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14567462 | Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population. | AIMS: In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries. | Novel association of HLA-haplotypes with /"primary sclerosing cholangitis"/ (/"PSC"/) in a southern European population. | AIMS: In patients with with /"primary sclerosing cholangitis"/ we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 /"PSC"/ patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, /"DQA1"/*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, /"DQA1"/*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, /"DQA1"/*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in /"PSC"/ patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, /"DQA1"/*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, /"DQA1"/*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in /"PSC"/ patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries. | [
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14567462 | Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population. | AIMS: In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries. | Novel association of HLA-haplotypes with /"primary sclerosing cholangitis"/ (/"PSC"/) in a southern European population. | AIMS: In patients with with /"primary sclerosing cholangitis"/ we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 /"PSC"/ patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, /"DQA1"/*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, /"DQA1"/*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, /"DQA1"/*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in /"PSC"/ patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, /"DQA1"/*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, /"DQA1"/*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in /"PSC"/ patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries. | [
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} | No |
14567462 | Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population. | AIMS: In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries. | Novel association of HLA-haplotypes with /"primary sclerosing cholangitis"/ (/"PSC"/) in a southern European population. | AIMS: In patients with with /"primary sclerosing cholangitis"/ we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 /"PSC"/ patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, /"DQA1"/*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, /"DQA1"/*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, /"DQA1"/*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in /"PSC"/ patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, /"DQA1"/*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, /"DQA1"/*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in /"PSC"/ patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries. | [
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"text_name": "HLA-DRB1"
},
{
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"entity_id": "7124",
"entity_type": "Gene",
"text_name": "tumour necrosis factor A"
},
{
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"entity_id": "7124",
"entity_type": "Gene",
"text_name": "TNFA"
}
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} | {
"begin_idx": "338",
"end_idx": "341",
"entity_id": "D015209",
"entity_type": "Disease",
"text_name": "PSC"
} | No |
14567462 | Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population. | AIMS: In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries. | Novel association of HLA-haplotypes with /"primary sclerosing cholangitis"/ (/"PSC"/) in a southern European population. | AIMS: In patients with with /"primary sclerosing cholangitis"/ we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 /"PSC"/ patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, /"DQA1"/*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, /"DQA1"/*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, /"DQA1"/*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in /"PSC"/ patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, /"DQA1"/*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, /"DQA1"/*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in /"PSC"/ patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries. | [
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} | No |
14602139 | Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk. | Since tamoxifen has been shown to reduce the risk of oestrogen receptor (ER)-positive, but not ER-negative, breast cancers in a chemoprevention trial (P-1), it is important to develop assays to assess risk factors for ER-positive breast cancer in order to appropriately select candidates for chemoprevention with tamoxifen. Thus, the significance of genetic polymorphisms of genes involved in oestrogen biosynthesis (CYP19) and metabolism (CYP1A1) as a risk factor for ER-positive breast cancers was evaluated. A case-control study was conducted with 257 breast cancer patients and 191 healthy female controls. Two polymorphisms, CYP19 (TTTA repeats) in intron 4 and CYP1A1 6235C/T in the 3' non-coding region, and their association with the breast cancer risk after adjustment for the other epidemiological risk factors were examined. CYP19 (TTTA)7(-3bp) allele carriers showed a significantly (P<0.05) increased risk of ER-positive breast cancers (Odds Ratio (OR)=1.72, 95% Confidence Interval (CI) 1.10-2.69), but not ER-negative breast cancers. CYP1A1 6235C allele carriers showed a non-significant (P=0.06) trend towards a decreased risk of ER-positive breast cancers (OR=0.65, 95% CI 0.42-1.02), but not ER-negative breast cancers. The combination of these two polymorphisms was found to be more useful in the assessment of the ER-positive breast cancer risk (OR=3.00, 95% CI=1.56-5.74) than the CYP19 (TTTA)7(-3bp) polymorphism alone. The combination of CYP19 (TTTA)7(-3bp) and CYP1A1 6235C/T polymorphisms is associated with an ER-positive, but not ER-negative, breast cancer risk, and, thus, would be useful in the selection of candidates for chemoprevention with tamoxifen. | Association of genetic polymorphisms in /"CYP19"/ and CYP1A1 with the oestrogen receptor-positive /"breast cancer"/ risk. | Since tamoxifen has been shown to reduce the risk of oestrogen receptor (ER)-positive, but not ER-negative, /"breast cancers"/ in a chemoprevention trial (P-1), it is important to develop assays to assess risk factors for /"ER-positive breast cancer"/ in order to appropriately select candidates for chemoprevention with tamoxifen. Thus, the significance of genetic polymorphisms of genes involved in oestrogen biosynthesis (/"CYP19"/) and metabolism (CYP1A1) as a risk factor for /"ER-positive breast cancers"/ was evaluated. A case-control study was conducted with 257 /"breast cancer"/ patients and 191 healthy female controls. Two polymorphisms, /"CYP19"/ (TTTA repeats) in intron 4 and CYP1A1 6235C/T in the 3' non-coding region, and their association with the /"breast cancer"/ risk after adjustment for the other epidemiological risk factors were examined. /"CYP19"/ (TTTA)7(-3bp) allele carriers showed a significantly (P<0.05) increased risk of /"ER-positive breast cancers"/ (Odds Ratio (OR)=1.72, 95% Confidence Interval (CI) 1.10-2.69), but not ER-negative /"breast cancers"/. CYP1A1 6235C allele carriers showed a non-significant (P=0.06) trend towards a decreased risk of /"ER-positive breast cancers"/ (OR=0.65, 95% CI 0.42-1.02), but not ER-negative /"breast cancers"/. The combination of these two polymorphisms was found to be more useful in the assessment of the /"ER-positive breast cancer"/ risk (OR=3.00, 95% CI=1.56-5.74) than the /"CYP19"/ (TTTA)7(-3bp) polymorphism alone. The combination of /"CYP19"/ (TTTA)7(-3bp) and CYP1A1 6235C/T polymorphisms is associated with an ER-positive, but not ER-negative, /"breast cancer"/ risk, and, thus, would be useful in the selection of candidates for chemoprevention with tamoxifen. | [
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14602139 | Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk. | Since tamoxifen has been shown to reduce the risk of oestrogen receptor (ER)-positive, but not ER-negative, breast cancers in a chemoprevention trial (P-1), it is important to develop assays to assess risk factors for ER-positive breast cancer in order to appropriately select candidates for chemoprevention with tamoxifen. Thus, the significance of genetic polymorphisms of genes involved in oestrogen biosynthesis (CYP19) and metabolism (CYP1A1) as a risk factor for ER-positive breast cancers was evaluated. A case-control study was conducted with 257 breast cancer patients and 191 healthy female controls. Two polymorphisms, CYP19 (TTTA repeats) in intron 4 and CYP1A1 6235C/T in the 3' non-coding region, and their association with the breast cancer risk after adjustment for the other epidemiological risk factors were examined. CYP19 (TTTA)7(-3bp) allele carriers showed a significantly (P<0.05) increased risk of ER-positive breast cancers (Odds Ratio (OR)=1.72, 95% Confidence Interval (CI) 1.10-2.69), but not ER-negative breast cancers. CYP1A1 6235C allele carriers showed a non-significant (P=0.06) trend towards a decreased risk of ER-positive breast cancers (OR=0.65, 95% CI 0.42-1.02), but not ER-negative breast cancers. The combination of these two polymorphisms was found to be more useful in the assessment of the ER-positive breast cancer risk (OR=3.00, 95% CI=1.56-5.74) than the CYP19 (TTTA)7(-3bp) polymorphism alone. The combination of CYP19 (TTTA)7(-3bp) and CYP1A1 6235C/T polymorphisms is associated with an ER-positive, but not ER-negative, breast cancer risk, and, thus, would be useful in the selection of candidates for chemoprevention with tamoxifen. | Association of genetic polymorphisms in CYP19 and /"CYP1A1"/ with the oestrogen receptor-positive /"breast cancer"/ risk. | Since tamoxifen has been shown to reduce the risk of oestrogen receptor (ER)-positive, but not ER-negative, /"breast cancers"/ in a chemoprevention trial (P-1), it is important to develop assays to assess risk factors for /"ER-positive breast cancer"/ in order to appropriately select candidates for chemoprevention with tamoxifen. Thus, the significance of genetic polymorphisms of genes involved in oestrogen biosynthesis (CYP19) and metabolism (/"CYP1A1"/) as a risk factor for /"ER-positive breast cancers"/ was evaluated. A case-control study was conducted with 257 /"breast cancer"/ patients and 191 healthy female controls. Two polymorphisms, CYP19 (TTTA repeats) in intron 4 and /"CYP1A1"/ 6235C/T in the 3' non-coding region, and their association with the /"breast cancer"/ risk after adjustment for the other epidemiological risk factors were examined. CYP19 (TTTA)7(-3bp) allele carriers showed a significantly (P<0.05) increased risk of /"ER-positive breast cancers"/ (Odds Ratio (OR)=1.72, 95% Confidence Interval (CI) 1.10-2.69), but not ER-negative /"breast cancers"/. /"CYP1A1"/ 6235C allele carriers showed a non-significant (P=0.06) trend towards a decreased risk of /"ER-positive breast cancers"/ (OR=0.65, 95% CI 0.42-1.02), but not ER-negative /"breast cancers"/. The combination of these two polymorphisms was found to be more useful in the assessment of the /"ER-positive breast cancer"/ risk (OR=3.00, 95% CI=1.56-5.74) than the CYP19 (TTTA)7(-3bp) polymorphism alone. The combination of CYP19 (TTTA)7(-3bp) and /"CYP1A1"/ 6235C/T polymorphisms is associated with an ER-positive, but not ER-negative, /"breast cancer"/ risk, and, thus, would be useful in the selection of candidates for chemoprevention with tamoxifen. | [
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14623371 | No association of tumor necrosis factor alpha gene polymorphisms with schizophrenia or response to clozapine. | Tumor necrosis factor alpha (TNF-alpha), a potent immunomodulator and proinflammatory cytokine, has been implicated in schizophrenia pathogenesis and clozapine response. Two studies have established an association between schizophrenia and the TNF-alpha gene -308G/A polymorphism; however, both increased and decreased -308A allele frequency have been reported in two analogous investigations. The present study examined the hypothesis that the TNF-alpha gene -308G/A polymorphism confers susceptibility to schizophrenia in 205 patients with schizophrenia compared with 192 controls. A subgroup of 99 clozapine-treated schizophrenia patients was also tested for the genetic effects of this polymorphism, as evidenced by clinical manifestation, and clozapine-related therapeutic outcome and body-weight change. The results of these investigations suggest that the TNF-alpha gene -308G/A variants do not play a major role in susceptibility to, clinical manifestations for, or clozapine response in, schizophrenia. | No association of /"tumor necrosis factor alpha"/ gene polymorphisms with /"schizophrenia"/ or response to clozapine. | /"Tumor necrosis factor alpha"/ (/"TNF-alpha"/), a potent immunomodulator and proinflammatory cytokine, has been implicated in /"schizophrenia"/ pathogenesis and clozapine response. Two studies have established an association between /"schizophrenia"/ and the /"TNF-alpha"/ gene -308G/A polymorphism; however, both increased and decreased -308A allele frequency have been reported in two analogous investigations. The present study examined the hypothesis that the /"TNF-alpha"/ gene -308G/A polymorphism confers susceptibility to /"schizophrenia"/ in 205 patients with /"schizophrenia"/ compared with 192 controls. A subgroup of 99 clozapine-treated /"schizophrenia"/ patients was also tested for the genetic effects of this polymorphism, as evidenced by clinical manifestation, and clozapine-related therapeutic outcome and body-weight change. The results of these investigations suggest that the /"TNF-alpha"/ gene -308G/A variants do not play a major role in susceptibility to, clinical manifestations for, or clozapine response in, /"schizophrenia"/. | [
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14630904 | Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family. | Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | Novel identification of a four-base-pair deletion mutation in PITX2 in a /"Rieger syndrome"/ family. | /"Rieger syndrome"/ is one of the most serious causes of tooth agenesis. Mutations in the PITX2, /"FOXC1"/, and PAX6 genes have been associated with /"Rieger syndrome"/. We have studied a three-generation Chinese family affected with /"Rieger syndrome"/ and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of /"Rieger syndrome"/ observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | [
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14630904 | Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family. | Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | Novel identification of a four-base-pair deletion mutation in PITX2 in a /"Rieger syndrome"/ family. | /"Rieger syndrome"/ is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and /"PAX6"/ genes have been associated with /"Rieger syndrome"/. We have studied a three-generation Chinese family affected with /"Rieger syndrome"/ and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of /"Rieger syndrome"/ observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | [
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14630904 | Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family. | Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | Novel identification of a four-base-pair deletion mutation in /"PITX2"/ in a /"Rieger syndrome"/ family. | /"Rieger syndrome"/ is one of the most serious causes of tooth agenesis. Mutations in the /"PITX2"/, FOXC1, and PAX6 genes have been associated with /"Rieger syndrome"/. We have studied a three-generation Chinese family affected with /"Rieger syndrome"/ and showing prominent dental abnormalities. Mutational screening and sequence analysis of the /"PITX2"/ gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of /"Rieger syndrome"/ observed in this family are due to this /"PITX2"/ mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | [
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14630904 | Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family. | Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family. | Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and /"PAX6"/ genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing /"prominent dental abnormalities"/. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | [
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14630904 | Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family. | Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | Novel identification of a four-base-pair deletion mutation in /"PITX2"/ in a Rieger syndrome family. | Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the /"PITX2"/, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing /"prominent dental abnormalities"/. Mutational screening and sequence analysis of the /"PITX2"/ gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this /"PITX2"/ mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | [
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14630904 | Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family. | Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | Novel identification of a four-base-pair deletion mutation in /"PITX2"/ in a Rieger syndrome family. | Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the /"PITX2"/, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the /"PITX2"/ gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the /"oligodontia"/ and other phenotypes of Rieger syndrome observed in this family are due to this /"PITX2"/ mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. | [
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14650112 | Genetic polymorphisms of the beta-2 adrenergic receptor in Israelis with severe asthma compared to non-asthmatic Israelis. | BACKGROUND: It has been argued that arginine replacement in locus 16 (Arg16) of beta 2 adrenergic receptor with glycin (Gly16) increases asthma severity, while glutamin replacement in locus 27 (Gln27) with glutamic acid (Glu27) decreases it. In addition, ethnic dependency of these polymorphisms has been described, but few studies investigated its relation to asthma severity in a non-anglosaxic population. OBJECTIVES: To investigate non-anglosaxic ethnic influences on beta 2AR polymorphisms and its correlations to asthma severity. METHODS: Sixty-six Israeli Jewish and Arab asthmatics who had near-fatal asthma and/or severe nocturnal asthma and/or steroid-dependency were investigated for genetic polymorphisms of beta 2AR and compared to matched controls. The Jewish patients included both Ashkenazi (of European origin) and non-Ashkenazi (originating from the Middle East or North Africa). The results were compared with those of ethnically matched 113 non-asthmatic Israelis and non-asthmatic Anglo-Saxons described in the literature. RESULTS: We found no significant genetic differences between the asthmatics and their controls or between the various ethnic groups of our population. However, the prevalence of Glu27 was significantly lower in non-asthmatic Israelis compared to non-asthmatic Anglo-Saxons. CONCLUSIONS: The genetic distribution of beta 2AR polymorphisms in severe Israeli asthmatics is not different from that of non-asthmatic Israelis and therefore its clinical impact on asthma is probably minimal. | Genetic polymorphisms of the beta-2 adrenergic receptor in Israelis with severe /"asthma"/ compared to non-asthmatic Israelis. | BACKGROUND: It has been argued that arginine replacement in locus 16 (Arg16) of beta 2 adrenergic receptor with glycin (Gly16) increases /"asthma"/ severity, while glutamin replacement in locus 27 (Gln27) with glutamic acid (Glu27) decreases it. In addition, ethnic dependency of these polymorphisms has been described, but few studies investigated its relation to /"asthma"/ severity in a non-anglosaxic population. OBJECTIVES: To investigate non-anglosaxic ethnic influences on /"beta 2AR"/ polymorphisms and its correlations to /"asthma"/ severity. METHODS: Sixty-six Israeli Jewish and Arab asthmatics who had near-fatal /"asthma"/ and/or severe nocturnal /"asthma"/ and/or steroid-dependency were investigated for genetic polymorphisms of /"beta 2AR"/ and compared to matched controls. The Jewish patients included both Ashkenazi (of European origin) and non-Ashkenazi (originating from the Middle East or North Africa). The results were compared with those of ethnically matched 113 non-asthmatic Israelis and non-asthmatic Anglo-Saxons described in the literature. RESULTS: We found no significant genetic differences between the asthmatics and their controls or between the various ethnic groups of our population. However, the prevalence of Glu27 was significantly lower in non-asthmatic Israelis compared to non-asthmatic Anglo-Saxons. CONCLUSIONS: The genetic distribution of /"beta 2AR"/ polymorphisms in severe Israeli asthmatics is not different from that of non-asthmatic Israelis and therefore its clinical impact on /"asthma"/ is probably minimal. | [
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"entity_type": "Disease",
"text_name": "asthma"
},
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},
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"entity_id": "154",
"entity_type": "Gene",
"text_name": "beta 2AR"
}
] | {
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"entity_id": "154",
"entity_type": "Gene",
"text_name": "beta 2AR"
} | {
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} | Yes |
14650112 | Genetic polymorphisms of the beta-2 adrenergic receptor in Israelis with severe asthma compared to non-asthmatic Israelis. | BACKGROUND: It has been argued that arginine replacement in locus 16 (Arg16) of beta 2 adrenergic receptor with glycin (Gly16) increases asthma severity, while glutamin replacement in locus 27 (Gln27) with glutamic acid (Glu27) decreases it. In addition, ethnic dependency of these polymorphisms has been described, but few studies investigated its relation to asthma severity in a non-anglosaxic population. OBJECTIVES: To investigate non-anglosaxic ethnic influences on beta 2AR polymorphisms and its correlations to asthma severity. METHODS: Sixty-six Israeli Jewish and Arab asthmatics who had near-fatal asthma and/or severe nocturnal asthma and/or steroid-dependency were investigated for genetic polymorphisms of beta 2AR and compared to matched controls. The Jewish patients included both Ashkenazi (of European origin) and non-Ashkenazi (originating from the Middle East or North Africa). The results were compared with those of ethnically matched 113 non-asthmatic Israelis and non-asthmatic Anglo-Saxons described in the literature. RESULTS: We found no significant genetic differences between the asthmatics and their controls or between the various ethnic groups of our population. However, the prevalence of Glu27 was significantly lower in non-asthmatic Israelis compared to non-asthmatic Anglo-Saxons. CONCLUSIONS: The genetic distribution of beta 2AR polymorphisms in severe Israeli asthmatics is not different from that of non-asthmatic Israelis and therefore its clinical impact on asthma is probably minimal. | Genetic polymorphisms of the beta-2 adrenergic receptor in Israelis with severe asthma compared to non-asthmatic Israelis. | BACKGROUND: It has been argued that arginine replacement in locus 16 (Arg16) of beta 2 adrenergic receptor with glycin (Gly16) increases asthma severity, while glutamin replacement in locus 27 (Gln27) with glutamic acid (Glu27) decreases it. In addition, ethnic dependency of these polymorphisms has been described, but few studies investigated its relation to asthma severity in a non-anglosaxic population. OBJECTIVES: To investigate non-anglosaxic ethnic influences on /"beta 2AR"/ polymorphisms and its correlations to asthma severity. METHODS: Sixty-six Israeli Jewish and Arab /"asthmatics"/ who had near-fatal asthma and/or severe nocturnal asthma and/or steroid-dependency were investigated for genetic polymorphisms of /"beta 2AR"/ and compared to matched controls. The Jewish patients included both Ashkenazi (of European origin) and non-Ashkenazi (originating from the Middle East or North Africa). The results were compared with those of ethnically matched 113 non-asthmatic Israelis and non-asthmatic Anglo-Saxons described in the literature. RESULTS: We found no significant genetic differences between the /"asthmatics"/ and their controls or between the various ethnic groups of our population. However, the prevalence of Glu27 was significantly lower in non-asthmatic Israelis compared to non-asthmatic Anglo-Saxons. CONCLUSIONS: The genetic distribution of /"beta 2AR"/ polymorphisms in severe Israeli /"asthmatics"/ is not different from that of non-asthmatic Israelis and therefore its clinical impact on asthma is probably minimal. | [
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"text_name": "asthmatics"
} | No |
14661542 | [Molecular genetic analysis for Japanese patients with autosomal dominant retinitis pigmentosa]. | PURPOSE: To identify the common mutations in Japanese patients with autosomal dominant retinitis pigmentosa(ADRP), and to show that the kind and frequency of mutations depend on race. METHODS: Previously reported mutations for ADRP are summarized, and the results of screening for 120 Japanese patients with ADRP of the human retinal bascin (FSCN 2) gene are presented. Clinical features are characterized by visual acuity, slit lamp biomicroscopy, fluorescein angiography, electroretinography, and kinetic visual field-testing. RESULTS AND CONCLUSION: The Pro 23 His and Pro 347 Leu mutations in the rhodopsin gene are representative mutations for ADRP in other countries, but the mutation in the rhodopsin gene is very rare in Japanese patients with ADRP. On the other hand, a novel 208 delG mutation in the FSCN 2 gene was identified in 14 patients from 4 Japanese families with ADRP. This mutation was found in 3.3% of patients with ADRP, which suggests that this mutation might be relatively common and characteristic in Japanese patients with ADRP. | [Molecular genetic analysis for Japanese patients with /"autosomal dominant retinitis pigmentosa"/]. | PURPOSE: To identify the common mutations in Japanese patients with /"autosomal dominant retinitis pigmentosa"/(ADRP), and to show that the kind and frequency of mutations depend on race. METHODS: Previously reported mutations for ADRP are summarized, and the results of screening for 120 Japanese patients with ADRP of the human retinal bascin (/"FSCN 2"/) gene are presented. Clinical features are characterized by visual acuity, slit lamp biomicroscopy, fluorescein angiography, electroretinography, and kinetic visual field-testing. RESULTS AND CONCLUSION: The Pro 23 His and Pro 347 Leu mutations in the rhodopsin gene are representative mutations for ADRP in other countries, but the mutation in the rhodopsin gene is very rare in Japanese patients with ADRP. On the other hand, a novel 208 delG mutation in the /"FSCN 2"/ gene was identified in 14 patients from 4 Japanese families with ADRP. This mutation was found in 3.3% of patients with ADRP, which suggests that this mutation might be relatively common and characteristic in Japanese patients with ADRP. | [
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}
] | {
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} | {
"begin_idx": "55",
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"entity_id": "D012174",
"entity_type": "Disease",
"text_name": "autosomal dominant retinitis pigmentosa"
} | Yes |
