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Matan Hofree - One of the best experts on this subject based on the ideXlab platform.
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Association of methylation of genes in the taurine/hypotaurine pathway with worse prognosis in renal cell carcinoma.
Journal of Clinical Oncology, 2013Co-Authors: Andrew M Gross, Michel Choueiri, John Paul Shen, James Michael Randall, Trey Ideker, Matan HofreeAbstract:e15562 Background: Epigenetic silencing of genes associated with the taurine/hypotaurine pathway has been associated with worse outcome in several tumors such as CDO1 in breast cancer, and GAD1 in prostate cancer. Our objective was to assess the prognostic value of methylation status of genes in the taurine/hypotaurine pathway in patients with renal cell carcinoma (RCC). Methods: We performed an analysis of 283 RCC samples using data from The Cancer Genome Atlas (TCGA). Ten genes belonging to the taurine/hypotaurine metabolic were analyzed using principal component analysis to determine a composite methylation profile of the pathway. A Cox proportional-hazards regression model was then used to determine the association of the composite methylation profile with patient survival. Results: CDO1, GAD2, and GAD1 influenced the outcome of the composite gene the most. Increasing degree of methylation correlated with more advanced tumor stage, and was an independent predictor of overall patient survival. Among pa...
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association of methylation of genes in the taurine hypotaurine pathway with worse prognosis in renal cell carcinoma
Journal of Clinical Oncology, 2013Co-Authors: Andrew M Gross, Michel Choueiri, John Paul Shen, James Michael Randall, Trey Ideker, Matan HofreeAbstract:e15562 Background: Epigenetic silencing of genes associated with the taurine/hypotaurine pathway has been associated with worse outcome in several tumors such as CDO1 in breast cancer, and GAD1 in prostate cancer. Our objective was to assess the prognostic value of methylation status of genes in the taurine/hypotaurine pathway in patients with renal cell carcinoma (RCC). Methods: We performed an analysis of 283 RCC samples using data from The Cancer Genome Atlas (TCGA). Ten genes belonging to the taurine/hypotaurine metabolic were analyzed using principal component analysis to determine a composite methylation profile of the pathway. A Cox proportional-hazards regression model was then used to determine the association of the composite methylation profile with patient survival. Results: CDO1, GAD2, and GAD1 influenced the outcome of the composite gene the most. Increasing degree of methylation correlated with more advanced tumor stage, and was an independent predictor of overall patient survival. Among pa...
Andrew M Gross - One of the best experts on this subject based on the ideXlab platform.
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Association of methylation of genes in the taurine/hypotaurine pathway with worse prognosis in renal cell carcinoma.
Journal of Clinical Oncology, 2013Co-Authors: Andrew M Gross, Michel Choueiri, John Paul Shen, James Michael Randall, Trey Ideker, Matan HofreeAbstract:e15562 Background: Epigenetic silencing of genes associated with the taurine/hypotaurine pathway has been associated with worse outcome in several tumors such as CDO1 in breast cancer, and GAD1 in prostate cancer. Our objective was to assess the prognostic value of methylation status of genes in the taurine/hypotaurine pathway in patients with renal cell carcinoma (RCC). Methods: We performed an analysis of 283 RCC samples using data from The Cancer Genome Atlas (TCGA). Ten genes belonging to the taurine/hypotaurine metabolic were analyzed using principal component analysis to determine a composite methylation profile of the pathway. A Cox proportional-hazards regression model was then used to determine the association of the composite methylation profile with patient survival. Results: CDO1, GAD2, and GAD1 influenced the outcome of the composite gene the most. Increasing degree of methylation correlated with more advanced tumor stage, and was an independent predictor of overall patient survival. Among pa...
