significant role in the detoxification of potential carcinogens. While there are many contradicting reports on the association of GSTM1 polymorphisms and cancer development, no studies exist to date describing polymorphisms in /"GSTM4"/. We have identified a new C-T polymorphism in intron 6 of the /"GSTM4"/ gene (T2517C, Genebank sequence accession number X68677) and termed the allele carrying T at this position allele *A and the allele carrying C, allele *B. Screening a population sample in Merseyside, England, revealed 23 carriers of the *B allele out of 156 healthy control individuals but only 12 carriers of the *B allele out of 163 individuals with /"lung cancer"/ (O.R.=2.23, Fisher's test P=0.026). The polymorphism did not demonstrate any associations with tumour type, gender, and age at presentation. This is the first report on the implication of a polymorphism in the /"GSTM4"/ gene in /"lung cancer"/ risk. Further studies are required to investigate the relation of this polymorphism to cancer risk to substantiate these findings. | [
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"text_name": "lung cancer"
} | Yes |
12140136 | A T2517C polymorphism in the GSTM4 gene is associated with risk of developing lung cancer. | The human Mu class Glutathione S-Transferases is a family of genes encoding phase II detoxifying enzymes thus playing a significant role in the detoxification of potential carcinogens. While there are many contradicting reports on the association of GSTM1 polymorphisms and cancer development, no studies exist to date describing polymorphisms in GSTM4. We have identified a new C-T polymorphism in intron 6 of the GSTM4 gene (T2517C, Genebank sequence accession number X68677) and termed the allele carrying T at this position allele *A and the allele carrying C, allele *B. Screening a population sample in Merseyside, England, revealed 23 carriers of the *B allele out of 156 healthy control individuals but only 12 carriers of the *B allele out of 163 individuals with lung cancer (O.R.=2.23, Fisher's test P=0.026). The polymorphism did not demonstrate any associations with tumour type, gender, and age at presentation. This is the first report on the implication of a polymorphism in the GSTM4 gene in lung cancer risk. Further studies are required to investigate the relation of this polymorphism to cancer risk to substantiate these findings. | A T2517C polymorphism in the /"GSTM4"/ gene is associated with risk of developing lung cancer. | The human Mu class Glutathione S-Transferases is a family of genes encoding phase II detoxifying enzymes thus playing a significant role in the detoxification of potential carcinogens. While there are many contradicting reports on the association of GSTM1 polymorphisms and /"cancer"/ development, no studies exist to date describing polymorphisms in /"GSTM4"/. We have identified a new C-T polymorphism in intron 6 of the /"GSTM4"/ gene (T2517C, Genebank sequence accession number X68677) and termed the allele carrying T at this position allele *A and the allele carrying C, allele *B. Screening a population sample in Merseyside, England, revealed 23 carriers of the *B allele out of 156 healthy control individuals but only 12 carriers of the *B allele out of 163 individuals with lung cancer (O.R.=2.23, Fisher's test P=0.026). The polymorphism did not demonstrate any associations with /"tumour"/ type, gender, and age at presentation. This is the first report on the implication of a polymorphism in the /"GSTM4"/ gene in lung cancer risk. Further studies are required to investigate the relation of this polymorphism to /"cancer"/ risk to substantiate these findings. | [
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12140789 | Genetic predisposition to obesity in bulimia nervosa: a mutation screen of the melanocortin-4 receptor gene. | Obesity has been identified as a risk factor for the development of bulimia nervosa (BN). Accordingly, we hypothesize that genotypes predisposing to obesity can be detected in patients with this eating disorder. In order to investigate this hypothesis we screened the melanocortin-4 receptor gene (MC4R) for mutations using single strand conformation analysis in 81 female inpatients treated for BN. A single patient with both extreme obesity and BN had a haplo-insufficiency mutation in the MC4R. Comparison of current and maximal body mass index (BMI) of all patients with cross-sectionally obtained BMI in the general population revealed an age appropriate distribution for current BMI and a substantially increased frequency for overweight at time of maximal BMI. Our findings suggest that overweight is a risk factor for BN in clinically ascertained patients. For the first time a genotype predisposing to obesity has been detected in an extremely obese patient with BN. | Genetic predisposition to /"obesity"/ in bulimia nervosa: a mutation screen of the /"melanocortin-4 receptor"/ gene. | /"Obesity"/ has been identified as a risk factor for the development of bulimia nervosa (BN). Accordingly, we hypothesize that genotypes predisposing to /"obesity"/ can be detected in patients with this eating disorder. In order to investigate this hypothesis we screened the /"melanocortin-4 receptor"/ gene (/"MC4R"/) for mutations using single strand conformation analysis in 81 female inpatients treated for BN. A single patient with both extreme /"obesity"/ and BN had a haplo-insufficiency mutation in the /"MC4R"/. Comparison of current and maximal body mass index (BMI) of all patients with cross-sectionally obtained BMI in the general population revealed an age appropriate distribution for current BMI and a substantially increased frequency for overweight at time of maximal BMI. Our findings suggest that overweight is a risk factor for BN in clinically ascertained patients. For the first time a genotype predisposing to /"obesity"/ has been detected in an /"extremely obese"/ patient with BN. | [
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12140789 | Genetic predisposition to obesity in bulimia nervosa: a mutation screen of the melanocortin-4 receptor gene. | Obesity has been identified as a risk factor for the development of bulimia nervosa (BN). Accordingly, we hypothesize that genotypes predisposing to obesity can be detected in patients with this eating disorder. In order to investigate this hypothesis we screened the melanocortin-4 receptor gene (MC4R) for mutations using single strand conformation analysis in 81 female inpatients treated for BN. A single patient with both extreme obesity and BN had a haplo-insufficiency mutation in the MC4R. Comparison of current and maximal body mass index (BMI) of all patients with cross-sectionally obtained BMI in the general population revealed an age appropriate distribution for current BMI and a substantially increased frequency for overweight at time of maximal BMI. Our findings suggest that overweight is a risk factor for BN in clinically ascertained patients. For the first time a genotype predisposing to obesity has been detected in an extremely obese patient with BN. | Genetic predisposition to obesity in /"bulimia nervosa"/: a mutation screen of the /"melanocortin-4 receptor"/ gene. | Obesity has been identified as a risk factor for the development of /"bulimia nervosa"/ (/"BN"/). Accordingly, we hypothesize that genotypes predisposing to obesity can be detected in patients with this eating disorder. In order to investigate this hypothesis we screened the /"melanocortin-4 receptor"/ gene (/"MC4R"/) for mutations using single strand conformation analysis in 81 female inpatients treated for /"BN"/. A single patient with both extreme obesity and /"BN"/ had a haplo-insufficiency mutation in the /"MC4R"/. Comparison of current and maximal body mass index (BMI) of all patients with cross-sectionally obtained BMI in the general population revealed an age appropriate distribution for current BMI and a substantially increased frequency for overweight at time of maximal BMI. Our findings suggest that overweight is a risk factor for /"BN"/ in clinically ascertained patients. For the first time a genotype predisposing to obesity has been detected in an extremely obese patient with /"BN"/. | [
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