14661542 | [Molecular genetic analysis for Japanese patients with autosomal dominant retinitis pigmentosa]. | PURPOSE: To identify the common mutations in Japanese patients with autosomal dominant retinitis pigmentosa(ADRP), and to show that the kind and frequency of mutations depend on race. METHODS: Previously reported mutations for ADRP are summarized, and the results of screening for 120 Japanese patients with ADRP of the human retinal bascin (FSCN 2) gene are presented. Clinical features are characterized by visual acuity, slit lamp biomicroscopy, fluorescein angiography, electroretinography, and kinetic visual field-testing. RESULTS AND CONCLUSION: The Pro 23 His and Pro 347 Leu mutations in the rhodopsin gene are representative mutations for ADRP in other countries, but the mutation in the rhodopsin gene is very rare in Japanese patients with ADRP. On the other hand, a novel 208 delG mutation in the FSCN 2 gene was identified in 14 patients from 4 Japanese families with ADRP. This mutation was found in 3.3% of patients with ADRP, which suggests that this mutation might be relatively common and characteristic in Japanese patients with ADRP. | [Molecular genetic analysis for Japanese patients with /"autosomal dominant retinitis pigmentosa"/]. | PURPOSE: To identify the common mutations in Japanese patients with /"autosomal dominant retinitis pigmentosa"/(/"ADRP"/), and to show that the kind and frequency of mutations depend on race. METHODS: Previously reported mutations for /"ADRP"/ are summarized, and the results of screening for 120 Japanese patients with /"ADRP"/ of the human retinal bascin (FSCN 2) gene are presented. Clinical features are characterized by visual acuity, slit lamp biomicroscopy, fluorescein angiography, electroretinography, and kinetic visual field-testing. RESULTS AND CONCLUSION: The Pro 23 His and Pro 347 Leu mutations in the rhodopsin gene are representative mutations for /"ADRP"/ in other countries, but the mutation in the rhodopsin gene is very rare in Japanese patients with /"ADRP"/. On the other hand, a novel 208 delG mutation in the FSCN 2 gene was identified in 14 patients from 4 Japanese families with /"ADRP"/. This mutation was found in 3.3% of patients with /"ADRP"/, which suggests that this mutation might be relatively common and characteristic in Japanese patients with /"ADRP"/. | [
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] | {
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} | {
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"entity_id": "D012174",
"entity_type": "Disease",
"text_name": "autosomal dominant retinitis pigmentosa"
} | No |
14672398 | E2F1 expression is related with the poor survival of lymph node-positive breast cancer patients treated with fluorouracil, doxorubicin and cyclophosphamide. | The expressions of E2F1 and retinoblastoma protein (pRB) were analyzed in 165 lymph node-positive breast cancers. All patients underwent adjuvant chemotherapy with fluorouracil, doxorubicin and cyclophosphamide (FAC). E2F1 was expressed in 43.6% and pRB was expressed in 46.1%. E2F1 expression was significantly increased in pRB-expressing tumors and was associated with an S-phase fraction. By univariate survival analyses, E2F1 expression and ER were identified as significant prognostic factors for disease recurrence and patient survival. E2F1 was the only significant prognostic factor of patient outcome after FAC chemotherapy by multivariate analysis. | E2F1 expression is related with the poor survival of lymph /"node-positive breast cancer"/ patients treated with fluorouracil, doxorubicin and cyclophosphamide. | The expressions of E2F1 and retinoblastoma protein (/"pRB"/) were analyzed in 165 lymph node-positive /"breast cancers"/. All patients underwent adjuvant chemotherapy with fluorouracil, doxorubicin and cyclophosphamide (FAC). E2F1 was expressed in 43.6% and /"pRB"/ was expressed in 46.1%. E2F1 expression was significantly increased in /"pRB"/-expressing tumors and was associated with an S-phase fraction. By univariate survival analyses, E2F1 expression and ER were identified as significant prognostic factors for disease recurrence and patient survival. E2F1 was the only significant prognostic factor of patient outcome after FAC chemotherapy by multivariate analysis. | [
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} | Yes |
14672398 | E2F1 expression is related with the poor survival of lymph node-positive breast cancer patients treated with fluorouracil, doxorubicin and cyclophosphamide. | The expressions of E2F1 and retinoblastoma protein (pRB) were analyzed in 165 lymph node-positive breast cancers. All patients underwent adjuvant chemotherapy with fluorouracil, doxorubicin and cyclophosphamide (FAC). E2F1 was expressed in 43.6% and pRB was expressed in 46.1%. E2F1 expression was significantly increased in pRB-expressing tumors and was associated with an S-phase fraction. By univariate survival analyses, E2F1 expression and ER were identified as significant prognostic factors for disease recurrence and patient survival. E2F1 was the only significant prognostic factor of patient outcome after FAC chemotherapy by multivariate analysis. | /"E2F1"/ expression is related with the poor survival of lymph /"node-positive breast cancer"/ patients treated with fluorouracil, doxorubicin and cyclophosphamide. | The expressions of /"E2F1"/ and retinoblastoma protein (pRB) were analyzed in 165 lymph node-positive /"breast cancers"/. All patients underwent adjuvant chemotherapy with fluorouracil, doxorubicin and cyclophosphamide (FAC). /"E2F1"/ was expressed in 43.6% and pRB was expressed in 46.1%. /"E2F1"/ expression was significantly increased in pRB-expressing tumors and was associated with an S-phase fraction. By univariate survival analyses, /"E2F1"/ expression and ER were identified as significant prognostic factors for disease recurrence and patient survival. /"E2F1"/ was the only significant prognostic factor of patient outcome after FAC chemotherapy by multivariate analysis. | [
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} | Yes |
14672398 | E2F1 expression is related with the poor survival of lymph node-positive breast cancer patients treated with fluorouracil, doxorubicin and cyclophosphamide. | The expressions of E2F1 and retinoblastoma protein (pRB) were analyzed in 165 lymph node-positive breast cancers. All patients underwent adjuvant chemotherapy with fluorouracil, doxorubicin and cyclophosphamide (FAC). E2F1 was expressed in 43.6% and pRB was expressed in 46.1%. E2F1 expression was significantly increased in pRB-expressing tumors and was associated with an S-phase fraction. By univariate survival analyses, E2F1 expression and ER were identified as significant prognostic factors for disease recurrence and patient survival. E2F1 was the only significant prognostic factor of patient outcome after FAC chemotherapy by multivariate analysis. | /"E2F1"/ expression is related with the poor survival of lymph node-positive breast cancer patients treated with fluorouracil, doxorubicin and cyclophosphamide. | The expressions of /"E2F1"/ and retinoblastoma protein (pRB) were analyzed in 165 lymph node-positive breast cancers. All patients underwent adjuvant chemotherapy with fluorouracil, doxorubicin and cyclophosphamide (FAC). /"E2F1"/ was expressed in 43.6% and pRB was expressed in 46.1%. /"E2F1"/ expression was significantly increased in pRB-expressing /"tumors"/ and was associated with an S-phase fraction. By univariate survival analyses, /"E2F1"/ expression and ER were identified as significant prognostic factors for disease recurrence and patient survival. /"E2F1"/ was the only significant prognostic factor of patient outcome after FAC chemotherapy by multivariate analysis. | [
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},
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"entity_type": "Disease",
"text_name": "tumors"
} | No |
14672398 | E2F1 expression is related with the poor survival of lymph node-positive breast cancer patients treated with fluorouracil, doxorubicin and cyclophosphamide. | The expressions of E2F1 and retinoblastoma protein (pRB) were analyzed in 165 lymph node-positive breast cancers. All patients underwent adjuvant chemotherapy with fluorouracil, doxorubicin and cyclophosphamide (FAC). E2F1 was expressed in 43.6% and pRB was expressed in 46.1%. E2F1 expression was significantly increased in pRB-expressing tumors and was associated with an S-phase fraction. By univariate survival analyses, E2F1 expression and ER were identified as significant prognostic factors for disease recurrence and patient survival. E2F1 was the only significant prognostic factor of patient outcome after FAC chemotherapy by multivariate analysis. | E2F1 expression is related with the poor survival of lymph node-positive breast cancer patients treated with fluorouracil, doxorubicin and cyclophosphamide. | The expressions of E2F1 and /"retinoblastoma"/ protein (/"pRB"/) were analyzed in 165 lymph node-positive breast cancers. All patients underwent adjuvant chemotherapy with fluorouracil, doxorubicin and cyclophosphamide (FAC). E2F1 was expressed in 43.6% and /"pRB"/ was expressed in 46.1%. E2F1 expression was significantly increased in /"pRB"/-expressing tumors and was associated with an S-phase fraction. By univariate survival analyses, E2F1 expression and ER were identified as significant prognostic factors for disease recurrence and patient survival. E2F1 was the only significant prognostic factor of patient outcome after FAC chemotherapy by multivariate analysis. | [
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} | {
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"entity_id": "D012175",
"entity_type": "Disease",
"text_name": "retinoblastoma"
} | No |
14676460 | Three novel mutations in Japanese patients with 21-hydroxylase deficiency. | OBJECTIVE: This study analyzed the mutation of 21-hydroxylase deficiency (21-OHD) in 36 unrelated Japanese patients with congenital adrenal hyperplasia (CAH). METHODS: All the exons of the functional CYP21 gene (CYP21A2) were analyzed by polymerase chain reaction (PCR) and PCR direct sequencing. RESULTS: Apparent gene deletions and conversions were present in 23.6% of the 72 CAH alleles, in which the most frequent mutation was the IVS2-13 A/C>G (27.8%), followed by I172N (26.3%), consistent with the frequencies reported for other countries. Previously described mutations were not present in three unrelated cases. Sequence analysis of the complete functional CYP21A2 gene revealed three, not yet described mutations that represent a common pseudogene sequence. These three putative novel mutations are located in exon 1 (M1I), in exon 5 (1210-1211insT), and in exon 3 (R124H). CONCLUSIONS: In this study, we have identified three putative novel mutations. It remains to be determined whether these three mutations are responsible for the significant number of as yet uncharacterized CAH patients in Japan. | Three novel mutations in Japanese patients with /"21-hydroxylase deficiency"/. | OBJECTIVE: This study analyzed the mutation of /"21-hydroxylase deficiency"/ (21-OHD) in 36 unrelated Japanese patients with congenital adrenal hyperplasia (CAH). METHODS: All the exons of the functional /"CYP21"/ gene (/"CYP21A2"/) were analyzed by polymerase chain reaction (PCR) and PCR direct sequencing. RESULTS: Apparent gene deletions and conversions were present in 23.6% of the 72 CAH alleles, in which the most frequent mutation was the IVS2-13 A/C>G (27.8%), followed by I172N (26.3%), consistent with the frequencies reported for other countries. Previously described mutations were not present in three unrelated cases. Sequence analysis of the complete functional /"CYP21A2"/ gene revealed three, not yet described mutations that represent a common pseudogene sequence. These three putative novel mutations are located in exon 1 (M1I), in exon 5 (1210-1211insT), and in exon 3 (R124H). CONCLUSIONS: In this study, we have identified three putative novel mutations. It remains to be determined whether these three mutations are responsible for the significant number of as yet uncharacterized CAH patients in Japan. | [
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"text_name": "21-hydroxylase deficiency"
} | Yes |
14676460 | Three novel mutations in Japanese patients with 21-hydroxylase deficiency. | OBJECTIVE: This study analyzed the mutation of 21-hydroxylase deficiency (21-OHD) in 36 unrelated Japanese patients with congenital adrenal hyperplasia (CAH). METHODS: All the exons of the functional CYP21 gene (CYP21A2) were analyzed by polymerase chain reaction (PCR) and PCR direct sequencing. RESULTS: Apparent gene deletions and conversions were present in 23.6% of the 72 CAH alleles, in which the most frequent mutation was the IVS2-13 A/C>G (27.8%), followed by I172N (26.3%), consistent with the frequencies reported for other countries. Previously described mutations were not present in three unrelated cases. Sequence analysis of the complete functional CYP21A2 gene revealed three, not yet described mutations that represent a common pseudogene sequence. These three putative novel mutations are located in exon 1 (M1I), in exon 5 (1210-1211insT), and in exon 3 (R124H). CONCLUSIONS: In this study, we have identified three putative novel mutations. It remains to be determined whether these three mutations are responsible for the significant number of as yet uncharacterized CAH patients in Japan. | Three novel mutations in Japanese patients with 21-hydroxylase deficiency. | OBJECTIVE: This study analyzed the mutation of 21-hydroxylase deficiency (21-/"OHD"/) in 36 unrelated Japanese patients with congenital adrenal hyperplasia (CAH). METHODS: All the exons of the functional /"CYP21"/ gene (/"CYP21A2"/) were analyzed by polymerase chain reaction (PCR) and PCR direct sequencing. RESULTS: Apparent gene deletions and conversions were present in 23.6% of the 72 CAH alleles, in which the most frequent mutation was the IVS2-13 A/C>G (27.8%), followed by I172N (26.3%), consistent with the frequencies reported for other countries. Previously described mutations were not present in three unrelated cases. Sequence analysis of the complete functional /"CYP21A2"/ gene revealed three, not yet described mutations that represent a common pseudogene sequence. These three putative novel mutations are located in exon 1 (M1I), in exon 5 (1210-1211insT), and in exon 3 (R124H). CONCLUSIONS: In this study, we have identified three putative novel mutations. It remains to be determined whether these three mutations are responsible for the significant number of as yet uncharacterized CAH patients in Japan. | [
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} | No |
14691540 | GAD2 on chromosome 10p12 is a candidate gene for human obesity. | The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity. | /"GAD2"/ on chromosome 10p12 is a candidate gene for human /"obesity"/. | The gene /"GAD2"/ encoding the glutamic acid decarboxylase enzyme (/"GAD65"/) is a positional candidate gene for /"obesity"/ on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. /"GAD65"/ catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing /"GAD2"/ variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the /"obesity"/ of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times /"GAD2"/ promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As /"GAD2"/ is highly expressed in pancreatic beta cells, we analyzed /"GAD65"/ antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower /"GAD65"/ autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity. | [
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14691540 | GAD2 on chromosome 10p12 is a candidate gene for human obesity. | The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity. | /"GAD2"/ on chromosome 10p12 is a candidate gene for human obesity. | The gene /"GAD2"/ encoding the glutamic acid decarboxylase enzyme (/"GAD65"/) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for /"morbid obesity"/ in four independent ethnic populations. /"GAD65"/ catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing /"GAD2"/ variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for /"morbid obesity"/ (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times /"GAD2"/ promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As /"GAD2"/ is highly expressed in pancreatic beta cells, we analyzed /"GAD65"/ antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower /"GAD65"/ autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of /"morbid obesity"/. | [
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} | No |
14695532 | Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. | Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid alpha-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid alpha-glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease. | Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (/"GAA"/) underscore the genotype-phenotype correlation in /"glycogen storage disease type II"/. | Patients with /"glycogen storage disease type II"/ (/"GSDII"/, /"Pompe disease"/) suffer from progressive muscle weakness due to acid /"alpha-glucosidase deficiency"/. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of /"GSDII"/ and thereby identified 55 pathogenic mutations of the acid alpha-glucosidase gene (/"GAA"/) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of /"GSDII"/ is largely dictated by the nature of the mutations in the /"GAA"/ alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease. | [
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} | Yes |
14695532 | Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. | Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid alpha-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid alpha-glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease. | Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (/"GAA"/) underscore the genotype-phenotype correlation in glycogen storage disease type II. | Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive /"muscle weakness"/ due to acid alpha-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid alpha-glucosidase gene (/"GAA"/) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the /"GAA"/ alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease. | [
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14695540 | Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. | Marfan syndrome (MFS) is a disorder of the extracellular matrix caused by mutations in the gene encoding fibrillin-1 (FBN1). Recent studies have illustrated the variability in disease severity and clinical manifestations of MFS. Useful genotype-phenotype correlations have been slow to emerge. We screened 57 unrelated patients with MFS or a Marfan-like phenotype using a combination of SSCP and/or DHPLC. We detected 49 different FBN1 mutations, 30 (62%) of which were novel. The mutations comprised 38 substitutions (78%), 10 deletions (20%), and one duplication (2%). There were 28 missense (57%), nine frameshift (18%), eight splice site (16%), and four nonsense mutations (8 %). Genotype-phenotype analysis revealed that patients with an identified FBN1 mutation were more likely to have ectopia lentis and cardiovascular complications compared to those without an identifiable mutation (relative risks of 4.6 and 1.9, respectively). Ectopia lentis was also found to be more prevalent in patients whose mutations involved a cysteine substitution (relative risk 1.6) and less prevalent in those with premature termination mutations (relative risk 0.4). In our hands, we achieved 93% mutation detection for DHPLC analysis of patients who fulfilled the Ghent criteria. Further analysis of detailed clinical information and mutation data may help to anticipate the clinical consequences of specific FBN1 mutations. | Detection of thirty novel /"FBN1"/ mutations in patients with /"Marfan syndrome"/ or a related fibrillinopathy. | /"Marfan syndrome"/ (/"MFS"/) is a disorder of the extracellular matrix caused by mutations in the gene encoding /"fibrillin-1"/ (/"FBN1"/). Recent studies have illustrated the variability in disease severity and clinical manifestations of /"MFS"/. Useful genotype-phenotype correlations have been slow to emerge. We screened 57 unrelated patients with /"MFS"/ or a Marfan-like phenotype using a combination of SSCP and/or DHPLC. We detected 49 different /"FBN1"/ mutations, 30 (62%) of which were novel. The mutations comprised 38 substitutions (78%), 10 deletions (20%), and one duplication (2%). There were 28 missense (57%), nine frameshift (18%), eight splice site (16%), and four nonsense mutations (8 %). Genotype-phenotype analysis revealed that patients with an identified /"FBN1"/ mutation were more likely to have ectopia lentis and cardiovascular complications compared to those without an identifiable mutation (relative risks of 4.6 and 1.9, respectively). Ectopia lentis was also found to be more prevalent in patients whose mutations involved a cysteine substitution (relative risk 1.6) and less prevalent in those with premature termination mutations (relative risk 0.4). In our hands, we achieved 93% mutation detection for DHPLC analysis of patients who fulfilled the Ghent criteria. Further analysis of detailed clinical information and mutation data may help to anticipate the clinical consequences of specific /"FBN1"/ mutations. | [
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14695540 | Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. | Marfan syndrome (MFS) is a disorder of the extracellular matrix caused by mutations in the gene encoding fibrillin-1 (FBN1). Recent studies have illustrated the variability in disease severity and clinical manifestations of MFS. Useful genotype-phenotype correlations have been slow to emerge. We screened 57 unrelated patients with MFS or a Marfan-like phenotype using a combination of SSCP and/or DHPLC. We detected 49 different FBN1 mutations, 30 (62%) of which were novel. The mutations comprised 38 substitutions (78%), 10 deletions (20%), and one duplication (2%). There were 28 missense (57%), nine frameshift (18%), eight splice site (16%), and four nonsense mutations (8 %). Genotype-phenotype analysis revealed that patients with an identified FBN1 mutation were more likely to have ectopia lentis and cardiovascular complications compared to those without an identifiable mutation (relative risks of 4.6 and 1.9, respectively). Ectopia lentis was also found to be more prevalent in patients whose mutations involved a cysteine substitution (relative risk 1.6) and less prevalent in those with premature termination mutations (relative risk 0.4). In our hands, we achieved 93% mutation detection for DHPLC analysis of patients who fulfilled the Ghent criteria. Further analysis of detailed clinical information and mutation data may help to anticipate the clinical consequences of specific FBN1 mutations. | Detection of thirty novel /"FBN1"/ mutations in patients with Marfan syndrome or a related fibrillinopathy. | Marfan syndrome (MFS) is a disorder of the extracellular matrix caused by mutations in the gene encoding /"fibrillin-1"/ (/"FBN1"/). Recent studies have illustrated the variability in disease severity and clinical manifestations of MFS. Useful genotype-phenotype correlations have been slow to emerge. We screened 57 unrelated patients with MFS or a Marfan-like phenotype using a combination of SSCP and/or DHPLC. We detected 49 different /"FBN1"/ mutations, 30 (62%) of which were novel. The mutations comprised 38 substitutions (78%), 10 deletions (20%), and one duplication (2%). There were 28 missense (57%), nine frameshift (18%), eight splice site (16%), and four nonsense mutations (8 %). Genotype-phenotype analysis revealed that patients with an identified /"FBN1"/ mutation were more likely to have /"ectopia lentis"/ and cardiovascular complications compared to those without an identifiable mutation (relative risks of 4.6 and 1.9, respectively). /"Ectopia lentis"/ was also found to be more prevalent in patients whose mutations involved a cysteine substitution (relative risk 1.6) and less prevalent in those with premature termination mutations (relative risk 0.4). In our hands, we achieved 93% mutation detection for DHPLC analysis of patients who fulfilled the Ghent criteria. Further analysis of detailed clinical information and mutation data may help to anticipate the clinical consequences of specific /"FBN1"/ mutations. | [
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14697642 | Chromosomal comparative genomic hybridization abnormalities in early- and late-onset human breast cancers: correlation with disease progression and TP53 mutations. | Nearly 30% of the breast cancer patients in the Taiwanese community have their diseases diagnosed before the age of 40. Their 5-year survival rate is poorer than that of their late-onset breast cancer counterparts. Genomic abnormalities between these two breast cancer age groups were compared using comparative genomic hybridization (CGH) analyses. The sample set was made up of 44 early-onset (<35 years old) and 54 late-onset cases (>63 years old). Frequent CGH changes were noted, such as gains on 8q, 1q, and 17q and losses on 16q, 17p, and 8p. These were very similar for the two age groups, as well as for Taiwanese women and other ethnic populations. In contrast, several less common lesions, such as gains on 16p and 8p and losses on 11q and 9p, were significantly different between the early- and late-onset breast tumors. In addition, more profound chromosomal changes were consistently associated with the more advanced-stage tumors, and less expression of the estrogen and the progesterone receptors, and of HER-2/neu. About 19% of the breast cancers examined carried a TP53 mutation in exons 4-9. Of these, 88% (15/17) were missense point mutations and these were distributed randomly along the tested gene fragments without apparent clustering, as has been shown in certain other ethnic or regional studies. On average, patients carrying these TP53 mutations had 9.5 CGH lesions per case, compared to only 2.8 changes in samples that had no TP53 mutation. Our results indicate that certain genomic lesions, especially 11q loss, may play a role in early-onset breast tumor formation, and that combined use of genomic patterns and molecular targets may provide a useful tool for diagnostic, therapeutic, and prognostic purposes. | Chromosomal comparative genomic hybridization abnormalities in early- and late-onset human /"breast cancers"/: correlation with disease progression and /"TP53"/ mutations. | Nearly 30% of the /"breast cancer"/ patients in the Taiwanese community have their diseases diagnosed before the age of 40. Their 5-year survival rate is poorer than that of their late-onset /"breast cancer"/ counterparts. Genomic abnormalities between these two /"breast cancer"/ age groups were compared using comparative genomic hybridization (CGH) analyses. The sample set was made up of 44 early-onset (<35 years old) and 54 late-onset cases (>63 years old). Frequent CGH changes were noted, such as gains on 8q, 1q, and 17q and losses on 16q, 17p, and 8p. These were very similar for the two age groups, as well as for Taiwanese women and other ethnic populations. In contrast, several less common lesions, such as gains on 16p and 8p and losses on 11q and 9p, were significantly different between the early- and late-onset /"breast tumors"/. In addition, more profound chromosomal changes were consistently associated with the more advanced-stage tumors, and less expression of the estrogen and the progesterone receptors, and of HER-2/neu. About 19% of the /"breast cancers"/ examined carried a /"TP53"/ mutation in exons 4-9. Of these, 88% (15/17) were missense point mutations and these were distributed randomly along the tested gene fragments without apparent clustering, as has been shown in certain other ethnic or regional studies. On average, patients carrying these /"TP53"/ mutations had 9.5 CGH lesions per case, compared to only 2.8 changes in samples that had no /"TP53"/ mutation. Our results indicate that certain genomic lesions, especially 11q loss, may play a role in early-onset /"breast tumor"/ formation, and that combined use of genomic patterns and molecular targets may provide a useful tool for diagnostic, therapeutic, and prognostic purposes. | [