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association of methylation of genes in the taurine hypotaurine pathway with worse prognosis in renal cell carcinoma
Journal of Clinical Oncology, 2013Co-Authors: Andrew M Gross, Michel Choueiri, John Paul Shen, James Michael Randall, Trey Ideker, Matan HofreeAbstract:e15562 Background: Epigenetic silencing of genes associated with the taurine/hypotaurine pathway has been associated with worse outcome in several tumors such as CDO1 in breast cancer, and GAD1 in prostate cancer. Our objective was to assess the prognostic value of methylation status of genes in the taurine/hypotaurine pathway in patients with renal cell carcinoma (RCC). Methods: We performed an analysis of 283 RCC samples using data from The Cancer Genome Atlas (TCGA). Ten genes belonging to the taurine/hypotaurine metabolic were analyzed using principal component analysis to determine a composite methylation profile of the pathway. A Cox proportional-hazards regression model was then used to determine the association of the composite methylation profile with patient survival. Results: CDO1, GAD2, and GAD1 influenced the outcome of the composite gene the most. Increasing degree of methylation correlated with more advanced tumor stage, and was an independent predictor of overall patient survival. Among pa...
John A. Todd - One of the best experts on this subject based on the ideXlab platform.
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A comprehensive, statistically powered analysis of GAD2 in type 1 diabetes.
Diabetes, 2002Co-Authors: Gillian C.l. Johnson, Felicity Payne, Sarah Nutland, Helen E. Stevens, Eva Tuomilehto-wolf, Jaakko Tuomilehto, John A. ToddAbstract:GAD2 maps to chromosome 10p11.23 and encodes the 65-kDa isoform of GAD65, a major autoantigen in type 1 diabetes. The genetic variation that influences expression of preproinsulin mRNA, encoding another major autoantigen in type 1 diabetes, has already been shown to be genetically associated with disease. Previous reports that have assessed the association of GAD2 with type 1 diabetes have not used a dense map of markers surrounding the gene and have relied on very small clinical sample sizes. Consequently, no definite conclusions can be drawn from their negative results. We have therefore systematically searched all exons, the 3' untranslated region (UTR), the 5' UTR, and the 5' upstream region of GAD2, for polymorphisms in 32 white European individuals. We have genotyped these polymorphisms in a maximum of 472 U.K. type 1 diabetic affected sib pair families exhibiting linkage to type 1 diabetes on chromosome 10p and have tested both single variants and haplotypes in the GAD2 region for association with disease. We subsequently followed up our results by genotyping a subset of these single-nucleotide polymorphisms in a maximum of 873 Finnish families with at least one affected child. Our results suggest that GAD2 does not play a major role in type 1 diabetes in these two European populations.
Diana G. Patterson - One of the best experts on this subject based on the ideXlab platform.
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Associations of glutamate decarboxylase genes with initial sensitivity and age-at-onset of alcohol dependence in the Irish Affected Sib Pair Study of Alcohol Dependence.
Drug and Alcohol Dependence, 2008Co-Authors: Po-hsiu Kuo, Gursharan Kalsi, Carol A. Prescott, Colin A. Hodgkinson, David Goldman, Jeffry Alexander, Edwin J. C. G. Van Den Oord, Xiangning Chen, Patrick F. Sullivan, Diana G. PattersonAbstract:Background The relation of γ-aminobutyric acid (GABA) to alcohol dependence (AD) has been widely studied. Several previous studies suggest that GABA may be involved in alcohol withdrawal, tolerance, and the symptoms that form an AD diagnosis. The genes coding for glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, are of potential interest for their association to ethanol consumption and AD. There are two isoforms of GAD, GAD1 and GAD2, which were reported to be associated with AD in males of Han Taiwanese (GAD1) and Russian (GAD2) ancestry. The present study examined the association of the two GAD isoforms with AD and relevant alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence [Prescott, C.A., Sullivan, P.F., Myers, J.M., Patterson, D.G., Devitt, M., Halberstadt, L.J., Walsh, D., Kendler, K.S., 2005. The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history. Alcohol.-Clin. Exp. Res. 29 (3) 417–429].