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14697642 | Chromosomal comparative genomic hybridization abnormalities in early- and late-onset human breast cancers: correlation with disease progression and TP53 mutations. | Nearly 30% of the breast cancer patients in the Taiwanese community have their diseases diagnosed before the age of 40. Their 5-year survival rate is poorer than that of their late-onset breast cancer counterparts. Genomic abnormalities between these two breast cancer age groups were compared using comparative genomic hybridization (CGH) analyses. The sample set was made up of 44 early-onset (<35 years old) and 54 late-onset cases (>63 years old). Frequent CGH changes were noted, such as gains on 8q, 1q, and 17q and losses on 16q, 17p, and 8p. These were very similar for the two age groups, as well as for Taiwanese women and other ethnic populations. In contrast, several less common lesions, such as gains on 16p and 8p and losses on 11q and 9p, were significantly different between the early- and late-onset breast tumors. In addition, more profound chromosomal changes were consistently associated with the more advanced-stage tumors, and less expression of the estrogen and the progesterone receptors, and of HER-2/neu. About 19% of the breast cancers examined carried a TP53 mutation in exons 4-9. Of these, 88% (15/17) were missense point mutations and these were distributed randomly along the tested gene fragments without apparent clustering, as has been shown in certain other ethnic or regional studies. On average, patients carrying these TP53 mutations had 9.5 CGH lesions per case, compared to only 2.8 changes in samples that had no TP53 mutation. Our results indicate that certain genomic lesions, especially 11q loss, may play a role in early-onset breast tumor formation, and that combined use of genomic patterns and molecular targets may provide a useful tool for diagnostic, therapeutic, and prognostic purposes. | Chromosomal comparative genomic hybridization abnormalities in early- and late-onset human breast cancers: correlation with disease progression and /"TP53"/ mutations. | Nearly 30% of the breast cancer patients in the Taiwanese community have their diseases diagnosed before the age of 40. Their 5-year survival rate is poorer than that of their late-onset breast cancer counterparts. Genomic abnormalities between these two breast cancer age groups were compared using comparative genomic hybridization (CGH) analyses. The sample set was made up of 44 early-onset (<35 years old) and 54 late-onset cases (>63 years old). Frequent CGH changes were noted, such as gains on 8q, 1q, and 17q and losses on 16q, 17p, and 8p. These were very similar for the two age groups, as well as for Taiwanese women and other ethnic populations. In contrast, several less common lesions, such as gains on 16p and 8p and losses on 11q and 9p, were significantly different between the early- and late-onset breast tumors. In addition, more profound chromosomal changes were consistently associated with the more /"advanced-stage tumors"/, and less expression of the estrogen and the progesterone receptors, and of HER-2/neu. About 19% of the breast cancers examined carried a /"TP53"/ mutation in exons 4-9. Of these, 88% (15/17) were missense point mutations and these were distributed randomly along the tested gene fragments without apparent clustering, as has been shown in certain other ethnic or regional studies. On average, patients carrying these /"TP53"/ mutations had 9.5 CGH lesions per case, compared to only 2.8 changes in samples that had no /"TP53"/ mutation. Our results indicate that certain genomic lesions, especially 11q loss, may play a role in early-onset breast tumor formation, and that combined use of genomic patterns and molecular targets may provide a useful tool for diagnostic, therapeutic, and prognostic purposes. | [
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14697747 | Prevalence of the chemokine receptor CCR5-Delta32 gene mutation in periodontal disease. | A 32-base-pair deletion in the CCR5 gene was previously shown to influence the susceptibility for several infectious diseases. The present study compared the frequency of the CCR5-Delta32 mutation among subjects with periodontal disease and healthy control individuals. The prevalence of the CCR5-Delta32 mutation was determined in 81 patients with generalized periodontitis and 121 healthy controls. Standardized clinical and radiographic criteria were used for the diagnosis of periodontitis for each subject. The CCR5-Delta32 mutation was identified by PCR amplification and subsequent agarose gel electrophoresis. Genotype and allele frequencies among both study groups were compared using Fisher's exact test at a level of significance of 5% (P<0.05). The frequency of the CCR5-Delta32 allele was 9.9% (16/162) for periodontitis patients and 10.7% (26/216) for the healthy controls. The allele frequencies between periodontitis patients and the control group for the CCR5-Delta32 mutation were not significantly different (P=0.801). The present study revealed no association between the CCR5-Delta32 mutation and susceptibility to periodontal disease. | Prevalence of the chemokine receptor /"CCR5"/-Delta32 gene mutation in periodontal disease. | A 32-base-pair deletion in the /"CCR5"/ gene was previously shown to influence the susceptibility for several infectious diseases. The present study compared the frequency of the /"CCR5"/-Delta32 mutation among subjects with periodontal disease and healthy control individuals. The prevalence of the /"CCR5"/-Delta32 mutation was determined in 81 patients with generalized /"periodontitis"/ and 121 healthy controls. Standardized clinical and radiographic criteria were used for the diagnosis of /"periodontitis"/ for each subject. The /"CCR5"/-Delta32 mutation was identified by PCR amplification and subsequent agarose gel electrophoresis. Genotype and allele frequencies among both study groups were compared using Fisher's exact test at a level of significance of 5% (P<0.05). The frequency of the /"CCR5"/-Delta32 allele was 9.9% (16/162) for /"periodontitis"/ patients and 10.7% (26/216) for the healthy controls. The allele frequencies between /"periodontitis"/ patients and the control group for the /"CCR5"/-Delta32 mutation were not significantly different (P=0.801). The present study revealed no association between the /"CCR5"/-Delta32 mutation and susceptibility to periodontal disease. | [
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14697747 | Prevalence of the chemokine receptor CCR5-Delta32 gene mutation in periodontal disease. | A 32-base-pair deletion in the CCR5 gene was previously shown to influence the susceptibility for several infectious diseases. The present study compared the frequency of the CCR5-Delta32 mutation among subjects with periodontal disease and healthy control individuals. The prevalence of the CCR5-Delta32 mutation was determined in 81 patients with generalized periodontitis and 121 healthy controls. Standardized clinical and radiographic criteria were used for the diagnosis of periodontitis for each subject. The CCR5-Delta32 mutation was identified by PCR amplification and subsequent agarose gel electrophoresis. Genotype and allele frequencies among both study groups were compared using Fisher's exact test at a level of significance of 5% (P<0.05). The frequency of the CCR5-Delta32 allele was 9.9% (16/162) for periodontitis patients and 10.7% (26/216) for the healthy controls. The allele frequencies between periodontitis patients and the control group for the CCR5-Delta32 mutation were not significantly different (P=0.801). The present study revealed no association between the CCR5-Delta32 mutation and susceptibility to periodontal disease. | Prevalence of the chemokine receptor /"CCR5"/-Delta32 gene mutation in periodontal disease. | A 32-base-pair deletion in the /"CCR5"/ gene was previously shown to influence the susceptibility for several /"infectious diseases"/. The present study compared the frequency of the /"CCR5"/-Delta32 mutation among subjects with periodontal disease and healthy control individuals. The prevalence of the /"CCR5"/-Delta32 mutation was determined in 81 patients with generalized periodontitis and 121 healthy controls. Standardized clinical and radiographic criteria were used for the diagnosis of periodontitis for each subject. The /"CCR5"/-Delta32 mutation was identified by PCR amplification and subsequent agarose gel electrophoresis. Genotype and allele frequencies among both study groups were compared using Fisher's exact test at a level of significance of 5% (P<0.05). The frequency of the /"CCR5"/-Delta32 allele was 9.9% (16/162) for periodontitis patients and 10.7% (26/216) for the healthy controls. The allele frequencies between periodontitis patients and the control group for the /"CCR5"/-Delta32 mutation were not significantly different (P=0.801). The present study revealed no association between the /"CCR5"/-Delta32 mutation and susceptibility to periodontal disease. | [
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14713779 | Association among an ornithine decarboxylase polymorphism, androgen receptor gene (CAG) repeat length and prostate cancer risk. | PURPOSE: A single nucleotide substitution of guanine to adenine (A) at base +316 in the ornithine decarboxylase (ODC) gene may be associated with greater ODC expression and increased tumor growth. ODC is induced by androgens in human prostatic epithelial cells, presumably via transcriptional activation of androgen receptor (AR) and also by nicotine. A nested case-control study was done to examine the association between this ODC genotype and prostate cancer risk, and whether it varies by AR gene CAG repeat length and smoking. MATERIALS AND METHODS: A total of 164 cases were matched to 2 controls each from a community based cohort. ODC and AR genotyping was performed using a TaqMan (PE Applied Biosystems, Foster City, California) based assay and automated fragment analysis, respectively. Conditional logistic regression was used to estimate the OR and 95% CI. RESULTS: The presence of the ODC A allele was not significantly associated with an increased risk of prostate cancer (OR 1.33, 95% CI 0.90 to 1.96). However, men who inherited at least 1 ODC A alleles and less than 22 AR CAG repeats were at twice the risk of prostate cancer compared with those with 2 guanine alleles and 22 or greater AR CAG repeats (OR 2.09, 95% CI 1.23 to 3.57). Smoking was associated with prostate cancer only in men carrying a least 1 ODC A allele (p interaction = 0.02). CONCLUSIONS: The ODC A allele was not associated with a statistically significant increased risk of prostate cancer. However, this association may vary according to the number of CAG repeats in the AR receptor and smoking status. | Association among an ornithine decarboxylase polymorphism, /"androgen receptor"/ gene (CAG) repeat length and /"prostate cancer"/ risk. | PURPOSE: A single nucleotide substitution of guanine to adenine (A) at base +316 in the ornithine decarboxylase (ODC) gene may be associated with greater ODC expression and increased tumor growth. ODC is induced by androgens in human prostatic epithelial cells, presumably via transcriptional activation of /"androgen receptor"/ (/"AR"/) and also by nicotine. A nested case-control study was done to examine the association between this ODC genotype and /"prostate cancer"/ risk, and whether it varies by /"AR"/ gene CAG repeat length and smoking. MATERIALS AND METHODS: A total of 164 cases were matched to 2 controls each from a community based cohort. ODC and /"AR"/ genotyping was performed using a TaqMan (PE Applied Biosystems, Foster City, California) based assay and automated fragment analysis, respectively. Conditional logistic regression was used to estimate the OR and 95% CI. RESULTS: The presence of the ODC A allele was not significantly associated with an increased risk of /"prostate cancer"/ (OR 1.33, 95% CI 0.90 to 1.96). However, men who inherited at least 1 ODC A alleles and less than 22 /"AR"/ CAG repeats were at twice the risk of /"prostate cancer"/ compared with those with 2 guanine alleles and 22 or greater /"AR"/ CAG repeats (OR 2.09, 95% CI 1.23 to 3.57). Smoking was associated with /"prostate cancer"/ only in men carrying a least 1 ODC A allele (p interaction = 0.02). CONCLUSIONS: The ODC A allele was not associated with a statistically significant increased risk of /"prostate cancer"/. However, this association may vary according to the number of CAG repeats in the AR receptor and smoking status. | [
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} | Yes |
14713779 | Association among an ornithine decarboxylase polymorphism, androgen receptor gene (CAG) repeat length and prostate cancer risk. | PURPOSE: A single nucleotide substitution of guanine to adenine (A) at base +316 in the ornithine decarboxylase (ODC) gene may be associated with greater ODC expression and increased tumor growth. ODC is induced by androgens in human prostatic epithelial cells, presumably via transcriptional activation of androgen receptor (AR) and also by nicotine. A nested case-control study was done to examine the association between this ODC genotype and prostate cancer risk, and whether it varies by AR gene CAG repeat length and smoking. MATERIALS AND METHODS: A total of 164 cases were matched to 2 controls each from a community based cohort. ODC and AR genotyping was performed using a TaqMan (PE Applied Biosystems, Foster City, California) based assay and automated fragment analysis, respectively. Conditional logistic regression was used to estimate the OR and 95% CI. RESULTS: The presence of the ODC A allele was not significantly associated with an increased risk of prostate cancer (OR 1.33, 95% CI 0.90 to 1.96). However, men who inherited at least 1 ODC A alleles and less than 22 AR CAG repeats were at twice the risk of prostate cancer compared with those with 2 guanine alleles and 22 or greater AR CAG repeats (OR 2.09, 95% CI 1.23 to 3.57). Smoking was associated with prostate cancer only in men carrying a least 1 ODC A allele (p interaction = 0.02). CONCLUSIONS: The ODC A allele was not associated with a statistically significant increased risk of prostate cancer. However, this association may vary according to the number of CAG repeats in the AR receptor and smoking status. | Association among an /"ornithine decarboxylase"/ polymorphism, androgen receptor gene (CAG) repeat length and /"prostate cancer"/ risk. | PURPOSE: A single nucleotide substitution of guanine to adenine (A) at base +316 in the /"ornithine decarboxylase"/ (/"ODC"/) gene may be associated with greater /"ODC"/ expression and increased tumor growth. /"ODC"/ is induced by androgens in human prostatic epithelial cells, presumably via transcriptional activation of androgen receptor (AR) and also by nicotine. A nested case-control study was done to examine the association between this /"ODC"/ genotype and /"prostate cancer"/ risk, and whether it varies by AR gene CAG repeat length and smoking. MATERIALS AND METHODS: A total of 164 cases were matched to 2 controls each from a community based cohort. /"ODC"/ and AR genotyping was performed using a TaqMan (PE Applied Biosystems, Foster City, California) based assay and automated fragment analysis, respectively. Conditional logistic regression was used to estimate the OR and 95% CI. RESULTS: The presence of the /"ODC"/ A allele was not significantly associated with an increased risk of /"prostate cancer"/ (OR 1.33, 95% CI 0.90 to 1.96). However, men who inherited at least 1 /"ODC"/ A alleles and less than 22 AR CAG repeats were at twice the risk of /"prostate cancer"/ compared with those with 2 guanine alleles and 22 or greater AR CAG repeats (OR 2.09, 95% CI 1.23 to 3.57). Smoking was associated with /"prostate cancer"/ only in men carrying a least 1 /"ODC"/ A allele (p interaction = 0.02). CONCLUSIONS: The /"ODC"/ A allele was not associated with a statistically significant increased risk of /"prostate cancer"/. However, this association may vary according to the number of CAG repeats in the AR receptor and smoking status. | [
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14717782 | Genetic variability of von Willebrand factor and risk of coronary heart disease: the Rotterdam Study. | The von Willebrand factor (VWF) may be causally associated with coronary heart disease (CHD) or merely be a marker of endothelial damage. The G allele of the -1793 C/G promoter polymorphism in the VWF gene has been associated with higher plasma levels of VWF. To investigate whether VWF has a causal role in CHD, we designed a case-cohort study, including 352 subjects with CHD and a random cohort (n = 736), and prospectively examined the association of the -1793 C/G polymorphism with CHD in subjects with and without advanced atherosclerosis. All subjects were </=75 years of age and participating in the population-based Rotterdam Study. Atherosclerosis was assessed by the ankle-arm index. Among subjects with advanced atherosclerosis, heterozygous and homozygous carriers of the G allele had a 3.5 (1.2-10.2) and 1.5 (0.4-5.7) fold increased risk of CHD respectively, compared with C/C homozygotes. The hazard ratio was 2.6 (1.0-6.8) for carriers of at least one copy of the G allele versus non-carriers. No associations were found in the absence of advanced atherosclerosis. In conclusion, this study suggests that the G allele of the -1793 C/G polymorphism in the VWF gene is associated with an increased risk of CHD, but only in subjects with advanced atherosclerosis. | Genetic variability of /"von Willebrand factor"/ and risk of /"coronary heart disease"/: the Rotterdam Study. | The /"von Willebrand factor"/ (/"VWF"/) may be causally associated with /"coronary heart disease"/ (/"CHD"/) or merely be a marker of endothelial damage. The G allele of the -1793 C/G promoter polymorphism in the /"VWF"/ gene has been associated with higher plasma levels of /"VWF"/. To investigate whether /"VWF"/ has a causal role in /"CHD"/, we designed a case-cohort study, including 352 subjects with /"CHD"/ and a random cohort (n = 736), and prospectively examined the association of the -1793 C/G polymorphism with /"CHD"/ in subjects with and without advanced atherosclerosis. All subjects were </=75 years of age and participating in the population-based Rotterdam Study. Atherosclerosis was assessed by the ankle-arm index. Among subjects with advanced atherosclerosis, heterozygous and homozygous carriers of the G allele had a 3.5 (1.2-10.2) and 1.5 (0.4-5.7) fold increased risk of /"CHD"/ respectively, compared with C/C homozygotes. The hazard ratio was 2.6 (1.0-6.8) for carriers of at least one copy of the G allele versus non-carriers. No associations were found in the absence of advanced atherosclerosis. In conclusion, this study suggests that the G allele of the -1793 C/G polymorphism in the /"VWF"/ gene is associated with an increased risk of /"CHD"/, but only in subjects with advanced atherosclerosis. | [
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14717782 | Genetic variability of von Willebrand factor and risk of coronary heart disease: the Rotterdam Study. | The von Willebrand factor (VWF) may be causally associated with coronary heart disease (CHD) or merely be a marker of endothelial damage. The G allele of the -1793 C/G promoter polymorphism in the VWF gene has been associated with higher plasma levels of VWF. To investigate whether VWF has a causal role in CHD, we designed a case-cohort study, including 352 subjects with CHD and a random cohort (n = 736), and prospectively examined the association of the -1793 C/G polymorphism with CHD in subjects with and without advanced atherosclerosis. All subjects were </=75 years of age and participating in the population-based Rotterdam Study. Atherosclerosis was assessed by the ankle-arm index. Among subjects with advanced atherosclerosis, heterozygous and homozygous carriers of the G allele had a 3.5 (1.2-10.2) and 1.5 (0.4-5.7) fold increased risk of CHD respectively, compared with C/C homozygotes. The hazard ratio was 2.6 (1.0-6.8) for carriers of at least one copy of the G allele versus non-carriers. No associations were found in the absence of advanced atherosclerosis. In conclusion, this study suggests that the G allele of the -1793 C/G polymorphism in the VWF gene is associated with an increased risk of CHD, but only in subjects with advanced atherosclerosis. | Genetic variability of /"von Willebrand factor"/ and risk of coronary heart disease: the Rotterdam Study. | The /"von Willebrand factor"/ (/"VWF"/) may be causally associated with coronary heart disease (CHD) or merely be a marker of endothelial damage. The G allele of the -1793 C/G promoter polymorphism in the /"VWF"/ gene has been associated with higher plasma levels of /"VWF"/. To investigate whether /"VWF"/ has a causal role in CHD, we designed a case-cohort study, including 352 subjects with CHD and a random cohort (n = 736), and prospectively examined the association of the -1793 C/G polymorphism with CHD in subjects with and without advanced /"atherosclerosis"/. All subjects were </=75 years of age and participating in the population-based Rotterdam Study. /"Atherosclerosis"/ was assessed by the ankle-arm index. Among subjects with advanced /"atherosclerosis"/, heterozygous and homozygous carriers of the G allele had a 3.5 (1.2-10.2) and 1.5 (0.4-5.7) fold increased risk of CHD respectively, compared with C/C homozygotes. The hazard ratio was 2.6 (1.0-6.8) for carriers of at least one copy of the G allele versus non-carriers. No associations were found in the absence of advanced /"atherosclerosis"/. In conclusion, this study suggests that the G allele of the -1793 C/G polymorphism in the /"VWF"/ gene is associated with an increased risk of CHD, but only in subjects with advanced /"atherosclerosis"/. | [
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14717963 | Folate, homocysteine levels, methylenetetrahydrofolate reductase (MTHFR) 677C --> T variant, and the risk of myocardial infarction in young women: effect of female hormones on homocysteine levels. | In young women data are limited about the association between myocardial infarction (MI) and hyperhomocysteinemia, low folate or methylenetetrahydrofolate reductase (MTHFR) genotypes. The effect of oral contraceptive (OC) use on plasma homocysteine levels is not clear. We assessed the association between hyperhomocysteinemia, low folate, MTHFR 677TT mutation and risk of MI, and we investigated the effect of OC use on homocysteine levels in controls. In 181 patients with a first MI and 601 controls 18-49 years of age from a population-based case-control study, non-fasting blood samples were available. The homozygote mutant allele (TT) was detected in 12% of the patients and in 10% of controls. The odds ratio (OR) for MI in TT patients compared with the wild-type (CC) controls was 1.3 [95% confidence interval (CI) 0.8, 2.3]. For all MTHFR genotypes combined, the OR for MI in the lowest quartile of folate (<5.4 nmol L-1) compared with the highest quartile (>10.4 nmol L-1) was 3.0 (95% CI 1.7, 5.1). A 2-fold increased risk of MI was found in women with the TT genotype who had folate levels below the median of 7.4 nmol L-1 compared with CC genotype and folate levels above the median (OR = 2.0; 95% CI 1.0, 3.7). Mean homocysteine levels were 12.2 micromol L-1 in OC users and 12.3 micromol L-1 in non-users. Only at the 97.5 percentile (cut-off 21.0 micromol L-1) was the adjusted OR for higher vs. lower homocysteine levels increased by 2.8-fold (95% CI 1.2, 6.8). Low folate is a risk factor for MI, particularly in women with the MTHFR 677TT genotype. Homocysteine levels were not influenced by OC use. | Folate, homocysteine levels, /"methylenetetrahydrofolate reductase"/ (/"MTHFR"/) 677C --> T variant, and the risk of /"myocardial infarction"/ in young women: effect of female hormones on homocysteine levels. | In young women data are limited about the association between /"myocardial infarction"/ (/"MI"/) and hyperhomocysteinemia, low folate or /"methylenetetrahydrofolate reductase"/ (/"MTHFR"/) genotypes. The effect of oral contraceptive (OC) use on plasma homocysteine levels is not clear. We assessed the association between hyperhomocysteinemia, low folate, /"MTHFR"/ 677TT mutation and risk of /"MI"/, and we investigated the effect of OC use on homocysteine levels in controls. In 181 patients with a first /"MI"/ and 601 controls 18-49 years of age from a population-based case-control study, non-fasting blood samples were available. The homozygote mutant allele (TT) was detected in 12% of the patients and in 10% of controls. The odds ratio (OR) for /"MI"/ in TT patients compared with the wild-type (CC) controls was 1.3 [95% confidence interval (CI) 0.8, 2.3]. For all /"MTHFR"/ genotypes combined, the OR for /"MI"/ in the lowest quartile of folate (<5.4 nmol L-1) compared with the highest quartile (>10.4 nmol L-1) was 3.0 (95% CI 1.7, 5.1). A 2-fold increased risk of /"MI"/ was found in women with the TT genotype who had folate levels below the median of 7.4 nmol L-1 compared with CC genotype and folate levels above the median (OR = 2.0; 95% CI 1.0, 3.7). Mean homocysteine levels were 12.2 micromol L-1 in OC users and 12.3 micromol L-1 in non-users. Only at the 97.5 percentile (cut-off 21.0 micromol L-1) was the adjusted OR for higher vs. lower homocysteine levels increased by 2.8-fold (95% CI 1.2, 6.8). Low folate is a risk factor for /"MI"/, particularly in women with the /"MTHFR"/ 677TT genotype. Homocysteine levels were not influenced by OC use. | [
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14717963 | Folate, homocysteine levels, methylenetetrahydrofolate reductase (MTHFR) 677C --> T variant, and the risk of myocardial infarction in young women: effect of female hormones on homocysteine levels. | In young women data are limited about the association between myocardial infarction (MI) and hyperhomocysteinemia, low folate or methylenetetrahydrofolate reductase (MTHFR) genotypes. The effect of oral contraceptive (OC) use on plasma homocysteine levels is not clear. We assessed the association between hyperhomocysteinemia, low folate, MTHFR 677TT mutation and risk of MI, and we investigated the effect of OC use on homocysteine levels in controls. In 181 patients with a first MI and 601 controls 18-49 years of age from a population-based case-control study, non-fasting blood samples were available. The homozygote mutant allele (TT) was detected in 12% of the patients and in 10% of controls. The odds ratio (OR) for MI in TT patients compared with the wild-type (CC) controls was 1.3 [95% confidence interval (CI) 0.8, 2.3]. For all MTHFR genotypes combined, the OR for MI in the lowest quartile of folate (<5.4 nmol L-1) compared with the highest quartile (>10.4 nmol L-1) was 3.0 (95% CI 1.7, 5.1). A 2-fold increased risk of MI was found in women with the TT genotype who had folate levels below the median of 7.4 nmol L-1 compared with CC genotype and folate levels above the median (OR = 2.0; 95% CI 1.0, 3.7). Mean homocysteine levels were 12.2 micromol L-1 in OC users and 12.3 micromol L-1 in non-users. Only at the 97.5 percentile (cut-off 21.0 micromol L-1) was the adjusted OR for higher vs. lower homocysteine levels increased by 2.8-fold (95% CI 1.2, 6.8). Low folate is a risk factor for MI, particularly in women with the MTHFR 677TT genotype. Homocysteine levels were not influenced by OC use. | Folate, homocysteine levels, /"methylenetetrahydrofolate reductase"/ (/"MTHFR"/) 677C --> T variant, and the risk of myocardial infarction in young women: effect of female hormones on homocysteine levels. | In young women data are limited about the association between myocardial infarction (MI) and /"hyperhomocysteinemia"/, low folate or /"methylenetetrahydrofolate reductase"/ (/"MTHFR"/) genotypes. The effect of oral contraceptive (OC) use on plasma homocysteine levels is not clear. We assessed the association between /"hyperhomocysteinemia"/, low folate, /"MTHFR"/ 677TT mutation and risk of MI, and we investigated the effect of OC use on homocysteine levels in controls. In 181 patients with a first MI and 601 controls 18-49 years of age from a population-based case-control study, non-fasting blood samples were available. The homozygote mutant allele (TT) was detected in 12% of the patients and in 10% of controls. The odds ratio (OR) for MI in TT patients compared with the wild-type (CC) controls was 1.3 [95% confidence interval (CI) 0.8, 2.3]. For all /"MTHFR"/ genotypes combined, the OR for MI in the lowest quartile of folate (<5.4 nmol L-1) compared with the highest quartile (>10.4 nmol L-1) was 3.0 (95% CI 1.7, 5.1). A 2-fold increased risk of MI was found in women with the TT genotype who had folate levels below the median of 7.4 nmol L-1 compared with CC genotype and folate levels above the median (OR = 2.0; 95% CI 1.0, 3.7). Mean homocysteine levels were 12.2 micromol L-1 in OC users and 12.3 micromol L-1 in non-users. Only at the 97.5 percentile (cut-off 21.0 micromol L-1) was the adjusted OR for higher vs. lower homocysteine levels increased by 2.8-fold (95% CI 1.2, 6.8). Low folate is a risk factor for MI, particularly in women with the /"MTHFR"/ 677TT genotype. Homocysteine levels were not influenced by OC use. | [
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14717963 | Folate, homocysteine levels, methylenetetrahydrofolate reductase (MTHFR) 677C --> T variant, and the risk of myocardial infarction in young women: effect of female hormones on homocysteine levels. | In young women data are limited about the association between myocardial infarction (MI) and hyperhomocysteinemia, low folate or methylenetetrahydrofolate reductase (MTHFR) genotypes. The effect of oral contraceptive (OC) use on plasma homocysteine levels is not clear. We assessed the association between hyperhomocysteinemia, low folate, MTHFR 677TT mutation and risk of MI, and we investigated the effect of OC use on homocysteine levels in controls. In 181 patients with a first MI and 601 controls 18-49 years of age from a population-based case-control study, non-fasting blood samples were available. The homozygote mutant allele (TT) was detected in 12% of the patients and in 10% of controls. The odds ratio (OR) for MI in TT patients compared with the wild-type (CC) controls was 1.3 [95% confidence interval (CI) 0.8, 2.3]. For all MTHFR genotypes combined, the OR for MI in the lowest quartile of folate (<5.4 nmol L-1) compared with the highest quartile (>10.4 nmol L-1) was 3.0 (95% CI 1.7, 5.1). A 2-fold increased risk of MI was found in women with the TT genotype who had folate levels below the median of 7.4 nmol L-1 compared with CC genotype and folate levels above the median (OR = 2.0; 95% CI 1.0, 3.7). Mean homocysteine levels were 12.2 micromol L-1 in OC users and 12.3 micromol L-1 in non-users. Only at the 97.5 percentile (cut-off 21.0 micromol L-1) was the adjusted OR for higher vs. lower homocysteine levels increased by 2.8-fold (95% CI 1.2, 6.8). Low folate is a risk factor for MI, particularly in women with the MTHFR 677TT genotype. Homocysteine levels were not influenced by OC use. | Folate, homocysteine levels, methylenetetrahydrofolate reductase (MTHFR) 677C --> T variant, and the risk of myocardial infarction in young women: effect of female hormones on homocysteine levels. | In young women data are limited about the association between myocardial infarction (MI) and /"hyperhomocysteinemia"/, low folate or methylenetetrahydrofolate reductase (MTHFR) genotypes. The effect of oral contraceptive (OC) use on plasma homocysteine levels is not clear. We assessed the association between /"hyperhomocysteinemia"/, low folate, MTHFR 677TT mutation and risk of MI, and we investigated the effect of OC use on homocysteine levels in controls. In 181 patients with a first MI and 601 controls 18-49 years of age from a population-based case-control study, non-fasting blood samples were available. The homozygote mutant allele (TT) was detected in 12% of the patients and in 10% of controls. The odds ratio (OR) for MI in TT patients compared with the wild-type (CC) controls was 1.3 [95% confidence interval (CI) 0.8, 2.3]. For all MTHFR genotypes combined, the OR for MI in the lowest quartile of folate (<5.4 nmol /"L-1"/) compared with the highest quartile (>10.4 nmol /"L-1"/) was 3.0 (95% CI 1.7, 5.1). A 2-fold increased risk of MI was found in women with the TT genotype who had folate levels below the median of 7.4 nmol /"L-1"/ compared with CC genotype and folate levels above the median (OR = 2.0; 95% CI 1.0, 3.7). Mean homocysteine levels were 12.2 micromol /"L-1"/ in OC users and 12.3 micromol /"L-1"/ in non-users. Only at the 97.5 percentile (cut-off 21.0 micromol /"L-1"/) was the adjusted OR for higher vs. lower homocysteine levels increased by 2.8-fold (95% CI 1.2, 6.8). Low folate is a risk factor for MI, particularly in women with the MTHFR 677TT genotype. Homocysteine levels were not influenced by OC use. | [
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14717963 | Folate, homocysteine levels, methylenetetrahydrofolate reductase (MTHFR) 677C --> T variant, and the risk of myocardial infarction in young women: effect of female hormones on homocysteine levels. | In young women data are limited about the association between myocardial infarction (MI) and hyperhomocysteinemia, low folate or methylenetetrahydrofolate reductase (MTHFR) genotypes. The effect of oral contraceptive (OC) use on plasma homocysteine levels is not clear. We assessed the association between hyperhomocysteinemia, low folate, MTHFR 677TT mutation and risk of MI, and we investigated the effect of OC use on homocysteine levels in controls. In 181 patients with a first MI and 601 controls 18-49 years of age from a population-based case-control study, non-fasting blood samples were available. The homozygote mutant allele (TT) was detected in 12% of the patients and in 10% of controls. The odds ratio (OR) for MI in TT patients compared with the wild-type (CC) controls was 1.3 [95% confidence interval (CI) 0.8, 2.3]. For all MTHFR genotypes combined, the OR for MI in the lowest quartile of folate (<5.4 nmol L-1) compared with the highest quartile (>10.4 nmol L-1) was 3.0 (95% CI 1.7, 5.1). A 2-fold increased risk of MI was found in women with the TT genotype who had folate levels below the median of 7.4 nmol L-1 compared with CC genotype and folate levels above the median (OR = 2.0; 95% CI 1.0, 3.7). Mean homocysteine levels were 12.2 micromol L-1 in OC users and 12.3 micromol L-1 in non-users. Only at the 97.5 percentile (cut-off 21.0 micromol L-1) was the adjusted OR for higher vs. lower homocysteine levels increased by 2.8-fold (95% CI 1.2, 6.8). Low folate is a risk factor for MI, particularly in women with the MTHFR 677TT genotype. Homocysteine levels were not influenced by OC use. | Folate, homocysteine levels, methylenetetrahydrofolate reductase (MTHFR) 677C --> T variant, and the risk of /"myocardial infarction"/ in young women: effect of female hormones on homocysteine levels. | In young women data are limited about the association between /"myocardial infarction"/ (/"MI"/) and hyperhomocysteinemia, low folate or methylenetetrahydrofolate reductase (MTHFR) genotypes. The effect of oral contraceptive (OC) use on plasma homocysteine levels is not clear. We assessed the association between hyperhomocysteinemia, low folate, MTHFR 677TT mutation and risk of /"MI"/, and we investigated the effect of OC use on homocysteine levels in controls. In 181 patients with a first /"MI"/ and 601 controls 18-49 years of age from a population-based case-control study, non-fasting blood samples were available. The homozygote mutant allele (TT) was detected in 12% of the patients and in 10% of controls. The odds ratio (OR) for /"MI"/ in TT patients compared with the wild-type (CC) controls was 1.3 [95% confidence interval (CI) 0.8, 2.3]. For all MTHFR genotypes combined, the OR for /"MI"/ in the lowest quartile of folate (<5.4 nmol /"L-1"/) compared with the highest quartile (>10.4 nmol /"L-1"/) was 3.0 (95% CI 1.7, 5.1). A 2-fold increased risk of /"MI"/ was found in women with the TT genotype who had folate levels below the median of 7.4 nmol /"L-1"/ compared with CC genotype and folate levels above the median (OR = 2.0; 95% CI 1.0, 3.7). Mean homocysteine levels were 12.2 micromol /"L-1"/ in OC users and 12.3 micromol /"L-1"/ in non-users. Only at the 97.5 percentile (cut-off 21.0 micromol /"L-1"/) was the adjusted OR for higher vs. lower homocysteine levels increased by 2.8-fold (95% CI 1.2, 6.8). Low folate is a risk factor for /"MI"/, particularly in women with the MTHFR 677TT genotype. Homocysteine levels were not influenced by OC use. | [
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14720258 | Asthma is associated with single-nucleotide polymorphisms in ADAM33. | BACKGROUND: The ADAM33 gene has recently been associated with asthma and bronchial hyper-reactivity. It codes for a disintegrin and metalloproteinase that triggers intra- and extracellular signalling by protein shedding. OBJECTIVE: We examined whether polymorphisms in ADAM33 are associated with asthma and related traits in two German populations. METHODS: We genotyped 15 intragenic single-nucleotide polymorphisms (SNPs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of allele-specific primer extension products. The transmission disequilibrium test was used for association analysis in the German asthma family study. Additionally, we tested for association of these SNPs in a case-control sample from the European Community Respiratory Health Study using Armitage's trend test. RESULTS: In both studies, we found SNPs that were significantly associated with asthma and related traits. In the family study, significant associations were observed for the SNPs F+1, ST+4 and ST+5 (with the lowest P-value for F+1, P=0.005). Remarkably, this association is seen even in the absence of linkage with two microsatellite markers from a previous genome scan either 3.1 million bases (Mb) up- or 5.6 Mb downstream. In the case-control study, SNP ST+7 (P=0.008) was significantly associated with asthma. Some of these SNPs overlapped with those found to be associated with elevated total IgE levels and bronchial hyper-responsiveness. CONCLUSION: This study replicates the recently published association between asthma and ADAM33 gene variants. However, most of the associated SNPs were at non-identical positions in the German, UK and US samples. As linkage disequilibrium is high among the tested SNPs, and there is no known functional polymorphism, either not-tested variants in ADAM33, unknown regulatory elements or a gene in close proximity is responsible for this association. | /"Asthma"/ is associated with single-nucleotide polymorphisms in /"ADAM33"/. | BACKGROUND: The /"ADAM33"/ gene has recently been associated with /"asthma"/ and bronchial hyper-reactivity. It codes for a disintegrin and metalloproteinase that triggers intra- and extracellular signalling by protein shedding. OBJECTIVE: We examined whether polymorphisms in /"ADAM33"/ are associated with /"asthma"/ and related traits in two German populations. METHODS: We genotyped 15 intragenic single-nucleotide polymorphisms (SNPs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of allele-specific primer extension products. The transmission disequilibrium test was used for association analysis in the German /"asthma"/ family study. Additionally, we tested for association of these SNPs in a case-control sample from the European Community Respiratory Health Study using Armitage's trend test. RESULTS: In both studies, we found SNPs that were significantly associated with /"asthma"/ and related traits. In the family study, significant associations were observed for the SNPs F+1, ST+4 and ST+5 (with the lowest P-value for F+1, P=0.005). Remarkably, this association is seen even in the absence of linkage with two microsatellite markers from a previous genome scan either 3.1 million bases (Mb) up- or 5.6 Mb downstream. In the case-control study, SNP ST+7 (P=0.008) was significantly associated with /"asthma"/. Some of these SNPs overlapped with those found to be associated with elevated total IgE levels and bronchial hyper-responsiveness. CONCLUSION: This study replicates the recently published association between /"asthma"/ and /"ADAM33"/ gene variants. However, most of the associated SNPs were at non-identical positions in the German, UK and US samples. As linkage disequilibrium is high among the tested SNPs, and there is no known functional polymorphism, either not-tested variants in /"ADAM33"/, unknown regulatory elements or a gene in close proximity is responsible for this association. | [
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} | Yes |
14728994 | Glucocerebrosidase mutations in subjects with parkinsonism. | Recent studies showing an association between glucocerebrosidase deficiency and parkinsonism in Gaucher disease prompted an examination of the glucocerebrosidase gene sequence (GBA) and enzyme activity in brain samples from 57 subjects carrying the diagnosis of Parkinson disease. Alterations in GBA were identified in 12 samples (21%) and were more frequent among the younger subjects. These included eight with mutations (N370S, L444P, K198T, and R329C) and four with probable polymorphisms (T369M and E326K). Our findings suggest that mutations in glucocerebrosidase may be a risk factor for the development of parkinsonism. | Glucocerebrosidase mutations in subjects with parkinsonism. | Recent studies showing an association between glucocerebrosidase deficiency and parkinsonism in Gaucher disease prompted an examination of the glucocerebrosidase gene sequence (/"GBA"/) and enzyme activity in brain samples from 57 subjects carrying the diagnosis of /"Parkinson disease"/. Alterations in /"GBA"/ were identified in 12 samples (21%) and were more frequent among the younger subjects. These included eight with mutations (N370S, L444P, K198T, and R329C) and four with probable polymorphisms (T369M and E326K). Our findings suggest that mutations in glucocerebrosidase may be a risk factor for the development of parkinsonism. | [
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"text_name": "Parkinson disease"
} | Yes |
14728994 | Glucocerebrosidase mutations in subjects with parkinsonism. | Recent studies showing an association between glucocerebrosidase deficiency and parkinsonism in Gaucher disease prompted an examination of the glucocerebrosidase gene sequence (GBA) and enzyme activity in brain samples from 57 subjects carrying the diagnosis of Parkinson disease. Alterations in GBA were identified in 12 samples (21%) and were more frequent among the younger subjects. These included eight with mutations (N370S, L444P, K198T, and R329C) and four with probable polymorphisms (T369M and E326K). Our findings suggest that mutations in glucocerebrosidase may be a risk factor for the development of parkinsonism. | Glucocerebrosidase mutations in subjects with parkinsonism. | Recent studies showing an association between /"glucocerebrosidase deficiency"/ and parkinsonism in /"Gaucher disease"/ prompted an examination of the glucocerebrosidase gene sequence (/"GBA"/) and enzyme activity in brain samples from 57 subjects carrying the diagnosis of Parkinson disease. Alterations in /"GBA"/ were identified in 12 samples (21%) and were more frequent among the younger subjects. These included eight with mutations (N370S, L444P, K198T, and R329C) and four with probable polymorphisms (T369M and E326K). Our findings suggest that mutations in glucocerebrosidase may be a risk factor for the development of parkinsonism. | [
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"text_name": "GBA"
} | {
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"text_name": "glucocerebrosidase deficiency"
} | No |
14732601 | A nonsense mutation in the synaptogyrin 1 gene in a family with schizophrenia. | BACKGROUND: Chromosome 22q is one of the important regions repeatedly being implicated in schizophrenia. In this region, our group previously reported an association of a CAG repeat marker (22CH3) with schizophrenia in the Indian population. Because Synaptogyrin 1 (SYNGR1), associated with presynaptic vesicles in neuronal cells, lies within 1 million base pairs of this marker, it is a potential candidate gene for schizophrenia. METHODS: We sequenced all six exons and flanking splice junctions of the SYNGR1 gene. We also carried out reverse transcriptase polymerase chain reaction and Northern blot analysis for exon 2 containing transcript of the SYNGR1 gene. RESULTS: We found a novel nonsense mutation (Trp27Ter) in exon 2 of the SYNGR1 gene in a family multiply affected with schizophrenia. Reverse transcriptase polymerase chain reaction and Northern blot analyses revealed that exon 2 containing transcript of this gene is expressed in the brain. CONCLUSIONS: Because the SYNGR1 gene is involved in presynaptic pathways, reduced levels of this protein might play some role in the pathogenesis of schizophrenia. | A nonsense mutation in the /"synaptogyrin 1"/ gene in a family with /"schizophrenia"/. | BACKGROUND: Chromosome 22q is one of the important regions repeatedly being implicated in /"schizophrenia"/. In this region, our group previously reported an association of a CAG repeat marker (22CH3) with /"schizophrenia"/ in the Indian population. Because /"Synaptogyrin 1"/ (/"SYNGR1"/), associated with presynaptic vesicles in neuronal cells, lies within 1 million base pairs of this marker, it is a potential candidate gene for /"schizophrenia"/. METHODS: We sequenced all six exons and flanking splice junctions of the /"SYNGR1"/ gene. We also carried out reverse transcriptase polymerase chain reaction and Northern blot analysis for exon 2 containing transcript of the /"SYNGR1"/ gene. RESULTS: We found a novel nonsense mutation (Trp27Ter) in exon 2 of the /"SYNGR1"/ gene in a family multiply affected with /"schizophrenia"/. Reverse transcriptase polymerase chain reaction and Northern blot analyses revealed that exon 2 containing transcript of this gene is expressed in the brain. CONCLUSIONS: Because the /"SYNGR1"/ gene is involved in presynaptic pathways, reduced levels of this protein might play some role in the pathogenesis of /"schizophrenia"/. | [
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"text_name": "schizophrenia"
} | Yes |
14763782 | Polymorphisms in an interferon-gamma receptor-1 gene marker and susceptibility to periodontitis. | Chronic marginal periodontitis is an inflammatory condition in which the supporting tissues of the teeth are destroyed. Interferon (IFN)-gamma is a cytokine that plays a pivotal role in the defense against infection, and mutations in the gene coding for the ligand binding chain (alpha, R1) of the IFN-gamma receptor (IFNGR1) confer suseptibility on infections caused by poorly virulent mycobacteria. Using an intronic (CA)n polymorphic microsatellite marker within the IFNGR1 gene we investigated whether genetic polymorphisms are associated with periodontitis. In 62 periodontitis patients and 56 healthy controls we found a total of 13 polymorphisms, 11 of which were found in the periodontitis patients and 9 in the controls. Although we observed a trend towards an association with disease for allele 192, there were no significant differences in allele frequency between patients and controls. We therefore cannot find any evidence to suggest that IFNGR1, as a single dominant gene, contributes to susceptibility to periodontitis. However, in combination with the environmental risk factor, smoking, the same allelic marker was significantly associated [OR = 5.56 (1.16<OR<36.31), P=0.014, Pcorr=0.027] with periodontitis. Our results support the multigene-environment interaction model of disease susceptibility to periodontitis. | Polymorphisms in an /"interferon-gamma receptor-1"/ gene marker and susceptibility to /"periodontitis"/. | Chronic /"marginal periodontitis"/ is an inflammatory condition in which the supporting tissues of the teeth are destroyed. Interferon (IFN)-gamma is a cytokine that plays a pivotal role in the defense against infection, and mutations in the gene coding for the ligand binding chain (alpha, R1) of the IFN-gamma receptor (/"IFNGR1"/) confer suseptibility on infections caused by poorly virulent mycobacteria. Using an intronic (CA)n polymorphic microsatellite marker within the /"IFNGR1"/ gene we investigated whether genetic polymorphisms are associated with /"periodontitis"/. In 62 /"periodontitis"/ patients and 56 healthy controls we found a total of 13 polymorphisms, 11 of which were found in the /"periodontitis"/ patients and 9 in the controls. Although we observed a trend towards an association with disease for allele 192, there were no significant differences in allele frequency between patients and controls. We therefore cannot find any evidence to suggest that /"IFNGR1"/, as a single dominant gene, contributes to susceptibility to /"periodontitis"/. However, in combination with the environmental risk factor, smoking, the same allelic marker was significantly associated [OR = 5.56 (1.16<OR<36.31), P=0.014, Pcorr=0.027] with /"periodontitis"/. Our results support the multigene-environment interaction model of disease susceptibility to /"periodontitis"/. | [
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14763782 | Polymorphisms in an interferon-gamma receptor-1 gene marker and susceptibility to periodontitis. | Chronic marginal periodontitis is an inflammatory condition in which the supporting tissues of the teeth are destroyed. Interferon (IFN)-gamma is a cytokine that plays a pivotal role in the defense against infection, and mutations in the gene coding for the ligand binding chain (alpha, R1) of the IFN-gamma receptor (IFNGR1) confer suseptibility on infections caused by poorly virulent mycobacteria. Using an intronic (CA)n polymorphic microsatellite marker within the IFNGR1 gene we investigated whether genetic polymorphisms are associated with periodontitis. In 62 periodontitis patients and 56 healthy controls we found a total of 13 polymorphisms, 11 of which were found in the periodontitis patients and 9 in the controls. Although we observed a trend towards an association with disease for allele 192, there were no significant differences in allele frequency between patients and controls. We therefore cannot find any evidence to suggest that IFNGR1, as a single dominant gene, contributes to susceptibility to periodontitis. However, in combination with the environmental risk factor, smoking, the same allelic marker was significantly associated [OR = 5.56 (1.16<OR<36.31), P=0.014, Pcorr=0.027] with periodontitis. Our results support the multigene-environment interaction model of disease susceptibility to periodontitis. | Polymorphisms in an /"interferon-gamma receptor-1"/ gene marker and susceptibility to periodontitis. | Chronic marginal periodontitis is an inflammatory condition in which the supporting tissues of the teeth are destroyed. Interferon (IFN)-gamma is a cytokine that plays a pivotal role in the defense against /"infection"/, and mutations in the gene coding for the ligand binding chain (alpha, R1) of the IFN-gamma receptor (/"IFNGR1"/) confer suseptibility on /"infections"/ caused by poorly virulent mycobacteria. Using an intronic (CA)n polymorphic microsatellite marker within the /"IFNGR1"/ gene we investigated whether genetic polymorphisms are associated with periodontitis. In 62 periodontitis patients and 56 healthy controls we found a total of 13 polymorphisms, 11 of which were found in the periodontitis patients and 9 in the controls. Although we observed a trend towards an association with disease for allele 192, there were no significant differences in allele frequency between patients and controls. We therefore cannot find any evidence to suggest that /"IFNGR1"/, as a single dominant gene, contributes to susceptibility to periodontitis. However, in combination with the environmental risk factor, smoking, the same allelic marker was significantly associated [OR = 5.56 (1.16<OR<36.31), P=0.014, Pcorr=0.027] with periodontitis. Our results support the multigene-environment interaction model of disease susceptibility to periodontitis. | [
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14962090 | Evaluation of the IRF-2 gene as a candidate for PSORS3. | Type 1 interferon can trigger flares of psoriasis. Hypersensitivity to type 1 interferon signaling causes a psoriasis-like skin disease in mice deficient for the transcription factor interferon regulatory factor 2 (IRF2). The human IRF2 gene is located at a previously identified candidate psoriasis susceptibility locus on chromosome 4q (PSORS3 at D4S1535). Therefore, we tested association of psoriasis with IRF2. We generated a sample consisting of 157 families with a total of 521 individuals. Five novel microsatellite markers were developed and typed, and complemented with three known markers to yield a set of eight markers spaced within 600 kb around the IRF2 gene, three of which are located in the gene. We detected association of IRF2 with type 1 psoriasis at two markers in the IRF2 gene. Haplotype sharing analysis confirmed association of IRF2 with type 1 psoriasis (p=0.0017; pcorr=0.03). The 921G/A SNP in exon 9 was found to obliterate a predicted exon splice enhancer in an allele-specific manner. There was a suggestive increase of homozygosity for the splicing-deficient allele in type 1 psoriasis patients. Our data identify IRF2 as a potential susceptibility gene for psoriasis. | Evaluation of the /"IRF-2"/ gene as a candidate for PSORS3. | Type 1 interferon can trigger flares of /"psoriasis"/. Hypersensitivity to type 1 interferon signaling causes a /"psoriasis"/-like skin disease in mice deficient for the transcription factor /"interferon regulatory factor 2"/ (/"IRF2"/). The human /"IRF2"/ gene is located at a previously identified candidate /"psoriasis"/ susceptibility locus on chromosome 4q (PSORS3 at D4S1535). Therefore, we tested association of /"psoriasis"/ with /"IRF2"/. We generated a sample consisting of 157 families with a total of 521 individuals. Five novel microsatellite markers were developed and typed, and complemented with three known markers to yield a set of eight markers spaced within 600 kb around the /"IRF2"/ gene, three of which are located in the gene. We detected association of /"IRF2"/ with type 1 /"psoriasis"/ at two markers in the /"IRF2"/ gene. Haplotype sharing analysis confirmed association of /"IRF2"/ with type 1 /"psoriasis"/ (p=0.0017; pcorr=0.03). The 921G/A SNP in exon 9 was found to obliterate a predicted exon splice enhancer in an allele-specific manner. There was a suggestive increase of homozygosity for the splicing-deficient allele in type 1 /"psoriasis"/ patients. Our data identify /"IRF2"/ as a potential susceptibility gene for /"psoriasis"/. | [
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} | Yes |
14962090 | Evaluation of the IRF-2 gene as a candidate for PSORS3. | Type 1 interferon can trigger flares of psoriasis. Hypersensitivity to type 1 interferon signaling causes a psoriasis-like skin disease in mice deficient for the transcription factor interferon regulatory factor 2 (IRF2). The human IRF2 gene is located at a previously identified candidate psoriasis susceptibility locus on chromosome 4q (PSORS3 at D4S1535). Therefore, we tested association of psoriasis with IRF2. We generated a sample consisting of 157 families with a total of 521 individuals. Five novel microsatellite markers were developed and typed, and complemented with three known markers to yield a set of eight markers spaced within 600 kb around the IRF2 gene, three of which are located in the gene. We detected association of IRF2 with type 1 psoriasis at two markers in the IRF2 gene. Haplotype sharing analysis confirmed association of IRF2 with type 1 psoriasis (p=0.0017; pcorr=0.03). The 921G/A SNP in exon 9 was found to obliterate a predicted exon splice enhancer in an allele-specific manner. There was a suggestive increase of homozygosity for the splicing-deficient allele in type 1 psoriasis patients. Our data identify IRF2 as a potential susceptibility gene for psoriasis. | Evaluation of the IRF-2 gene as a candidate for /"PSORS3"/. | Type 1 interferon can trigger flares of /"psoriasis"/. Hypersensitivity to type 1 interferon signaling causes a /"psoriasis"/-like skin disease in mice deficient for the transcription factor interferon regulatory factor 2 (IRF2). The human IRF2 gene is located at a previously identified candidate /"psoriasis"/ susceptibility locus on chromosome 4q (/"PSORS3"/ at D4S1535). Therefore, we tested association of /"psoriasis"/ with IRF2. We generated a sample consisting of 157 families with a total of 521 individuals. Five novel microsatellite markers were developed and typed, and complemented with three known markers to yield a set of eight markers spaced within 600 kb around the IRF2 gene, three of which are located in the gene. We detected association of IRF2 with type 1 /"psoriasis"/ at two markers in the IRF2 gene. Haplotype sharing analysis confirmed association of IRF2 with type 1 /"psoriasis"/ (p=0.0017; pcorr=0.03). The 921G/A SNP in exon 9 was found to obliterate a predicted exon splice enhancer in an allele-specific manner. There was a suggestive increase of homozygosity for the splicing-deficient allele in type 1 /"psoriasis"/ patients. Our data identify IRF2 as a potential susceptibility gene for /"psoriasis"/. | [