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Associations of glutamate decarboxylase genes with initial sensitivity and age-at-onset of alcohol dependence in the Irish Affected Sib Pair Study of Alcohol Dependence.
Drug and alcohol dependence, 2008Co-Authors: Po-hsiu Kuo, Gursharan Kalsi, Carol A. Prescott, Colin A. Hodgkinson, David Goldman, Jeffry Alexander, Edwin J. C. G. Van Den Oord, Xiangning Chen, Patrick F. Sullivan, Diana G. PattersonAbstract:The relation of gamma-aminobutyric acid (GABA) to alcohol dependence (AD) has been widely studied. Several previous studies suggest that GABA may be involved in alcohol withdrawal, tolerance, and the symptoms that form an AD diagnosis. The genes coding for glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, are of potential interest for their association to ethanol consumption and AD. There are two isoforms of GAD, GAD1 and GAD2, which were reported to be associated with AD in males of Han Taiwanese (GAD1) and Russian (GAD2) ancestry. The present study examined the association of the two GAD isoforms with AD and relevant alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence [Prescott, C.A., Sullivan, P.F., Myers, J.M., Patterson, D.G., Devitt, M., Halberstadt, L.J., Walsh, D., Kendler, K.S., 2005. The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history. Alcohol.-Clin. Exp. Res. 29 (3) 417-429]. Participants were recruited in Ireland, including 575 independent cases who met DSM-IV AD criteria and 530 controls, screened for heavy drinking. We first conducted case-control analyses of the GAD genes with AD and, within the cases, examined associations with age at onset of AD, withdrawal symptoms, and two quantitative measures: initial sensitivity and tolerance (based on scales from the Self-Rating of the Effects of Ethanol) [Schuckit, M.A., Smith, T.L., Tipp, J.E., 1997. The self-rating of the effects of alcohol (SRE) form as a retrospective measure of the risk for alcoholism. Addiction 92, 979-988]. A total of 29 SNPs were genotyped for GAD1 and GAD2 using the Illumina GoldenGate protocols. Statistical procedures were implemented to control for false discovery rates (FDR). Nine of 29 markers with minor allele frequencies less than 0.01 were removed from standard analysis; the remaining 20 markers were all in Hardy-Weinberg equilibrium. Three markers in the intronic regions of GAD1 were associated with initial sensitivity to alcohol (P=0.002); the associations remained significant after a FDR based correction for multiple testing. In addition, one marker located 3kb upstream of GAD1 exhibited association with age at onset of AD (P=0.0001). Gender specific effects were observed in results of both single marker and haplotype analyses. We found no evidence for the association of GAD genes with AD but significant association of GAD1 with initial sensitivity and age at onset of AD. Our findings suggest that the underlying pathophysiology regulated by genes like GAD1 may be more directly related to the component processes that form AD than to the clinical disorder.
Xiangning Chen - One of the best experts on this subject based on the ideXlab platform.
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Associations of glutamate decarboxylase genes with initial sensitivity and age-at-onset of alcohol dependence in the Irish Affected Sib Pair Study of Alcohol Dependence.
Drug and Alcohol Dependence, 2008Co-Authors: Po-hsiu Kuo, Gursharan Kalsi, Carol A. Prescott, Colin A. Hodgkinson, David Goldman, Jeffry Alexander, Edwin J. C. G. Van Den Oord, Xiangning Chen, Patrick F. Sullivan, Diana G. PattersonAbstract:Background The relation of γ-aminobutyric acid (GABA) to alcohol dependence (AD) has been widely studied. Several previous studies suggest that GABA may be involved in alcohol withdrawal, tolerance, and the symptoms that form an AD diagnosis. The genes coding for glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, are of potential interest for their association to ethanol consumption and AD. There are two isoforms of GAD, GAD1 and GAD2, which were reported to be associated with AD in males of Han Taiwanese (GAD1) and Russian (GAD2) ancestry. The present study examined the association of the two GAD isoforms with AD and relevant alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence [Prescott, C.A., Sullivan, P.F., Myers, J.M., Patterson, D.G., Devitt, M., Halberstadt, L.J., Walsh, D., Kendler, K.S., 2005. The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history. Alcohol.-Clin. Exp. Res. 29 (3) 417–429].