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14970845 | Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease. | The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD. | Polymorphisms in the /"prion protein"/ gene and in the doppel gene increase susceptibility for /"Creutzfeldt-Jakob disease"/. | The /"prion protein"/ gene (/"PRNP"/) plays a central role in the origin of /"Creutzfeldt-Jakob disease"/ (/"CJD"/), but there is growing interest in other polymorphisms that may be involved in /"CJD"/. Polymorphisms upstream of /"PRNP"/ that may modulate the /"prion protein"/ production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of /"PRNP"/ and three polymorphisms in PRND (T26M, P56L and T174M) in /"CJD"/. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and /"PRNP"/ M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to /"CJD"/ independent of /"PRNP"/ M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for /"PRNP"/ 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to /"CJD"/, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to /"CJD"/. | [
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14970845 | Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease. | The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD. | Polymorphisms in the prion protein gene and in the /"doppel"/ gene increase susceptibility for /"Creutzfeldt-Jakob disease"/. | The prion protein gene (PRNP) plays a central role in the origin of /"Creutzfeldt-Jakob disease"/ (/"CJD"/), but there is growing interest in other polymorphisms that may be involved in /"CJD"/. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like /"doppel"/ gene (/"PRND"/) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in /"PRND"/ (T26M, P56L and T174M) in /"CJD"/. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on /"PRND"/ T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to /"CJD"/ independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at /"PRND"/ T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and /"PRND"/ 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the /"PRND"/ T174M polymorphism did not show a consistent effect across studies, raising the question as to whether /"PRND"/ 174M is causally related to /"CJD"/, or whether the /"PRND"/ allele is in linkage disequilibrium with another polymorphism related to /"CJD"/. | [
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14970845 | Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease. | The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD. | Polymorphisms in the prion protein gene and in the /"doppel"/ gene increase susceptibility for Creutzfeldt-Jakob disease. | The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like /"doppel"/ gene (/"PRND"/) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in /"PRND"/ (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with /"sporadic CJD"/ and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on /"PRND"/ T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at /"PRND"/ T174M among /"sporadic CJD"/ patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and /"PRND"/ 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the /"PRND"/ T174M polymorphism did not show a consistent effect across studies, raising the question as to whether /"PRND"/ 174M is causally related to CJD, or whether the /"PRND"/ allele is in linkage disequilibrium with another polymorphism related to CJD. | [
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14970845 | Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease. | The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD. | Polymorphisms in the /"prion protein"/ gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease. | The /"prion protein"/ gene (/"PRNP"/) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of /"PRNP"/ that may modulate the /"prion protein"/ production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of /"PRNP"/ and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with /"sporadic CJD"/ and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and /"PRNP"/ M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of /"PRNP"/ M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among /"sporadic CJD"/ patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for /"PRNP"/ 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD. | [
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14974362 | [Arterial hypertension in glomerulonephritis]. | Numerous factors causing the disturbances of pressure natriuresis mechanism may be involved in the development of arterial hypertension in kidney diseases. In particular patients with parenchymatous kidney disease, the relative effect of the impaired renal sodium excretion causing extracellular fluid volume expansion and the disequilibrium of vasoconstricting and vasorelaxating factors may differ, and in addition, these effects are influenced by the type of kidney disease, the degree of the kidney function impairment and sodium intake. In our studies on the hypertension in kidney disease we have choosen the evaluation of incidence of hypertension in the early stage of primary glomerulonephritis (GN) and the comparison of distribution of genotypes and alleles depending on insertion/deletion polymorphism of angiotensin converting enzyme (ACE) gene in patients with early stage of GN and healthy subjects. Arterial hypertension was diagnosed according to actual criteria in 46% out of 74 patients with early stage of GN. It was also found that hypertension was more common in patients with nephrotic syndrome (63%) than in patients with lower proteinuria (36% of patients). Among 50 patients with early stage of GN the distribution of genotypes and alleles depending on the polymorphism ACE gene was significantly different from 100 healthy controls. These results indicate that hypertension is often present in early stage of GN, particularly in patients with nephrotic syndrome and depends on the morphological type of glomerular disease. Further studies are needed for verification of the role of ACE gene polymorphism in the predisposition to development of GN and associated arterial hypertension. | [Arterial hypertension in glomerulonephritis]. | Numerous factors causing the disturbances of pressure natriuresis mechanism may be involved in the development of arterial hypertension in /"kidney diseases"/. In particular patients with /"parenchymatous kidney disease"/, the relative effect of the impaired renal sodium excretion causing extracellular fluid volume expansion and the disequilibrium of vasoconstricting and vasorelaxating factors may differ, and in addition, these effects are influenced by the type of /"kidney disease, the degree of the kidney function impairment"/ and sodium intake. In our studies on the hypertension in /"kidney disease"/ we have choosen the evaluation of incidence of hypertension in the early stage of primary glomerulonephritis (GN) and the comparison of distribution of genotypes and alleles depending on insertion/deletion polymorphism of /"angiotensin converting enzyme"/ (/"ACE"/) gene in patients with early stage of GN and healthy subjects. Arterial hypertension was diagnosed according to actual criteria in 46% out of 74 patients with early stage of GN. It was also found that hypertension was more common in patients with nephrotic syndrome (63%) than in patients with lower proteinuria (36% of patients). Among 50 patients with early stage of GN the distribution of genotypes and alleles depending on the polymorphism /"ACE"/ gene was significantly different from 100 healthy controls. These results indicate that hypertension is often present in early stage of GN, particularly in patients with nephrotic syndrome and depends on the morphological /"type of glomerular disease"/. Further studies are needed for verification of the role of /"ACE"/ gene polymorphism in the predisposition to development of GN and associated arterial hypertension. | [
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14974362 | [Arterial hypertension in glomerulonephritis]. | Numerous factors causing the disturbances of pressure natriuresis mechanism may be involved in the development of arterial hypertension in kidney diseases. In particular patients with parenchymatous kidney disease, the relative effect of the impaired renal sodium excretion causing extracellular fluid volume expansion and the disequilibrium of vasoconstricting and vasorelaxating factors may differ, and in addition, these effects are influenced by the type of kidney disease, the degree of the kidney function impairment and sodium intake. In our studies on the hypertension in kidney disease we have choosen the evaluation of incidence of hypertension in the early stage of primary glomerulonephritis (GN) and the comparison of distribution of genotypes and alleles depending on insertion/deletion polymorphism of angiotensin converting enzyme (ACE) gene in patients with early stage of GN and healthy subjects. Arterial hypertension was diagnosed according to actual criteria in 46% out of 74 patients with early stage of GN. It was also found that hypertension was more common in patients with nephrotic syndrome (63%) than in patients with lower proteinuria (36% of patients). Among 50 patients with early stage of GN the distribution of genotypes and alleles depending on the polymorphism ACE gene was significantly different from 100 healthy controls. These results indicate that hypertension is often present in early stage of GN, particularly in patients with nephrotic syndrome and depends on the morphological type of glomerular disease. Further studies are needed for verification of the role of ACE gene polymorphism in the predisposition to development of GN and associated arterial hypertension. | [Arterial /"hypertension"/ in glomerulonephritis]. | Numerous factors causing the disturbances of pressure natriuresis mechanism may be involved in the development of /"arterial hypertension"/ in kidney diseases. In particular patients with parenchymatous kidney disease, the relative effect of the impaired renal sodium excretion causing extracellular fluid volume expansion and the disequilibrium of vasoconstricting and vasorelaxating factors may differ, and in addition, these effects are influenced by the type of kidney disease, the degree of the kidney function impairment and sodium intake. In our studies on the /"hypertension"/ in kidney disease we have choosen the evaluation of incidence of /"hypertension"/ in the early stage of primary glomerulonephritis (GN) and the comparison of distribution of genotypes and alleles depending on insertion/deletion polymorphism of /"angiotensin converting enzyme"/ (/"ACE"/) gene in patients with early stage of GN and healthy subjects. Arterial /"hypertension"/ was diagnosed according to actual criteria in 46% out of 74 patients with early stage of GN. It was also found that /"hypertension"/ was more common in patients with nephrotic syndrome (63%) than in patients with lower proteinuria (36% of patients). Among 50 patients with early stage of GN the distribution of genotypes and alleles depending on the polymorphism /"ACE"/ gene was significantly different from 100 healthy controls. These results indicate that /"hypertension"/ is often present in early stage of GN, particularly in patients with nephrotic syndrome and depends on the morphological type of glomerular disease. Further studies are needed for verification of the role of /"ACE"/ gene polymorphism in the predisposition to development of GN and associated /"arterial hypertension"/. | [
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15007140 | Association of APOE polymorphisms with disease severity in MS is limited to women. | The authors studied the association of an exon 4 (E4*epsilon2/3/4) and three promoter polymorphisms of APOE with disease course and severity stratified by gender in 221 patients with multiple sclerosis from two overlapping population-based prevalence cohorts. Women carriers of the E4*epsilon2 allele took longer to attain an Expanded Disability Status Scale score of 6 (p = 0.015) and had more favorable ranked severity scores than noncarriers (p = 0.009). There was no association in men. Alleles epsilon3 or epsilon4 and promoter polymorphisms were not associated with disease course or severity. | Association of /"APOE"/ polymorphisms with disease severity in /"MS"/ is limited to women. | The authors studied the association of an exon 4 (E4*epsilon2/3/4) and three promoter polymorphisms of /"APOE"/ with disease course and severity stratified by gender in 221 patients with /"multiple sclerosis"/ from two overlapping population-based prevalence cohorts. Women carriers of the E4*epsilon2 allele took longer to attain an Expanded Disability Status Scale score of 6 (p = 0.015) and had more favorable ranked severity scores than noncarriers (p = 0.009). There was no association in men. Alleles epsilon3 or epsilon4 and promoter polymorphisms were not associated with disease course or severity. | [
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15018693 | Sleep/wake disruption in Alzheimer's disease: APOE status and longitudinal course. | Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (APOE epsilon4) carrier status may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele. | Sleep/wake disruption in /"Alzheimer's disease"/: /"APOE"/ status and longitudinal course. | Disturbed sleep is a major clinical problem in /"Alzheimer's disease"/ (/"AD"/). Apolipoprotein epsilon4 (/"APOE"/ epsilon4) carrier status may increase risk of /"AD"/, yet there are no data on relations between /"APOE"/ status and progression of sleep disturbance in /"AD"/. The objective of this study was to determine if sleep parameters in /"AD"/ patients change over time as a function of /"APOE"/ carrier status. Forty-four community-dwelling /"AD"/ patients with diagnosis of probable /"AD"/ were followed from early stages of disease. Their sleep/wake parameters were compared according to /"APOE"/ status. For /"APOE"/ epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, /"APOE"/ status was associated with the progression of sleep/wake disturbances in /"AD"/. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele. | [
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15018693 | Sleep/wake disruption in Alzheimer's disease: APOE status and longitudinal course. | Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (APOE epsilon4) carrier status may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele. | Sleep/wake disruption in Alzheimer's disease: /"APOE"/ status and longitudinal course. | Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (/"APOE"/ epsilon4) carrier status may increase risk of AD, yet there are no data on relations between /"APOE"/ status and progression of /"sleep disturbance"/ in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of /"APOE"/ carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to /"APOE"/ status. For /"APOE"/ epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, /"APOE"/ status was associated with the progression of /"sleep/wake disturbances"/ in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele. | [
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15022317 | Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1 locus. | OBJECTIVE: Rheumatoid arthritis (RA) has an estimated genetic contribution of 30-50%, approximately one-third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a shared epitope. However, several recent studies have suggested that additional telomeric genetic influences may exist. In this study, we sought to investigate whether a separate non-DRB1 effect could be detected and to determine its likely location. METHODS: We typed 13 single-nucleotide polymorphisms, located mainly in the telomeric class III region of the major histocompatibility complex, in 164 British Caucasian families with RA that had at least 1 affected offspring and used unconditioned and DRB1-conditioned transmission disequilibrium tests (TDTs). RESULTS: Unconditioned TDTs revealed overtransmission of shared epitope alleles (P = 2.12 x 10(-5)) and an allele of the HLA-B-associated transcript 1 (BAT1) gene in the telomeric class III region (P = 0.009). Using a DRB1-conditioned TDT to assess whether an independent effect existed, we detected unequal transmission of alleles of lymphocyte-specific transcript 1 (P = 0.004), BAT1 (P = 0.003), and PG8 (P = 0.003). CONCLUSION: At least 1 additional non-DRB1 susceptibility locus for RA exists in an interval that encompasses the junction of the class III and I regions. This is a genomic segment of high linkage disequilibrium containing a large number of poorly characterized immunomodulatory genes. | Additional genetic susceptibility for /"rheumatoid arthritis"/ telomeric of the /"DRB1"/ locus. | OBJECTIVE: /"Rheumatoid arthritis"/ (/"RA"/) has an estimated genetic contribution of 30-50%, approximately one-third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of /"DRB1"/ that encode a shared epitope. However, several recent studies have suggested that additional telomeric genetic influences may exist. In this study, we sought to investigate whether a separate non-/"DRB1"/ effect could be detected and to determine its likely location. METHODS: We typed 13 single-nucleotide polymorphisms, located mainly in the telomeric class III region of the major histocompatibility complex, in 164 British Caucasian families with /"RA"/ that had at least 1 affected offspring and used unconditioned and /"DRB1"/-conditioned transmission disequilibrium tests (TDTs). RESULTS: Unconditioned TDTs revealed overtransmission of shared epitope alleles (P = 2.12 x 10(-5)) and an allele of the HLA-B-associated transcript 1 (BAT1) gene in the telomeric class III region (P = 0.009). Using a /"DRB1"/-conditioned TDT to assess whether an independent effect existed, we detected unequal transmission of alleles of lymphocyte-specific transcript 1 (P = 0.004), BAT1 (P = 0.003), and PG8 (P = 0.003). CONCLUSION: At least 1 additional non-/"DRB1"/ susceptibility locus for /"RA"/ exists in an interval that encompasses the junction of the class III and I regions. This is a genomic segment of high linkage disequilibrium containing a large number of poorly characterized immunomodulatory genes. | [
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15022317 | Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1 locus. | OBJECTIVE: Rheumatoid arthritis (RA) has an estimated genetic contribution of 30-50%, approximately one-third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a shared epitope. However, several recent studies have suggested that additional telomeric genetic influences may exist. In this study, we sought to investigate whether a separate non-DRB1 effect could be detected and to determine its likely location. METHODS: We typed 13 single-nucleotide polymorphisms, located mainly in the telomeric class III region of the major histocompatibility complex, in 164 British Caucasian families with RA that had at least 1 affected offspring and used unconditioned and DRB1-conditioned transmission disequilibrium tests (TDTs). RESULTS: Unconditioned TDTs revealed overtransmission of shared epitope alleles (P = 2.12 x 10(-5)) and an allele of the HLA-B-associated transcript 1 (BAT1) gene in the telomeric class III region (P = 0.009). Using a DRB1-conditioned TDT to assess whether an independent effect existed, we detected unequal transmission of alleles of lymphocyte-specific transcript 1 (P = 0.004), BAT1 (P = 0.003), and PG8 (P = 0.003). CONCLUSION: At least 1 additional non-DRB1 susceptibility locus for RA exists in an interval that encompasses the junction of the class III and I regions. This is a genomic segment of high linkage disequilibrium containing a large number of poorly characterized immunomodulatory genes. | Additional genetic susceptibility for /"rheumatoid arthritis"/ telomeric of the DRB1 locus. | OBJECTIVE: /"Rheumatoid arthritis"/ (/"RA"/) has an estimated genetic contribution of 30-50%, approximately one-third of which arises from the major histocompatibility complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a shared epitope. However, several recent studies have suggested that additional telomeric genetic influences may exist. In this study, we sought to investigate whether a separate non-DRB1 effect could be detected and to determine its likely location. METHODS: We typed 13 single-nucleotide polymorphisms, located mainly in the telomeric class III region of the major histocompatibility complex, in 164 British Caucasian families with /"RA"/ that had at least 1 affected offspring and used unconditioned and DRB1-conditioned transmission disequilibrium tests (TDTs). RESULTS: Unconditioned TDTs revealed overtransmission of shared epitope alleles (P = 2.12 x 10(-5)) and an allele of the /"HLA-B-associated transcript 1"/ (/"BAT1"/) gene in the telomeric class III region (P = 0.009). Using a DRB1-conditioned TDT to assess whether an independent effect existed, we detected unequal transmission of alleles of lymphocyte-specific transcript 1 (P = 0.004), /"BAT1"/ (P = 0.003), and PG8 (P = 0.003). CONCLUSION: At least 1 additional non-DRB1 susceptibility locus for /"RA"/ exists in an interval that encompasses the junction of the class III and I regions. This is a genomic segment of high linkage disequilibrium containing a large number of poorly characterized immunomodulatory genes. | [
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15024131 | Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. | Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8(+) T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to abacavir. | Predisposition to abacavir /"hypersensitivity"/ conferred by /"HLA-B"/*5701 and a haplotypic Hsp70-Hom variant. | Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of /"HLA-B"/*5701 strongly predicts abacavir /"hypersensitivity"/ and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir /"hypersensitivity"/ (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. /"HLA-B"/*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with /"HLA-B"/*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir /"hypersensitivity"/ demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8(+) T cell depletion. These data indicate that the concurrence of /"HLA-B"/*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir /"hypersensitivity"/, which is likely to be mediated by an /"HLA-B"/*5701-restricted immune response to abacavir. | [
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15024131 | Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. | Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8(+) T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to abacavir. | Predisposition to abacavir hypersensitivity conferred by /"HLA-B"/*5701 and a haplotypic Hsp70-Hom variant. | Susceptibility to a clinically significant /"drug hypersensitivity syndrome"/ associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of /"HLA-B"/*5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. /"HLA-B"/*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with /"HLA-B"/*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8(+) T cell depletion. These data indicate that the concurrence of /"HLA-B"/*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an /"HLA-B"/*5701-restricted immune response to abacavir. | [
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15048896 | Accelerated evolution of brain atrophy and "black holes" in MS patients with APOE-epsilon 4. | Apolipoprotein E (APOE)-epsilon4 has been associated with an unfavorable course of multiple sclerosis (MS). The mechanisms responsible for this are unclear, although cross-sectional MRI demonstrated a higher extent of "black holes" (BHs) in such patients. Here, we have studied the impact of the APOE genotype on both the longitudinal evolution of focal (BH ratio) and global (brain volume change [BVC]) brain tissue damage. Ninety-nine MS patients underwent ApoE genotyping, clinical examination, and magnetic resonance imaging at baseline and after 2.7 +/- 1.1 years to assess lesion load (LL) and BVC. In APOE-epsilon4 patients, the annual reduction in brain volume was fivefold higher (-0.65 +/- 0.61%) than in those without APOE-epsilon4 (-0.13 +/- 0.36%; p = 0.0001). At baseline, T(2) LL and T(1) LL were non-significantly higher in epsilon4 carriers, despite a shorter disease duration and absence of significant clinical differences. During follow-up, T(1) LL increased from 1.2 +/- 2.3 ccm to 1.7 +/- 2.7 ccm in the epsilon4 group, although T(2) LL did not change, leading to a significantly higher increase in the BH ratio [(T(1) LL/T(2) LL) x 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-epsilon4 patients (5.0 vs 5.7%). Accelerated brain tissue loss and a higher proportion of lesions evolving into BH therefore provide magnetic resonance imaging evidence for more pronounced tissue destruction in MS patients with APOE-epsilon4. | Accelerated evolution of brain atrophy and "black holes" in /"MS"/ patients with /"APOE"/-epsilon 4. | /"Apolipoprotein E"/ (/"APOE"/)-epsilon4 has been associated with an unfavorable course of /"multiple sclerosis"/ (/"MS"/). The mechanisms responsible for this are unclear, although cross-sectional MRI demonstrated a higher extent of "black holes" (BHs) in such patients. Here, we have studied the impact of the /"APOE"/ genotype on both the longitudinal evolution of focal (BH ratio) and global (brain volume change [BVC]) brain tissue damage. Ninety-nine /"MS"/ patients underwent /"ApoE"/ genotyping, clinical examination, and magnetic resonance imaging at baseline and after 2.7 +/- 1.1 years to assess lesion load (LL) and BVC. In /"APOE"/-epsilon4 patients, the annual reduction in brain volume was fivefold higher (-0.65 +/- 0.61%) than in those without /"APOE"/-epsilon4 (-0.13 +/- 0.36%; p = 0.0001). At baseline, T(2) LL and T(1) LL were non-significantly higher in epsilon4 carriers, despite a shorter disease duration and absence of significant clinical differences. During follow-up, T(1) LL increased from 1.2 +/- 2.3 ccm to 1.7 +/- 2.7 ccm in the epsilon4 group, although T(2) LL did not change, leading to a significantly higher increase in the BH ratio [(T(1) LL/T(2) LL) x 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-epsilon4 patients (5.0 vs 5.7%). Accelerated brain tissue loss and a higher proportion of lesions evolving into BH therefore provide magnetic resonance imaging evidence for more pronounced tissue destruction in /"MS"/ patients with /"APOE"/-epsilon4. | [
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15048896 | Accelerated evolution of brain atrophy and "black holes" in MS patients with APOE-epsilon 4. | Apolipoprotein E (APOE)-epsilon4 has been associated with an unfavorable course of multiple sclerosis (MS). The mechanisms responsible for this are unclear, although cross-sectional MRI demonstrated a higher extent of "black holes" (BHs) in such patients. Here, we have studied the impact of the APOE genotype on both the longitudinal evolution of focal (BH ratio) and global (brain volume change [BVC]) brain tissue damage. Ninety-nine MS patients underwent ApoE genotyping, clinical examination, and magnetic resonance imaging at baseline and after 2.7 +/- 1.1 years to assess lesion load (LL) and BVC. In APOE-epsilon4 patients, the annual reduction in brain volume was fivefold higher (-0.65 +/- 0.61%) than in those without APOE-epsilon4 (-0.13 +/- 0.36%; p = 0.0001). At baseline, T(2) LL and T(1) LL were non-significantly higher in epsilon4 carriers, despite a shorter disease duration and absence of significant clinical differences. During follow-up, T(1) LL increased from 1.2 +/- 2.3 ccm to 1.7 +/- 2.7 ccm in the epsilon4 group, although T(2) LL did not change, leading to a significantly higher increase in the BH ratio [(T(1) LL/T(2) LL) x 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-epsilon4 patients (5.0 vs 5.7%). Accelerated brain tissue loss and a higher proportion of lesions evolving into BH therefore provide magnetic resonance imaging evidence for more pronounced tissue destruction in MS patients with APOE-epsilon4. | Accelerated evolution of brain atrophy and "black holes" in MS patients with /"APOE"/-epsilon 4. | /"Apolipoprotein E"/ (/"APOE"/)-epsilon4 has been associated with an unfavorable course of multiple sclerosis (MS). The mechanisms responsible for this are unclear, although cross-sectional MRI demonstrated a higher extent of "black holes" (BHs) in such patients. Here, we have studied the impact of the /"APOE"/ genotype on both the longitudinal evolution of focal (BH ratio) and global (brain volume change [BVC]) brain tissue damage. Ninety-nine MS patients underwent /"ApoE"/ genotyping, clinical examination, and magnetic resonance imaging at baseline and after 2.7 +/- 1.1 years to assess lesion load (LL) and BVC. In /"APOE"/-epsilon4 patients, the annual reduction in brain volume was fivefold higher (-0.65 +/- 0.61%) than in those without /"APOE"/-epsilon4 (-0.13 +/- 0.36%; p = 0.0001). At baseline, T(2) LL and T(1) LL were non-significantly higher in epsilon4 carriers, despite a /"shorter disease"/ duration and absence of significant clinical differences. During follow-up, T(1) LL increased from 1.2 +/- 2.3 ccm to 1.7 +/- 2.7 ccm in the epsilon4 group, although T(2) LL did not change, leading to a significantly higher increase in the BH ratio [(T(1) LL/T(2) LL) x 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-epsilon4 patients (5.0 vs 5.7%). Accelerated brain tissue loss and a higher proportion of lesions evolving into BH therefore provide magnetic resonance imaging evidence for more pronounced tissue destruction in MS patients with /"APOE"/-epsilon4. | [
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15057267 | Interleukin-10 polymorphisms in Spanish type 1 diabetes patients. | The MHC accounts for half of the genetic susceptibility to type 1 diabetes (T1D). Evidence suggests that an imbalance in Th1/Th2 responses may play a key role in the development of autoimmune diabetes. Since interleukin-10 (IL-10) modulates immune and inflammatory responses and has been implicated in many autoimmune diseases, it seemed interesting to examine whether IL-10 polymorphisms participate in diabetes predisposition. In fact, this is the first association study investigating the role of the IL- 10 polymorphisms in susceptibility to T1D in a Caucasian population. Three promoter polymorphisms (-1082G/A, -819C/T, -592C/A) and two CA-repeat microsatellites (IL-10R and IL-10G at -4 and -1.1 kb) were tested in a case-control study with 294 T1D patients and 574 healthy controls. Our results prove a minor role of IL-10 in the autoimmune diabetes risk, although we found the same association trend with IL-10G(*)12 allele as was previously observed for multiple sclerosis and rheumatoid arthritis. | /"Interleukin-10"/ polymorphisms in Spanish /"type 1 diabetes"/ patients. | The MHC accounts for half of the genetic susceptibility to /"type 1 diabetes"/ (/"T1D"/). Evidence suggests that an imbalance in Th1/Th2 responses may play a key role in the development of autoimmune diabetes. Since /"interleukin-10"/ (/"IL-10"/) modulates immune and inflammatory responses and has been implicated in many autoimmune diseases, it seemed interesting to examine whether /"IL-10"/ polymorphisms participate in diabetes predisposition. In fact, this is the first association study investigating the role of the /"IL- 10"/ polymorphisms in susceptibility to /"T1D"/ in a Caucasian population. Three promoter polymorphisms (-1082G/A, -819C/T, -592C/A) and two CA-repeat microsatellites (IL-10R and IL-10G at -4 and -1.1 kb) were tested in a case-control study with 294 /"T1D"/ patients and 574 healthy controls. Our results prove a minor role of /"IL-10"/ in the autoimmune diabetes risk, although we found the same association trend with IL-10G(*)12 allele as was previously observed for multiple sclerosis and rheumatoid arthritis. | [
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15057267 | Interleukin-10 polymorphisms in Spanish type 1 diabetes patients. | The MHC accounts for half of the genetic susceptibility to type 1 diabetes (T1D). Evidence suggests that an imbalance in Th1/Th2 responses may play a key role in the development of autoimmune diabetes. Since interleukin-10 (IL-10) modulates immune and inflammatory responses and has been implicated in many autoimmune diseases, it seemed interesting to examine whether IL-10 polymorphisms participate in diabetes predisposition. In fact, this is the first association study investigating the role of the IL- 10 polymorphisms in susceptibility to T1D in a Caucasian population. Three promoter polymorphisms (-1082G/A, -819C/T, -592C/A) and two CA-repeat microsatellites (IL-10R and IL-10G at -4 and -1.1 kb) were tested in a case-control study with 294 T1D patients and 574 healthy controls. Our results prove a minor role of IL-10 in the autoimmune diabetes risk, although we found the same association trend with IL-10G(*)12 allele as was previously observed for multiple sclerosis and rheumatoid arthritis. | /"Interleukin-10"/ polymorphisms in Spanish type 1 diabetes patients. | The MHC accounts for half of the genetic susceptibility to type 1 diabetes (T1D). Evidence suggests that an imbalance in Th1/Th2 responses may play a key role in the development of /"autoimmune diabetes"/. Since /"interleukin-10"/ (/"IL-10"/) modulates immune and inflammatory responses and has been implicated in many autoimmune diseases, it seemed interesting to examine whether /"IL-10"/ polymorphisms participate in diabetes predisposition. In fact, this is the first association study investigating the role of the /"IL- 10"/ polymorphisms in susceptibility to T1D in a Caucasian population. Three promoter polymorphisms (-1082G/A, -819C/T, -592C/A) and two CA-repeat microsatellites (IL-10R and IL-10G at -4 and -1.1 kb) were tested in a case-control study with 294 T1D patients and 574 healthy controls. Our results prove a minor role of /"IL-10"/ in the /"autoimmune diabetes"/ risk, although we found the same association trend with IL-10G(*)12 allele as was previously observed for multiple sclerosis and rheumatoid arthritis. | [
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15057872 | Alterations of the M6p/Igf2 receptor gene in hepatocellular carcinomas induced by N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet in rats. | To elucidate whether the M6p/Igf2 receptor (M6p/Igf2r) gene might be involved in exogenous and endogenous liver carcinogenesis, we investigated its alteration in hepatocellular carcinomas (HCCs) induced by N-nitrosodiethylamine (DEN) and by a choline-deficient L-amino acid-defined (CDAA) diet in rats. Male F344 rats, 6 wk old, received a single intraperitoneal (i.p.) injection of DEN at a dose of 10 mg/kg body weight, followed by combined treatment with partial hepatectomy and colchicine to induce cell cycle disturbance, and a selection procedure regimen, HCCs being obtained after 42 wk. With continuous CDAA diet feeding, tumors were sampled after 75 wk. Total RNA was extracted from individual HCCs for assessment of mutations within exons 27, 28, 31, 33, and 34, and aberrant transcript of the M6p/Igf2r gene by reverse transcription (RT)-polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and RT-PCR analyses, respectively. Mutations were detected in three of 15 HCCs (20%) induced by the CDAA diet, a TTT to TTG (Phe to Leu) transversion at codon 1516 and two AAG to AGG (Lys to Arg) transitions at codon 1620, but in none of those caused by DEN. Aberrant transcripts were found in seven of 15 HCCs after DEN treatment (46.7%) and in two of 15 HCCs induced by the CDAA diet (13.3%). These results suggest that alterations of the M6p/Igf2r gene may be involved in both exogenous and endogenous liver carcinogenesis with the different patterns and frequencies. | Alterations of the M6p/Igf2 receptor gene in /"hepatocellular carcinomas"/ induced by N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet in rats. | To elucidate whether the M6p/Igf2 receptor (M6p//"Igf2r"/) gene might be involved in exogenous and endogenous liver carcinogenesis, we investigated its alteration in /"hepatocellular carcinomas"/ (/"HCCs"/) induced by N-nitrosodiethylamine (DEN) and by a choline-deficient L-amino acid-defined (CDAA) diet in rats. Male F344 rats, 6 wk old, received a single intraperitoneal (i.p.) injection of DEN at a dose of 10 mg/kg body weight, followed by combined treatment with partial hepatectomy and colchicine to induce cell cycle disturbance, and a selection procedure regimen, /"HCCs"/ being obtained after 42 wk. With continuous CDAA diet feeding, tumors were sampled after 75 wk. Total RNA was extracted from individual /"HCCs"/ for assessment of mutations within exons 27, 28, 31, 33, and 34, and aberrant transcript of the M6p//"Igf2r"/ gene by reverse transcription (RT)-polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and RT-PCR analyses, respectively. Mutations were detected in three of 15 /"HCCs"/ (20%) induced by the CDAA diet, a TTT to TTG (Phe to Leu) transversion at codon 1516 and two AAG to AGG (Lys to Arg) transitions at codon 1620, but in none of those caused by DEN. Aberrant transcripts were found in seven of 15 /"HCCs"/ after DEN treatment (46.7%) and in two of 15 /"HCCs"/ induced by the CDAA diet (13.3%). These results suggest that alterations of the M6p//"Igf2r"/ gene may be involved in both exogenous and endogenous liver carcinogenesis with the different patterns and frequencies. | [
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} | Yes |
15057872 | Alterations of the M6p/Igf2 receptor gene in hepatocellular carcinomas induced by N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet in rats. | To elucidate whether the M6p/Igf2 receptor (M6p/Igf2r) gene might be involved in exogenous and endogenous liver carcinogenesis, we investigated its alteration in hepatocellular carcinomas (HCCs) induced by N-nitrosodiethylamine (DEN) and by a choline-deficient L-amino acid-defined (CDAA) diet in rats. Male F344 rats, 6 wk old, received a single intraperitoneal (i.p.) injection of DEN at a dose of 10 mg/kg body weight, followed by combined treatment with partial hepatectomy and colchicine to induce cell cycle disturbance, and a selection procedure regimen, HCCs being obtained after 42 wk. With continuous CDAA diet feeding, tumors were sampled after 75 wk. Total RNA was extracted from individual HCCs for assessment of mutations within exons 27, 28, 31, 33, and 34, and aberrant transcript of the M6p/Igf2r gene by reverse transcription (RT)-polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and RT-PCR analyses, respectively. Mutations were detected in three of 15 HCCs (20%) induced by the CDAA diet, a TTT to TTG (Phe to Leu) transversion at codon 1516 and two AAG to AGG (Lys to Arg) transitions at codon 1620, but in none of those caused by DEN. Aberrant transcripts were found in seven of 15 HCCs after DEN treatment (46.7%) and in two of 15 HCCs induced by the CDAA diet (13.3%). These results suggest that alterations of the M6p/Igf2r gene may be involved in both exogenous and endogenous liver carcinogenesis with the different patterns and frequencies. | Alterations of the M6p/Igf2 receptor gene in hepatocellular carcinomas induced by N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet in rats. | To elucidate whether the M6p/Igf2 receptor (M6p//"Igf2r"/) gene might be involved in exogenous and endogenous /"liver carcinogenesis"/, we investigated its alteration in hepatocellular carcinomas (HCCs) induced by N-nitrosodiethylamine (DEN) and by a choline-deficient L-amino acid-defined (CDAA) diet in rats. Male F344 rats, 6 wk old, received a single intraperitoneal (i.p.) injection of DEN at a dose of 10 mg/kg body weight, followed by combined treatment with partial hepatectomy and colchicine to induce cell cycle disturbance, and a selection procedure regimen, HCCs being obtained after 42 wk. With continuous CDAA diet feeding, tumors were sampled after 75 wk. Total RNA was extracted from individual HCCs for assessment of mutations within exons 27, 28, 31, 33, and 34, and aberrant transcript of the M6p//"Igf2r"/ gene by reverse transcription (RT)-polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and RT-PCR analyses, respectively. Mutations were detected in three of 15 HCCs (20%) induced by the CDAA diet, a TTT to TTG (Phe to Leu) transversion at codon 1516 and two AAG to AGG (Lys to Arg) transitions at codon 1620, but in none of those caused by DEN. Aberrant transcripts were found in seven of 15 HCCs after DEN treatment (46.7%) and in two of 15 HCCs induced by the CDAA diet (13.3%). These results suggest that alterations of the M6p//"Igf2r"/ gene may be involved in both exogenous and endogenous /"liver carcinogenesis"/ with the different patterns and frequencies. | [
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15059717 | Cholesterol and age-related macular degeneration: is there a link? | PURPOSE: To examine the relation among serum cholesterol, apolipoprotein E genotype (APOE), and the risk of early and late age-related macular degeneration (AMD). DESIGN: The Rotterdam Study, a population based prospective cohort study. METHODS: Serum levels of total and high-density lipoprotein (HDL) cholesterol as well as APOE genotype were determined at baseline. Of 3,944 subjects, 400 were diagnosed with incident early and late AMD after a mean follow-up of 5.2 years. RESULTS: Serum HDL, but not total, cholesterol was associated with an increased risk of AMD (odds ratio/SD, 1.20; 95% confidence interval; 1.06-1.35). The association remained unchanged after adjustment for APOE genotype. When stratifying for APOE genotype, the association was strongest in persons with the e 4 allele; an inverse association seemed to be present for e 2 carriers. CONCLUSION: Elevated HDL but not total cholesterol is associated with an increased risk of AMD. Apolipoprotein E genotype does not explain this association but may be an effect modifier. | Cholesterol and /"age-related macular degeneration"/: is there a link? | PURPOSE: To examine the relation among serum cholesterol, /"apolipoprotein E"/ genotype (/"APOE"/), and the risk of early and late /"age-related macular degeneration"/ (/"AMD"/). DESIGN: The Rotterdam Study, a population based prospective cohort study. METHODS: Serum levels of total and high-density lipoprotein (HDL) cholesterol as well as /"APOE"/ genotype were determined at baseline. Of 3,944 subjects, 400 were diagnosed with incident early and late /"AMD"/ after a mean follow-up of 5.2 years. RESULTS: Serum HDL, but not total, cholesterol was associated with an increased risk of /"AMD"/ (odds ratio/SD, 1.20; 95% confidence interval; 1.06-1.35). The association remained unchanged after adjustment for /"APOE"/ genotype. When stratifying for /"APOE"/ genotype, the association was strongest in persons with the e 4 allele; an inverse association seemed to be present for e 2 carriers. CONCLUSION: Elevated HDL but not total cholesterol is associated with an increased risk of /"AMD"/. /"Apolipoprotein E"/ genotype does not explain this association but may be an effect modifier. | [
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"entity_id": "D008268",
"entity_type": "Disease",
"text_name": "age-related macular degeneration"
} | Yes |
15060116 | Assessment of association between variants and haplotypes of the remaining TBX1 gene and manifestations of congenital heart defects in 22q11.2 deletion patients. | Assessment of association between variants and haplotypes of the remaining /"TBX1"/ gene and manifestations of /"congenital heart defects"/ in 22q11.2 deletion patients. | [
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"text_name": "congenital heart defects"
} | Yes |
||
15071492 | An analysis of tumor necrosis factor alpha gene polymorphisms and haplotypes with natural clearance of hepatitis C virus infection. | The cytokine tumor necrosis factor alpha (TNF-alpha) is important in generating an immune response against a hepatitis C virus (HCV) infection. The functions of TNF-alpha may be altered by single-nucleotide polymorphisms (SNPs) in its gene, TNF. We hypothesized that SNPs in TNF may be important in determining the outcome of an HCV infection. To test this hypothesis, we typed nine TNF SNPs in a cohort of individuals with well-defined HCV outcomes. Three of these SNPs were typed in a second cohort. Data were analyzed using logistic regression stratifying by ethnicity, since rates of HCV clearance differ in black subjects versus white subjects. The SNP -863A was associated with viral clearance in black subjects (odds ratios (OR) 0.52, 95% confidence interval (CI) 0.29-0.93). Furthermore, the common wild-type haplotype -863C/-308G was associated with viral persistence in black subjects (OR 1.91, 95% CI 1.24-2.95). These findings were independent of linkage with human leukocyte antigen (HLA) alleles. Further study of this polymorphism and haplotype is needed to understand these associations and the role of TNF-alpha in determining outcomes of HCV infection. | An analysis of tumor necrosis factor alpha gene polymorphisms and haplotypes with natural clearance of /"hepatitis C virus infection"/. | The cytokine tumor necrosis factor alpha (/"TNF-alpha"/) is important in generating an immune response against /"a hepatitis C virus (HCV) infection"/. The functions of /"TNF-alpha"/ may be altered by single-nucleotide polymorphisms (SNPs) in its gene, /"TNF"/. We hypothesized that SNPs in /"TNF"/ may be important in determining the outcome of an /"HCV infection"/. To test this hypothesis, we typed nine /"TNF"/ SNPs in a cohort of individuals with well-defined HCV outcomes. Three of these SNPs were typed in a second cohort. Data were analyzed using logistic regression stratifying by ethnicity, since rates of HCV clearance differ in black subjects versus white subjects. The SNP -863A was associated with viral clearance in black subjects (odds ratios (OR) 0.52, 95% confidence interval (CI) 0.29-0.93). Furthermore, the common wild-type haplotype -863C/-308G was associated with viral persistence in black subjects (OR 1.91, 95% CI 1.24-2.95). These findings were independent of linkage with human leukocyte antigen (HLA) alleles. Further study of this polymorphism and haplotype is needed to understand these associations and the role of /"TNF-alpha"/ in determining outcomes of /"HCV infection"/. | [
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"begin_idx": "239",
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"text_name": "a hepatitis C virus (HCV) infection"
} | Yes |
15071492 | An analysis of tumor necrosis factor alpha gene polymorphisms and haplotypes with natural clearance of hepatitis C virus infection. | The cytokine tumor necrosis factor alpha (TNF-alpha) is important in generating an immune response against a hepatitis C virus (HCV) infection. The functions of TNF-alpha may be altered by single-nucleotide polymorphisms (SNPs) in its gene, TNF. We hypothesized that SNPs in TNF may be important in determining the outcome of an HCV infection. To test this hypothesis, we typed nine TNF SNPs in a cohort of individuals with well-defined HCV outcomes. Three of these SNPs were typed in a second cohort. Data were analyzed using logistic regression stratifying by ethnicity, since rates of HCV clearance differ in black subjects versus white subjects. The SNP -863A was associated with viral clearance in black subjects (odds ratios (OR) 0.52, 95% confidence interval (CI) 0.29-0.93). Furthermore, the common wild-type haplotype -863C/-308G was associated with viral persistence in black subjects (OR 1.91, 95% CI 1.24-2.95). These findings were independent of linkage with human leukocyte antigen (HLA) alleles. Further study of this polymorphism and haplotype is needed to understand these associations and the role of TNF-alpha in determining outcomes of HCV infection. | An analysis of /"tumor"/ necrosis factor alpha gene polymorphisms and haplotypes with natural clearance of hepatitis C virus infection. | The cytokine /"tumor"/ necrosis factor alpha (/"TNF-alpha"/) is important in generating an immune response against a hepatitis C virus (HCV) infection. The functions of /"TNF-alpha"/ may be altered by single-nucleotide polymorphisms (SNPs) in its gene, /"TNF"/. We hypothesized that SNPs in /"TNF"/ may be important in determining the outcome of an HCV infection. To test this hypothesis, we typed nine /"TNF"/ SNPs in a cohort of individuals with well-defined HCV outcomes. Three of these SNPs were typed in a second cohort. Data were analyzed using logistic regression stratifying by ethnicity, since rates of HCV clearance differ in black subjects versus white subjects. The SNP -863A was associated with viral clearance in black subjects (odds ratios (OR) 0.52, 95% confidence interval (CI) 0.29-0.93). Furthermore, the common wild-type haplotype -863C/-308G was associated with viral persistence in black subjects (OR 1.91, 95% CI 1.24-2.95). These findings were independent of linkage with human leukocyte antigen (HLA) alleles. Further study of this polymorphism and haplotype is needed to understand these associations and the role of /"TNF-alpha"/ in determining outcomes of HCV infection. | [
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"text_name": "tumor"
} | No |
15075790 | Estimating the relative risk of developing melanoma in INK4A carriers. | Estimation of the relative risk of cancer due to rare germline mutations using population-based epidemiological techniques is challenging, since studies with very large numbers of subjects are required. In this pilot study using a novel study design, we evaluated the role of INK4A mutations in melanoma by comparing patients with multiple primary melanomas to those with single primaries. Patients were ascertained from the Surgery and Dermatology Clinics at Memorial Sloan-Kettering Cancer Center and at the Yale University Pigmented Lesion Clinic. Subjects completed a questionnaire covering risk factors for melanoma and were tested for INK4A mutations. Five (8%) of 65 patients with multiple primaries had a mutation, compared with none of 88 patients with single primaries (P=0.03). Examination of other factors, such as number of nevi on the arms of the patients, fair skin, hair and eye colour, and other phenotypic characteristics associated with the risk of melanoma, demonstrates that these factors exhibit higher prevalence in the multiple primary cases than in the single primaries. These results provide evidence of the utility of the new study design in evaluating the impact of rare but highly penetrant cancer risk factors. | Estimating the relative risk of developing /"melanoma"/ in /"INK4A"/ carriers. | Estimation of the relative risk of cancer due to rare germline mutations using population-based epidemiological techniques is challenging, since studies with very large numbers of subjects are required. In this pilot study using a novel study design, we evaluated the role of /"INK4A"/ mutations in /"melanoma"/ by comparing patients with multiple primary /"melanomas"/ to those with single primaries. Patients were ascertained from the Surgery and Dermatology Clinics at Memorial Sloan-Kettering Cancer Center and at the Yale University Pigmented Lesion Clinic. Subjects completed a questionnaire covering risk factors for /"melanoma"/ and were tested for /"INK4A"/ mutations. Five (8%) of 65 patients with multiple primaries had a mutation, compared with none of 88 patients with single primaries (P=0.03). Examination of other factors, such as number of nevi on the arms of the patients, fair skin, hair and eye colour, and other phenotypic characteristics associated with the risk of /"melanoma"/, demonstrates that these factors exhibit higher prevalence in the multiple primary cases than in the single primaries. These results provide evidence of the utility of the new study design in evaluating the impact of rare but highly penetrant cancer risk factors. | [
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} | Yes |
15075790 | Estimating the relative risk of developing melanoma in INK4A carriers. | Estimation of the relative risk of cancer due to rare germline mutations using population-based epidemiological techniques is challenging, since studies with very large numbers of subjects are required. In this pilot study using a novel study design, we evaluated the role of INK4A mutations in melanoma by comparing patients with multiple primary melanomas to those with single primaries. Patients were ascertained from the Surgery and Dermatology Clinics at Memorial Sloan-Kettering Cancer Center and at the Yale University Pigmented Lesion Clinic. Subjects completed a questionnaire covering risk factors for melanoma and were tested for INK4A mutations. Five (8%) of 65 patients with multiple primaries had a mutation, compared with none of 88 patients with single primaries (P=0.03). Examination of other factors, such as number of nevi on the arms of the patients, fair skin, hair and eye colour, and other phenotypic characteristics associated with the risk of melanoma, demonstrates that these factors exhibit higher prevalence in the multiple primary cases than in the single primaries. These results provide evidence of the utility of the new study design in evaluating the impact of rare but highly penetrant cancer risk factors. | Estimating the relative risk of developing melanoma in /"INK4A"/ carriers. | Estimation of the relative risk of /"cancer"/ due to rare germline mutations using population-based epidemiological techniques is challenging, since studies with very large numbers of subjects are required. In this pilot study using a novel study design, we evaluated the role of /"INK4A"/ mutations in melanoma by comparing patients with multiple primary melanomas to those with single primaries. Patients were ascertained from the Surgery and Dermatology Clinics at Memorial Sloan-Kettering Cancer Center and at the Yale University Pigmented Lesion Clinic. Subjects completed a questionnaire covering risk factors for melanoma and were tested for /"INK4A"/ mutations. Five (8%) of 65 patients with multiple primaries had a mutation, compared with none of 88 patients with single primaries (P=0.03). Examination of other factors, such as number of nevi on the arms of the patients, fair skin, hair and eye colour, and other phenotypic characteristics associated with the risk of melanoma, demonstrates that these factors exhibit higher prevalence in the multiple primary cases than in the single primaries. These results provide evidence of the utility of the new study design in evaluating the impact of rare but highly penetrant /"cancer"/ risk factors. | [
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"entity_id": "D009369",
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"text_name": "cancer"
} | No |