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Associations of glutamate decarboxylase genes with initial sensitivity and age-at-onset of alcohol dependence in the Irish Affected Sib Pair Study of Alcohol Dependence.
Drug and alcohol dependence, 2008Co-Authors: Po-hsiu Kuo, Gursharan Kalsi, Carol A. Prescott, Colin A. Hodgkinson, David Goldman, Jeffry Alexander, Edwin J. C. G. Van Den Oord, Xiangning Chen, Patrick F. Sullivan, Diana G. PattersonAbstract:The relation of gamma-aminobutyric acid (GABA) to alcohol dependence (AD) has been widely studied. Several previous studies suggest that GABA may be involved in alcohol withdrawal, tolerance, and the symptoms that form an AD diagnosis. The genes coding for glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, are of potential interest for their association to ethanol consumption and AD. There are two isoforms of GAD, GAD1 and GAD2, which were reported to be associated with AD in males of Han Taiwanese (GAD1) and Russian (GAD2) ancestry. The present study examined the association of the two GAD isoforms with AD and relevant alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence [Prescott, C.A., Sullivan, P.F., Myers, J.M., Patterson, D.G., Devitt, M., Halberstadt, L.J., Walsh, D., Kendler, K.S., 2005. The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history. Alcohol.-Clin. Exp. Res. 29 (3) 417-429]. Participants were recruited in Ireland, including 575 independent cases who met DSM-IV AD criteria and 530 controls, screened for heavy drinking. We first conducted case-control analyses of the GAD genes with AD and, within the cases, examined associations with age at onset of AD, withdrawal symptoms, and two quantitative measures: initial sensitivity and tolerance (based on scales from the Self-Rating of the Effects of Ethanol) [Schuckit, M.A., Smith, T.L., Tipp, J.E., 1997. The self-rating of the effects of alcohol (SRE) form as a retrospective measure of the risk for alcoholism. Addiction 92, 979-988]. A total of 29 SNPs were genotyped for GAD1 and GAD2 using the Illumina GoldenGate protocols. Statistical procedures were implemented to control for false discovery rates (FDR). Nine of 29 markers with minor allele frequencies less than 0.01 were removed from standard analysis; the remaining 20 markers were all in Hardy-Weinberg equilibrium. Three markers in the intronic regions of GAD1 were associated with initial sensitivity to alcohol (P=0.002); the associations remained significant after a FDR based correction for multiple testing. In addition, one marker located 3kb upstream of GAD1 exhibited association with age at onset of AD (P=0.0001). Gender specific effects were observed in results of both single marker and haplotype analyses. We found no evidence for the association of GAD genes with AD but significant association of GAD1 with initial sensitivity and age at onset of AD. Our findings suggest that the underlying pathophysiology regulated by genes like GAD1 may be more directly related to the component processes that form AD than to the clinical disorder.
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Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism
Molecular psychiatry, 2006Co-Authors: John M. Hettema, M. C. Neale, József Bukszár, E J C G Van Den Oord, Kenneth S. Kendler, Xiangning ChenAbstract:Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We used multivariate structural equation modeling to identify common genetic risk factors for major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and neuroticism (N) in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available was selected as a case or control based on scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls was entered into a two-stage association study in which candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Several of the six single-nucleotide polymorphisms tested in the GAD1 region demonstrated significant association in both stages, and a combined analysis in all 1128 subjects indicated that they formed a common high-risk haplotype that was significantly over-represented in cases (P=0.003) with effect size OR=1.23. Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in stage 2. This marker, plus three others that formed significant haplotype combinations in stage 1, did not replicate their association with the phenotype in stage 2. Subject to confirmation in an independent sample, our study suggests that variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression.