15081804 | alpha-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients. | alpha-L-Iduronidase is a glycosyl hydrolase involved in the sequential degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate. A deficiency in alpha-L-iduronidase results in the lysosomal accumulation and urinary secretion of partially degraded glycosaminoglycans and is the cause of the lysosomal storage disorder mucopolysaccharidosis type I (MPS I; Hurler and Scheie syndromes; McKusick 25280). The premature stop codons Q70X and W402X are two of the most common alpha-l-iduronidase gene (IDUA) mutations accounting for up to 70% of MPS I disease alleles in some populations. Here, we have reported a new mutation, making a total of 15 different mutations that can cause premature IDUA stop codons and have investigated the biochemistry of these mutations. Natural stop codon read-through was dependent on the fidelity of the codon when evaluated at Q70X and W402X in CHO-K1 cells, but the three possible stop codons TAA, TAG and TGA, had different effects on mRNA stability and this effect was context dependent. In CHO-K1 cells expressing the Q70X and W402X mutations, the level of gentamicin-enhanced stop codon read-through was slightly less than the increment in activity caused by a lower fidelity stop codon. In this system, gentamicin had more effect on read-through for the TAA and TGA stop codons when compared to the TAG stop codon. In an MPS I patient study, premature TGA stop codons were associated with a slightly attenuated clinical phenotype, when compared to classical Hurler syndrome (e.g. W402X/W402X and Q70X/Q70X genotypes with TAG stop codons). Natural read-through of premature stop codons is a potential explanation for variable clinical phenotype in MPS I patients. Enhanced stop codon read-through is a potential treatment strategy for a large sub-group of MPS I patients. | alpha-L-iduronidase premature stop codons and potential read-through in /"mucopolysaccharidosis type I"/ patients. | alpha-L-Iduronidase is a glycosyl hydrolase involved in the sequential degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate. A deficiency in alpha-L-iduronidase results in the lysosomal accumulation and urinary secretion of partially degraded glycosaminoglycans and is the cause of the lysosomal storage disorder /"mucopolysaccharidosis type I"/ (/"MPS I"/; /"Hurler and Scheie syndromes"/; McKusick 25280). The premature stop codons Q70X and W402X are two of the most common alpha-l-iduronidase gene (/"IDUA"/) mutations accounting for up to 70% of /"MPS I disease"/ alleles in some populations. Here, we have reported a new mutation, making a total of 15 different mutations that can cause premature /"IDUA"/ stop codons and have investigated the biochemistry of these mutations. Natural stop codon read-through was dependent on the fidelity of the codon when evaluated at Q70X and W402X in CHO-K1 cells, but the three possible stop codons TAA, TAG and TGA, had different effects on mRNA stability and this effect was context dependent. In CHO-K1 cells expressing the Q70X and W402X mutations, the level of gentamicin-enhanced stop codon read-through was slightly less than the increment in activity caused by a lower fidelity stop codon. In this system, gentamicin had more effect on read-through for the TAA and TGA stop codons when compared to the TAG stop codon. In an /"MPS I"/ patient study, premature TGA stop codons were associated with a slightly attenuated clinical phenotype, when compared to classical /"Hurler syndrome"/ (e.g. W402X/W402X and Q70X/Q70X genotypes with TAG stop codons). Natural read-through of premature stop codons is a potential explanation for variable clinical phenotype in /"MPS I"/ patients. Enhanced stop codon read-through is a potential treatment strategy for a large sub-group of /"MPS I"/ patients. | [
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},
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] | {
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} | Yes |
15081804 | alpha-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients. | alpha-L-Iduronidase is a glycosyl hydrolase involved in the sequential degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate. A deficiency in alpha-L-iduronidase results in the lysosomal accumulation and urinary secretion of partially degraded glycosaminoglycans and is the cause of the lysosomal storage disorder mucopolysaccharidosis type I (MPS I; Hurler and Scheie syndromes; McKusick 25280). The premature stop codons Q70X and W402X are two of the most common alpha-l-iduronidase gene (IDUA) mutations accounting for up to 70% of MPS I disease alleles in some populations. Here, we have reported a new mutation, making a total of 15 different mutations that can cause premature IDUA stop codons and have investigated the biochemistry of these mutations. Natural stop codon read-through was dependent on the fidelity of the codon when evaluated at Q70X and W402X in CHO-K1 cells, but the three possible stop codons TAA, TAG and TGA, had different effects on mRNA stability and this effect was context dependent. In CHO-K1 cells expressing the Q70X and W402X mutations, the level of gentamicin-enhanced stop codon read-through was slightly less than the increment in activity caused by a lower fidelity stop codon. In this system, gentamicin had more effect on read-through for the TAA and TGA stop codons when compared to the TAG stop codon. In an MPS I patient study, premature TGA stop codons were associated with a slightly attenuated clinical phenotype, when compared to classical Hurler syndrome (e.g. W402X/W402X and Q70X/Q70X genotypes with TAG stop codons). Natural read-through of premature stop codons is a potential explanation for variable clinical phenotype in MPS I patients. Enhanced stop codon read-through is a potential treatment strategy for a large sub-group of MPS I patients. | alpha-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients. | alpha-L-Iduronidase is a glycosyl hydrolase involved in the sequential degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate. A deficiency in alpha-L-iduronidase results in the lysosomal accumulation and urinary secretion of partially degraded glycosaminoglycans and is the cause of the /"lysosomal storage disorder"/ mucopolysaccharidosis type I (MPS I; Hurler and Scheie syndromes; McKusick 25280). The premature stop codons Q70X and W402X are two of the most common alpha-l-iduronidase gene (/"IDUA"/) mutations accounting for up to 70% of MPS I disease alleles in some populations. Here, we have reported a new mutation, making a total of 15 different mutations that can cause premature /"IDUA"/ stop codons and have investigated the biochemistry of these mutations. Natural stop codon read-through was dependent on the fidelity of the codon when evaluated at Q70X and W402X in CHO-K1 cells, but the three possible stop codons TAA, TAG and TGA, had different effects on mRNA stability and this effect was context dependent. In CHO-K1 cells expressing the Q70X and W402X mutations, the level of gentamicin-enhanced stop codon read-through was slightly less than the increment in activity caused by a lower fidelity stop codon. In this system, gentamicin had more effect on read-through for the TAA and TGA stop codons when compared to the TAG stop codon. In an MPS I patient study, premature TGA stop codons were associated with a slightly attenuated clinical phenotype, when compared to classical Hurler syndrome (e.g. W402X/W402X and Q70X/Q70X genotypes with TAG stop codons). Natural read-through of premature stop codons is a potential explanation for variable clinical phenotype in MPS I patients. Enhanced stop codon read-through is a potential treatment strategy for a large sub-group of MPS I patients. | [
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"text_name": "lysosomal storage disorder"
} | No |
15082902 | Prevalence of BRCA1 and BRCA2 mutations in Korean breast cancer patients. | The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female cancer. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ cancer including breast (13%) and younger breast cancer patients (aged<35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two high risk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer. | Prevalence of /"BRCA1"/ and BRCA2 mutations in /"Korean breast cancer"/ patients. | The incidence of /"breast cancer"/ in Korea has been increasing in recent years, such that it is now the most common female cancer. /"Breast cancer"/ in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the /"BRCA"/ genes to evaluate their genetic pathology in /"Korean breast cancer"/ patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the /"BRCA1"/ and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. /"BRCA"/ mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), /"bilateral breast cancer"/ (20%), multiple organ cancer including breast (13%) and younger /"breast cancer"/ patients (aged<35 yr) (8.1%). Moreover, /"BRCA"/ mutations were detected in 34.8% of patients having two high risk factors. These findings suggest that /"BRCA"/ gene mutation analysis should be performed on Korean patients with high-risk factors for /"breast cancer"/. | [
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},
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15082902 | Prevalence of BRCA1 and BRCA2 mutations in Korean breast cancer patients. | The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female cancer. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ cancer including breast (13%) and younger breast cancer patients (aged<35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two high risk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer. | Prevalence of BRCA1 and /"BRCA2"/ mutations in /"Korean breast cancer"/ patients. | The incidence of /"breast cancer"/ in Korea has been increasing in recent years, such that it is now the most common female cancer. /"Breast cancer"/ in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in /"Korean breast cancer"/ patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and /"BRCA2"/ genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), /"bilateral breast cancer"/ (20%), multiple organ cancer including breast (13%) and younger /"breast cancer"/ patients (aged<35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two high risk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for /"breast cancer"/. | [
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15082902 | Prevalence of BRCA1 and BRCA2 mutations in Korean breast cancer patients. | The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female cancer. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ cancer including breast (13%) and younger breast cancer patients (aged<35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two high risk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer. | Prevalence of BRCA1 and /"BRCA2"/ mutations in Korean breast cancer patients. | The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female /"cancer"/. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and /"BRCA2"/ genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ /"cancer"/ including breast (13%) and younger breast cancer patients (aged<35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two high risk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer. | [
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15082902 | Prevalence of BRCA1 and BRCA2 mutations in Korean breast cancer patients. | The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female cancer. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ cancer including breast (13%) and younger breast cancer patients (aged<35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two high risk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer. | Prevalence of /"BRCA1"/ and BRCA2 mutations in Korean breast cancer patients. | The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female /"cancer"/. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the /"BRCA"/ genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the /"BRCA1"/ and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. /"BRCA"/ mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ /"cancer"/ including breast (13%) and younger breast cancer patients (aged<35 yr) (8.1%). Moreover, /"BRCA"/ mutations were detected in 34.8% of patients having two high risk factors. These findings suggest that /"BRCA"/ gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer. | [
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} | No |
15091236 | Nonsyndromic 35 delG mutation of the connexin 26 gene associated with deafness in syndromic children: two case reports. | OBJECTIVES/HYPOTHESIS: Several genetic diseases, such as velocardiofacial syndrome Del(22q11) and Down syndrome, are associated with hearing impairment. STUDY DESIGN: Case reports. METHODS: The authors reported two cases of hearing-impaired children, one with Del (22q11) and one with Down syndrome, both with bilateral nonevolutive profound sensorineural deafness. Because of unusual features of their deafness and familial history, genetic evaluation was proposed. A homozygous 35delG mutation on the Connexin 26 gene was found in both children (DFNB1 phenotype). RESULTS: A review of the reported otological features of Del (22q11) and Down syndrome showed that sensorineural deafness is rare and seldom profound. The authors found no evidence for a genetic link between Del(22q11) or Down syndrome and 35delG mutation on the Connexin 26 gene. CONCLUSION: The case reports reveal a coincidental association between DFNB1 and a multiple congenital anomaly syndrome. The clinician must be aware of this type of association to manage genetic counseling, appropriate otological care, and suitable treatment. | Nonsyndromic 35 delG mutation of the /"connexin 26"/ gene associated with deafness in syndromic children: two case reports. | OBJECTIVES/HYPOTHESIS: Several genetic diseases, such as velocardiofacial syndrome Del(22q11) and Down syndrome, are associated with hearing impairment. STUDY DESIGN: Case reports. METHODS: The authors reported two cases of hearing-impaired children, one with Del (22q11) and one with Down syndrome, both with bilateral nonevolutive profound /"sensorineural deafness"/. Because of unusual features of their deafness and familial history, genetic evaluation was proposed. A homozygous 35delG mutation on the /"Connexin 26"/ gene was found in both children (/"DFNB1"/ phenotype). RESULTS: A review of the reported otological features of Del (22q11) and Down syndrome showed that /"sensorineural deafness"/ is rare and seldom profound. The authors found no evidence for a genetic link between Del(22q11) or Down syndrome and 35delG mutation on the /"Connexin 26"/ gene. CONCLUSION: The case reports reveal a coincidental association between /"DFNB1"/ and a multiple congenital anomaly syndrome. The clinician must be aware of this type of association to manage genetic counseling, appropriate otological care, and suitable treatment. | [
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15091236 | Nonsyndromic 35 delG mutation of the connexin 26 gene associated with deafness in syndromic children: two case reports. | OBJECTIVES/HYPOTHESIS: Several genetic diseases, such as velocardiofacial syndrome Del(22q11) and Down syndrome, are associated with hearing impairment. STUDY DESIGN: Case reports. METHODS: The authors reported two cases of hearing-impaired children, one with Del (22q11) and one with Down syndrome, both with bilateral nonevolutive profound sensorineural deafness. Because of unusual features of their deafness and familial history, genetic evaluation was proposed. A homozygous 35delG mutation on the Connexin 26 gene was found in both children (DFNB1 phenotype). RESULTS: A review of the reported otological features of Del (22q11) and Down syndrome showed that sensorineural deafness is rare and seldom profound. The authors found no evidence for a genetic link between Del(22q11) or Down syndrome and 35delG mutation on the Connexin 26 gene. CONCLUSION: The case reports reveal a coincidental association between DFNB1 and a multiple congenital anomaly syndrome. The clinician must be aware of this type of association to manage genetic counseling, appropriate otological care, and suitable treatment. | Nonsyndromic 35 delG mutation of the /"connexin 26"/ gene associated with /"deafness"/ in syndromic children: two case reports. | OBJECTIVES/HYPOTHESIS: Several genetic diseases, such as velocardiofacial syndrome Del(22q11) and Down syndrome, are associated with hearing impairment. STUDY DESIGN: Case reports. METHODS: The authors reported two cases of hearing-impaired children, one with Del (22q11) and one with Down syndrome, both with bilateral nonevolutive profound sensorineural deafness. Because of unusual features of their /"deafness"/ and familial history, genetic evaluation was proposed. A homozygous 35delG mutation on the /"Connexin 26"/ gene was found in both children (/"DFNB1"/ phenotype). RESULTS: A review of the reported otological features of Del (22q11) and Down syndrome showed that sensorineural deafness is rare and seldom profound. The authors found no evidence for a genetic link between Del(22q11) or Down syndrome and 35delG mutation on the /"Connexin 26"/ gene. CONCLUSION: The case reports reveal a coincidental association between /"DFNB1"/ and a multiple congenital anomaly syndrome. The clinician must be aware of this type of association to manage genetic counseling, appropriate otological care, and suitable treatment. | [
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15110323 | Novel mutations in CPT 1A define molecular heterogeneity of hepatic carnitine palmitoyltransferase I deficiency. | Liver carnitine palmitoyltransferase I (CPT I) deficiency is a rare disorder of hepatic mitochondrial long-chain fatty acid oxidation. It characteristically presents with symptoms associated with failure of ketogenesis (hypoketotic hypoglycemia). The disorder is due to mutations in the CPT 1A gene for which few patients have been characterized. We present here four novel mutations in five patients from four families with severe enzyme deficiency. Three of these are missense mutations (G465W, R316G, and F343V) and the fourth a nonsense mutation (R160X). Other than small Inuit and Hutterite populations in Canada and the Northern plains, there is complete heterogeneity of disease-causing mutations within CPT I deficient families with each demonstrating unique mutations. Because there are no easily recognizable disease-specific metabolite markers, diagnostic confirmation of this disorder requires a combination of enzymatic analysis and whole gene sequencing. | Novel mutations in /"CPT 1A"/ define molecular heterogeneity of hepatic /"carnitine palmitoyltransferase I deficiency"/. | /"Liver carnitine palmitoyltransferase I (CPT I) deficiency"/ency is a rare disorder of hepatic mitochondrial long-chain fatty acid oxidation. It characteristically presents with symptoms associated with failure of ketogenesis (hypoketotic hypoglycemia). The disorder is due to mutations in the /"CPT 1A"/ gene for which few patients have been characterized. We present here four novel mutations in five patients from four families with severe enzyme deficiency. Three of these are missense mutations (G465W, R316G, and F343V) and the fourth a nonsense mutation (R160X). Other than small Inuit and Hutterite populations in Canada and the Northern plains, there is complete heterogeneity of disease-causing mutations within /"CPT I deficient"/ families with each demonstrating unique mutations. Because there are no easily recognizable disease-specific metabolite markers, diagnostic confirmation of this disorder requires a combination of enzymatic analysis and whole gene sequencing. | [
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"text_name": "Liver carnitine palmitoyltransferase I (CPT I) deficiency"
} | Yes |
15110323 | Novel mutations in CPT 1A define molecular heterogeneity of hepatic carnitine palmitoyltransferase I deficiency. | Liver carnitine palmitoyltransferase I (CPT I) deficiency is a rare disorder of hepatic mitochondrial long-chain fatty acid oxidation. It characteristically presents with symptoms associated with failure of ketogenesis (hypoketotic hypoglycemia). The disorder is due to mutations in the CPT 1A gene for which few patients have been characterized. We present here four novel mutations in five patients from four families with severe enzyme deficiency. Three of these are missense mutations (G465W, R316G, and F343V) and the fourth a nonsense mutation (R160X). Other than small Inuit and Hutterite populations in Canada and the Northern plains, there is complete heterogeneity of disease-causing mutations within CPT I deficient families with each demonstrating unique mutations. Because there are no easily recognizable disease-specific metabolite markers, diagnostic confirmation of this disorder requires a combination of enzymatic analysis and whole gene sequencing. | Novel mutations in /"CPT 1A"/ define molecular heterogeneity of hepatic carnitine palmitoyltransferase I deficiency. | Liver carnitine palmitoyltransferase I (/"CPT I"/) deficiency is a rare disorder of hepatic mitochondrial long-chain fatty acid oxidation. It characteristically presents with symptoms associated with failure of ketogenesis (/"hypoketotic hypoglycemia"/). The disorder is due to mutations in the /"CPT 1A"/ gene for which few patients have been characterized. We present here four novel mutations in five patients from four families with severe enzyme deficiency. Three of these are missense mutations (G465W, R316G, and F343V) and the fourth a nonsense mutation (R160X). Other than small Inuit and Hutterite populations in Canada and the Northern plains, there is complete heterogeneity of disease-causing mutations within CPT I deficient families with each demonstrating unique mutations. Because there are no easily recognizable disease-specific metabolite markers, diagnostic confirmation of this disorder requires a combination of enzymatic analysis and whole gene sequencing. | [
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"text_name": "carnitine palmitoyltransferase I deficiency"
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15111581 | Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. | PURPOSE: To examine the effect of apolipoprotein E (APOE) alleles on age-related macular degeneration (AMD) risk and on age at diagnosis of AMD in a large patient cohort recruited from a single center. METHODS: The frequency of APOE alleles was analyzed in 632 unrelated AMD patients and 206 unrelated controls, all of whom were of white ancestry. The presence or absence of disease symptoms in all patients and controls was based on clinical examination and/or ophthalmic records. The association with APOE was explored in the context of AMD subtypes, family history status, possible interaction with smoking, and distribution of age at diagnosis of AMD. RESULTS: The frequency of the epsilon4 allele was significantly reduced in patients compared with controls (0.10 vs. 0.14, P < or = 0.02). Gender- and age-adjusted odds ratios indicated that epsilon4-carriers have significantly lower risk of developing AMD compared to epsilon3epsilon3 subjects (OR = 0.55, 95% CI: 0.37-0.82, P = 0.004). In the cohort, AMD patients with a positive family history exhibited a significant 3.5 years earlier age at diagnosis (P = 0.001); however, APOE alleles did not appear to modulate the age at diagnosis of AMD. CONCLUSIONS: The association between the APOE-epsilon4 allele and a reduced risk of AMD was established in a large cohort with sufficient statistical power. How distinct APOE alleles affect AMD susceptibility warrants further investigation. | Association of /"apolipoprotein E"/ alleles with susceptibility to /"age-related macular degeneration"/ in a large cohort from a single center. | PURPOSE: To examine the effect of /"apolipoprotein E"/ (/"APOE"/) alleles on /"age-related macular degeneration"/ (/"AMD"/) risk and on age at diagnosis of /"AMD"/ in a large patient cohort recruited from a single center. METHODS: The frequency of /"APOE"/ alleles was analyzed in 632 unrelated /"AMD"/ patients and 206 unrelated controls, all of whom were of white ancestry. The presence or absence of disease symptoms in all patients and controls was based on clinical examination and/or ophthalmic records. The association with /"APOE"/ was explored in the context of /"AMD"/ subtypes, family history status, possible interaction with smoking, and distribution of age at diagnosis of /"AMD"/. RESULTS: The frequency of the epsilon4 allele was significantly reduced in patients compared with controls (0.10 vs. 0.14, P < or = 0.02). Gender- and age-adjusted odds ratios indicated that epsilon4-carriers have significantly lower risk of developing /"AMD"/ compared to epsilon3epsilon3 subjects (OR = 0.55, 95% CI: 0.37-0.82, P = 0.004). In the cohort, /"AMD"/ patients with a positive family history exhibited a significant 3.5 years earlier age at diagnosis (P = 0.001); however, /"APOE"/ alleles did not appear to modulate the age at diagnosis of /"AMD"/. CONCLUSIONS: The association between the /"APOE"/-epsilon4 allele and a reduced risk of /"AMD"/ was established in a large cohort with sufficient statistical power. How distinct /"APOE"/ alleles affect /"AMD"/ susceptibility warrants further investigation. | [
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} | Yes |
15123604 | A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. | Three SUMO (small ubiquitin-related modifier) genes have been identified in humans, which tag proteins to modulate subcellular localization and/or enhance protein stability and activity. We report the identification of a novel intronless SUMO gene, SUMO-4, that encodes a 95-amino acid protein having an 86% amino acid homology with SUMO-2. In contrast to SUMO-2, which is highly expressed in all of the tissues examined, SUMO-4 mRNA was detected mainly in the kidney. A single nucleotide polymorphism was detected in SUMO-4, substituting a highly conserved methionine with a valine residue (M55V). In HepG2 (liver carcinoma) cells transiently transfected with SUMO-4 expression vectors, Met-55 was associated with the elevated levels of activated heat shock factor transcription factors as compared with Val-55, whereas the levels of NF-kappaB were suppressed to an identical degree. The SUMO-4M (Met) variant is associated with type I diabetes mellitus susceptibility in families (p = 4.0 x 10(-4)), suggesting that it may be involved in the pathogenesis of type I diabetes. | A M55V polymorphism in a novel SUMO gene (/"SUMO-4"/) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. | Three SUMO (small ubiquitin-related modifier) genes have been identified in humans, which tag proteins to modulate subcellular localization and/or enhance protein stability and activity. We report the identification of a novel intronless SUMO gene, /"SUMO-4"/, that encodes a 95-amino acid protein having an 86% amino acid homology with SUMO-2. In contrast to SUMO-2, which is highly expressed in all of the tissues examined, /"SUMO-4"/ mRNA was detected mainly in the kidney. A single nucleotide polymorphism was detected in /"SUMO-4"/, substituting a highly conserved methionine with a valine residue (M55V). In HepG2 (liver carcinoma) cells transiently transfected with /"SUMO-4"/ expression vectors, Met-55 was associated with the elevated levels of activated heat shock factor transcription factors as compared with Val-55, whereas the levels of NF-kappaB were suppressed to an identical degree. The SUMO-4M (Met) variant is associated with type I diabetes mellitus susceptibility in families (p = 4.0 x 10(-4)), suggesting that it may be involved in the pathogenesis of /"type I diabetes"/. | [
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} | Yes |
15123604 | A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. | Three SUMO (small ubiquitin-related modifier) genes have been identified in humans, which tag proteins to modulate subcellular localization and/or enhance protein stability and activity. We report the identification of a novel intronless SUMO gene, SUMO-4, that encodes a 95-amino acid protein having an 86% amino acid homology with SUMO-2. In contrast to SUMO-2, which is highly expressed in all of the tissues examined, SUMO-4 mRNA was detected mainly in the kidney. A single nucleotide polymorphism was detected in SUMO-4, substituting a highly conserved methionine with a valine residue (M55V). In HepG2 (liver carcinoma) cells transiently transfected with SUMO-4 expression vectors, Met-55 was associated with the elevated levels of activated heat shock factor transcription factors as compared with Val-55, whereas the levels of NF-kappaB were suppressed to an identical degree. The SUMO-4M (Met) variant is associated with type I diabetes mellitus susceptibility in families (p = 4.0 x 10(-4)), suggesting that it may be involved in the pathogenesis of type I diabetes. | A M55V polymorphism in a novel SUMO gene (/"SUMO-4"/) differentially activates heat shock transcription factors and is associated with susceptibility to /"type I diabetes mellitus"/. | Three SUMO (small ubiquitin-related modifier) genes have been identified in humans, which tag proteins to modulate subcellular localization and/or enhance protein stability and activity. We report the identification of a novel intronless SUMO gene, /"SUMO-4"/, that encodes a 95-amino acid protein having an 86% amino acid homology with SUMO-2. In contrast to SUMO-2, which is highly expressed in all of the tissues examined, /"SUMO-4"/ mRNA was detected mainly in the kidney. A single nucleotide polymorphism was detected in /"SUMO-4"/, substituting a highly conserved methionine with a valine residue (M55V). In HepG2 (liver carcinoma) cells transiently transfected with /"SUMO-4"/ expression vectors, Met-55 was associated with the elevated levels of activated heat shock factor transcription factors as compared with Val-55, whereas the levels of NF-kappaB were suppressed to an identical degree. The SUMO-4M (Met) variant is associated with /"type I diabetes mellitus"/ susceptibility in families (p = 4.0 x 10(-4)), suggesting that it may be involved in the pathogenesis of type I diabetes. | [
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15124102 | Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. | Craniofrontonasal syndrome (CFNS) is an X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations, whereas the genetic defect causes no or only mild abnormalities in male carriers. Recently, we have mapped a gene for CFNS in the pericentromeric region of the X chromosome that contains the EFNB1 gene, which encodes the ephrin-B1 ligand for Eph receptors. Since Efnb1 mutant mice display a spectrum of malformations and an unusual inheritance reminiscent of CFNS, we analyzed the EFNB1 gene in three families with CFNS. In one family, a deletion of exons 2-5 was identified in an obligate carrier male, his mildly affected brother, and in the affected females. In the two other families, missense mutations in EFNB1 were detected that lead to amino acid exchanges P54L and T111I. Both mutations are located in multimerization and receptor-interaction motifs found within the ephrin-B1 extracellular domain. In all cases, mutations were found consistently in obligate male carriers, clinically affected males, and affected heterozygous females. We conclude that mutations in EFNB1 cause CFNS. | Mutations of the /"ephrin-B1"/ gene cause craniofrontonasal syndrome. | /"Craniofrontonasal syndrome"/ (/"CFNS"/) is an X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations, whereas the genetic defect causes no or only mild abnormalities in male carriers. Recently, we have mapped a gene for /"CFNS"/ in the pericentromeric region of the X chromosome that contains the /"EFNB1"/ gene, which encodes the /"ephrin-B1"/ ligand for Eph receptors. Since /"Efnb1"/ mutant mice display a spectrum of malformations and an unusual inheritance reminiscent of /"CFNS"/, we analyzed the /"EFNB1"/ gene in three families with /"CFNS"/. In one family, a deletion of exons 2-5 was identified in an obligate carrier male, his mildly affected brother, and in the affected females. In the two other families, missense mutations in /"EFNB1"/ were detected that lead to amino acid exchanges P54L and T111I. Both mutations are located in multimerization and receptor-interaction motifs found within the /"ephrin-B1"/ extracellular domain. In all cases, mutations were found consistently in obligate male carriers, clinically affected males, and affected heterozygous females. We conclude that mutations in /"EFNB1"/ cause /"CFNS"/. | [
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15124102 | Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. | Craniofrontonasal syndrome (CFNS) is an X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations, whereas the genetic defect causes no or only mild abnormalities in male carriers. Recently, we have mapped a gene for CFNS in the pericentromeric region of the X chromosome that contains the EFNB1 gene, which encodes the ephrin-B1 ligand for Eph receptors. Since Efnb1 mutant mice display a spectrum of malformations and an unusual inheritance reminiscent of CFNS, we analyzed the EFNB1 gene in three families with CFNS. In one family, a deletion of exons 2-5 was identified in an obligate carrier male, his mildly affected brother, and in the affected females. In the two other families, missense mutations in EFNB1 were detected that lead to amino acid exchanges P54L and T111I. Both mutations are located in multimerization and receptor-interaction motifs found within the ephrin-B1 extracellular domain. In all cases, mutations were found consistently in obligate male carriers, clinically affected males, and affected heterozygous females. We conclude that mutations in EFNB1 cause CFNS. | Mutations of the /"ephrin-B1"/ gene cause craniofrontonasal syndrome. | Craniofrontonasal syndrome (CFNS) is an X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations, whereas the /"genetic defect"/ causes no or only mild abnormalities in male carriers. Recently, we have mapped a gene for CFNS in the pericentromeric region of the X chromosome that contains the /"EFNB1"/ gene, which encodes the /"ephrin-B1"/ ligand for Eph receptors. Since /"Efnb1"/ mutant mice display a spectrum of malformations and an unusual inheritance reminiscent of CFNS, we analyzed the /"EFNB1"/ gene in three families with CFNS. In one family, a deletion of exons 2-5 was identified in an obligate carrier male, his mildly affected brother, and in the affected females. In the two other families, missense mutations in /"EFNB1"/ were detected that lead to amino acid exchanges P54L and T111I. Both mutations are located in multimerization and receptor-interaction motifs found within the /"ephrin-B1"/ extracellular domain. In all cases, mutations were found consistently in obligate male carriers, clinically affected males, and affected heterozygous females. We conclude that mutations in /"EFNB1"/ cause CFNS. | [
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15126571 | Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. | CYP11A, the gene encoding p450scc, a key enzyme in steroid biosynthesis, is a strong biological candidate for polycystic ovary syndrome (PCOS) susceptibility. Four of the five published studies that have examined CYP11A for evidence of linkage and/or association have reported significant relationships with polycystic ovary (PCO) status and/or serum testosterone levels. However, study sizes have been modest, and the current study aimed to reevaluate these findings using significantly larger clinical resources. A pair of CYP11A promoter microsatellites, including the pentanucleotide (D15S520) previously implicated in trait susceptibility, were genotyped in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1589 women from a population-based birth cohort from Finland characterized for PCO symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study (for example, an excess of the pentanucleotide four-repeat allele in cases, P = 0.005), these findings were not substantiated in the other analyses, and no discernable relationship was seen between variation at these loci and serum testosterone levels. These studies indicate that the strength of, and indeed the existence of, associations between CYP11A promoter variation and androgen-related phenotypes has been substantially overestimated in previous studies. | Large-scale analysis of the relationship between /"CYP11A"/ promoter variation, /"polycystic ovarian syndrome"/, and serum testosterone. | /"CYP11A"/, the gene encoding /"p450scc"/, a key enzyme in steroid biosynthesis, is a strong biological candidate for /"polycystic ovary syndrome"/ (/"PCOS"/) susceptibility. Four of the five published studies that have examined /"CYP11A"/ for evidence of linkage and/or association have reported significant relationships with polycystic ovary (PCO) status and/or serum testosterone levels. However, study sizes have been modest, and the current study aimed to reevaluate these findings using significantly larger clinical resources. A pair of /"CYP11A"/ promoter microsatellites, including the pentanucleotide (D15S520) previously implicated in trait susceptibility, were genotyped in 371 /"PCOS"/ patients of United Kingdom origin, using both case-control and family-based association methods, and in 1589 women from a population-based birth cohort from Finland characterized for PCO symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study (for example, an excess of the pentanucleotide four-repeat allele in cases, P = 0.005), these findings were not substantiated in the other analyses, and no discernable relationship was seen between variation at these loci and serum testosterone levels. These studies indicate that the strength of, and indeed the existence of, associations between /"CYP11A"/ promoter variation and androgen-related phenotypes has been substantially overestimated in previous studies. | [
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15126571 | Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. | CYP11A, the gene encoding p450scc, a key enzyme in steroid biosynthesis, is a strong biological candidate for polycystic ovary syndrome (PCOS) susceptibility. Four of the five published studies that have examined CYP11A for evidence of linkage and/or association have reported significant relationships with polycystic ovary (PCO) status and/or serum testosterone levels. However, study sizes have been modest, and the current study aimed to reevaluate these findings using significantly larger clinical resources. A pair of CYP11A promoter microsatellites, including the pentanucleotide (D15S520) previously implicated in trait susceptibility, were genotyped in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1589 women from a population-based birth cohort from Finland characterized for PCO symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study (for example, an excess of the pentanucleotide four-repeat allele in cases, P = 0.005), these findings were not substantiated in the other analyses, and no discernable relationship was seen between variation at these loci and serum testosterone levels. These studies indicate that the strength of, and indeed the existence of, associations between CYP11A promoter variation and androgen-related phenotypes has been substantially overestimated in previous studies. | Large-scale analysis of the relationship between /"CYP11A"/ promoter variation, polycystic ovarian syndrome, and serum testosterone. | /"CYP11A"/, the gene encoding /"p450scc"/, a key enzyme in steroid biosynthesis, is a strong biological candidate for polycystic ovary syndrome (PCOS) susceptibility. Four of the five published studies that have examined /"CYP11A"/ for evidence of linkage and/or association have reported significant relationships with /"polycystic"/ ovary (PCO) status and/or serum testosterone levels. However, study sizes have been modest, and the current study aimed to reevaluate these findings using significantly larger clinical resources. A pair of /"CYP11A"/ promoter microsatellites, including the pentanucleotide (D15S520) previously implicated in trait susceptibility, were genotyped in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1589 women from a population-based birth cohort from Finland characterized for PCO symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study (for example, an excess of the pentanucleotide four-repeat allele in cases, P = 0.005), these findings were not substantiated in the other analyses, and no discernable relationship was seen between variation at these loci and serum testosterone levels. These studies indicate that the strength of, and indeed the existence of, associations between /"CYP11A"/ promoter variation and androgen-related phenotypes has been substantially overestimated in previous studies. | [
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15128052 | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and Coronary Atherosclerosis Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of coronary atherosclerosis and its response to therapy. | Effects of /"PPARalpha"/, gamma and delta haplotypes on plasma levels of lipids, severity and progression of /"coronary atherosclerosis"/ and response to statin therapy in the lipoprotein /"coronary atherosclerosis"/ study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of /"PPAR"/ haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and /"Coronary Atherosclerosis"/ Study subjects for seven single nucleotide polymorphisms (SNPs) in /"PPARalpha"/ (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between /"PPARA"/ haplotypes and the phenotypes or significant interactions between /"PPAR"/ haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of /"coronary atherosclerosis"/ and its response to therapy. | [
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15128052 | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and Coronary Atherosclerosis Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of coronary atherosclerosis and its response to therapy. | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of /"coronary atherosclerosis"/ and response to statin therapy in the lipoprotein /"coronary atherosclerosis"/ study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and /"Coronary Atherosclerosis"/ Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and /"PPARG"/ SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with /"PPARG"/ haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and /"PPARG"/ haplotypes are independent determinants of plasma levels of lipids, severity of /"coronary atherosclerosis"/ and its response to therapy. | [
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15128052 | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and Coronary Atherosclerosis Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of coronary atherosclerosis and its response to therapy. | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of /"coronary atherosclerosis"/ and response to statin therapy in the lipoprotein /"coronary atherosclerosis"/ study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and /"Coronary Atherosclerosis"/ Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The /"PPARD"/ and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with /"PPARD"/ haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. /"PPARD"/ haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. /"PPARD"/ and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of /"coronary atherosclerosis"/ and its response to therapy. | [
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15128052 | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and Coronary Atherosclerosis Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of coronary atherosclerosis and its response to therapy. | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of /"coronary atherosclerosis"/ and response to statin therapy in the lipoprotein /"coronary atherosclerosis"/ study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and /"Coronary Atherosclerosis"/ Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and /"apoC-III"/ (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and /"apoC-III"/ (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of /"coronary atherosclerosis"/ and its response to therapy. | [
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15128052 | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and Coronary Atherosclerosis Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of coronary atherosclerosis and its response to therapy. | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of /"coronary atherosclerosis"/ and response to statin therapy in the lipoprotein /"coronary atherosclerosis"/ study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and /"Coronary Atherosclerosis"/ Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and /"apoC-III"/ (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and /"apoC-III"/ (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of /"coronary atherosclerosis"/ and its response to therapy. | [
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15128052 | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and Coronary Atherosclerosis Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and apoC-III (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and apoC-III (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of coronary atherosclerosis and its response to therapy. | Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of /"coronary atherosclerosis"/ and response to statin therapy in the lipoprotein /"coronary atherosclerosis"/ study. | Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that regulate fatty acid biosynthesis. Our objectives were to determine the effects of PPAR haplotypes on biochemical, angiographic, clinical phenotypes and their responses to treatment with fluvastatin. We genotyped 372 Lipoprotein and /"Coronary Atherosclerosis"/ Study subjects for seven single nucleotide polymorphisms (SNPs) in PPARalpha (-35 089A>C, 484C>G), delta (-4401C>T, 294T>C) and gamma (34C>G, 25 506C>T, 161C>T) by restriction mapping or 5' exonuclease assay. We reconstructed and estimated haplotypes frequencies using four algorithms. Linkage disequilibrium (LD) was calculated by D' and haplotype effects by permutation and regression analyses. The PPARD and PPARG SNPs were in LD. The baseline plasma triglyceride levels and their responses to treatment with fluvastatin were associated with PPARD haplotypes (P = 0.01). Triglyceride levels were lowest and highest in homozygotes with diplotypes 3 and 4 (130.1 +/- 40.8 and 194.2 +/- 44.6 mg/dl, P < 0.001), respectively. PPARD haplotype 3 was also an independent determinant of plasma apolipoprotein (apo)B (P = 0.021) and /"apoC-III"/ (P = 0.001) levels, mean number of coronary lesions (P = 0.046) and changes in triglyceride (P = 0.01) and /"apoC-III"/ (P = 0.047) levels in response to fluvastatin. Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes. No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected. PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of /"coronary atherosclerosis"/ and its response to therapy. | [
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15142050 | Apolipoprotein E gene polymorphism in renal transplant recipients: effects on lipid metabolism, atherosclerosis and allograft function. | INTRODUCTION: Atherosclerosis is a serious complication and leading cause of mortality in renal transplant recipients (RTRs). Hyperlipidemia may be associated with progression of renal disease and chronic allograft dysfunction. Similarities in the pathogenesis of glomerulosclerosis and atherosclerosis have been proposed. Apolipoprotein (apo) E gene code forms three major isoforms (E2, E3, and E4) with variable effects on lipid metabolism. PATIENTS AND METHODS: A total of 118 patients, at a mean age of 40 +/- 8 yr, were included in the study. Apo E genotyping was carried out on genomic DNA using polymerase chain reaction and restriction enzyme. Carotid artery intima media thickness and atherosclerotic plaques were evaluated by B-mode ultrasonography. The plasma levels of lipids and lipoproteins and acute phase reactants were also studied. Allograft function was evaluated by measuring serum creatinine and creatinine clearance values. RESULTS: The frequencies of E2, E3, and E4 alleles were 0.10, 0.78, and 0.12 respectively. Carotid artery atherosclerosis was found in 25% of E2 carriers, 30% of E3 carriers, and 57% of E4 carriers. Total cholesterol, total triglyceride, low-density lipoprotein, very low-density lipoprotein, apo B 100 levels were found to be higher in apo E4 carriers. Median apo A1 level was higher and allograft functions were better in apo E2 carriers (p < 0.05). Multiple regression analysis showed that allograft functions were negatively correlated with elevated acute phase reactants (p < 0.01) and only the age, but not the apo E genotypes, was an independent risk factor for atherosclerotic vascular disease (p < 0.01). DISCUSSION: The pathogenetic events linking lipid metabolism and allograft functions and development of atherosclerosis are complex and multifactorial in RTRs. Our results showed that apo E genotypes have influences on lipids, lipoproteins and allograft functions. The ultimate role of apo E4 gene polymorphism as a risk factor for development and progression of atherosclerosis in RTRs should be sought in further studies. | /"Apolipoprotein E"/ gene polymorphism in renal transplant recipients: effects on lipid metabolism, /"atherosclerosis"/ and allograft function. | INTRODUCTION: /"Atherosclerosis"/ is a serious complication and leading cause of mortality in renal transplant recipients (RTRs). Hyperlipidemia may be associated with progression of renal disease and chronic allograft dysfunction. Similarities in the pathogenesis of glomerulosclerosis and /"atherosclerosis"/ have been proposed. /"Apolipoprotein (apo) E"/ gene code forms three major isoforms (E2, E3, and E4) with variable effects on lipid metabolism. PATIENTS AND METHODS: A total of 118 patients, at a mean age of 40 +/- 8 yr, were included in the study. /"Apo E"/ genotyping was carried out on genomic DNA using polymerase chain reaction and restriction enzyme. Carotid artery intima media thickness and /"atherosclerotic"/ plaques were evaluated by B-mode ultrasonography. The plasma levels of lipids and lipoproteins and acute phase reactants were also studied. Allograft function was evaluated by measuring serum creatinine and creatinine clearance values. RESULTS: The frequencies of E2, E3, and E4 alleles were 0.10, 0.78, and 0.12 respectively. Carotid artery /"atherosclerosis"/ was found in 25% of E2 carriers, 30% of E3 carriers, and 57% of E4 carriers. Total cholesterol, total triglyceride, low-density lipoprotein, very low-density lipoprotein, apo B 100 levels were found to be higher in /"apo E4"/ carriers. Median apo A1 level was higher and allograft functions were better in /"apo E2"/ carriers (p < 0.05). Multiple regression analysis showed that allograft functions were negatively correlated with elevated acute phase reactants (p < 0.01) and only the age, but not the /"apo E"/ genotypes, was an independent risk factor for /"atherosclerotic vascular disease"/ (p < 0.01). DISCUSSION: The pathogenetic events linking lipid metabolism and allograft functions and development of /"atherosclerosis"/ are complex and multifactorial in RTRs. Our results showed that /"apo E"/ genotypes have influences on lipids, lipoproteins and allograft functions. The ultimate role of /"apo E4"/ gene polymorphism as a risk factor for development and progression of /"atherosclerosis"/ in RTRs should be sought in further studies. | [
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15142050 | Apolipoprotein E gene polymorphism in renal transplant recipients: effects on lipid metabolism, atherosclerosis and allograft function. | INTRODUCTION: Atherosclerosis is a serious complication and leading cause of mortality in renal transplant recipients (RTRs). Hyperlipidemia may be associated with progression of renal disease and chronic allograft dysfunction. Similarities in the pathogenesis of glomerulosclerosis and atherosclerosis have been proposed. Apolipoprotein (apo) E gene code forms three major isoforms (E2, E3, and E4) with variable effects on lipid metabolism. PATIENTS AND METHODS: A total of 118 patients, at a mean age of 40 +/- 8 yr, were included in the study. Apo E genotyping was carried out on genomic DNA using polymerase chain reaction and restriction enzyme. Carotid artery intima media thickness and atherosclerotic plaques were evaluated by B-mode ultrasonography. The plasma levels of lipids and lipoproteins and acute phase reactants were also studied. Allograft function was evaluated by measuring serum creatinine and creatinine clearance values. RESULTS: The frequencies of E2, E3, and E4 alleles were 0.10, 0.78, and 0.12 respectively. Carotid artery atherosclerosis was found in 25% of E2 carriers, 30% of E3 carriers, and 57% of E4 carriers. Total cholesterol, total triglyceride, low-density lipoprotein, very low-density lipoprotein, apo B 100 levels were found to be higher in apo E4 carriers. Median apo A1 level was higher and allograft functions were better in apo E2 carriers (p < 0.05). Multiple regression analysis showed that allograft functions were negatively correlated with elevated acute phase reactants (p < 0.01) and only the age, but not the apo E genotypes, was an independent risk factor for atherosclerotic vascular disease (p < 0.01). DISCUSSION: The pathogenetic events linking lipid metabolism and allograft functions and development of atherosclerosis are complex and multifactorial in RTRs. Our results showed that apo E genotypes have influences on lipids, lipoproteins and allograft functions. The ultimate role of apo E4 gene polymorphism as a risk factor for development and progression of atherosclerosis in RTRs should be sought in further studies. | /"Apolipoprotein E"/ gene polymorphism in renal transplant recipients: effects on lipid metabolism, atherosclerosis and allograft function. | INTRODUCTION: Atherosclerosis is a serious complication and leading cause of mortality in renal transplant recipients (RTRs). Hyperlipidemia may be associated with progression of /"renal disease"/ and chronic allograft dysfunction. Similarities in the pathogenesis of glomerulosclerosis and atherosclerosis have been proposed. /"Apolipoprotein (apo) E"/ gene code forms three major isoforms (E2, E3, and E4) with variable effects on lipid metabolism. PATIENTS AND METHODS: A total of 118 patients, at a mean age of 40 +/- 8 yr, were included in the study. /"Apo E"/ genotyping was carried out on genomic DNA using polymerase chain reaction and restriction enzyme. Carotid artery intima media thickness and atherosclerotic plaques were evaluated by B-mode ultrasonography. The plasma levels of lipids and lipoproteins and acute phase reactants were also studied. Allograft function was evaluated by measuring serum creatinine and creatinine clearance values. RESULTS: The frequencies of E2, E3, and E4 alleles were 0.10, 0.78, and 0.12 respectively. Carotid artery atherosclerosis was found in 25% of E2 carriers, 30% of E3 carriers, and 57% of E4 carriers. Total cholesterol, total triglyceride, low-density lipoprotein, very low-density lipoprotein, apo B 100 levels were found to be higher in /"apo E4"/ carriers. Median apo A1 level was higher and allograft functions were better in /"apo E2"/ carriers (p < 0.05). Multiple regression analysis showed that allograft functions were negatively correlated with elevated acute phase reactants (p < 0.01) and only the age, but not the /"apo E"/ genotypes, was an independent risk factor for atherosclerotic vascular disease (p < 0.01). DISCUSSION: The pathogenetic events linking lipid metabolism and allograft functions and development of atherosclerosis are complex and multifactorial in RTRs. Our results showed that /"apo E"/ genotypes have influences on lipids, lipoproteins and allograft functions. The ultimate role of /"apo E4"/ gene polymorphism as a risk factor for development and progression of atherosclerosis in RTRs should be sought in further studies. | [
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