Rector Arya

Publications (30)179.1 Total impact

• Article: The Gly(972)Arg variant of human IRS1 gene is associated with variation in glomerular filtration rate likely through impaired insulin receptor signaling.

  Farook Thameem, Sobha Puppala, Jennifer Schneider, Basant Bhandari, Rector Arya, Nedal H Arar, Tetyana L Vasylyeva, Vidya S Farook, Sharon Fowler, Laura Almasy, John Blangero, Ravindranath Duggirala, Hanna E Abboud
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  ABSTRACT: The objective of this study is to identify and characterize the genetic variants related to the glomerular filtration rate (GFR) linkage on 2q37. Of the positional candidate genes, we selected IRS1 and resequenced its 2-kb promoter region and exons for sequence variants in 32 subjects. A total of 11 single nucleotide polymorphisms (SNPs) were identified. To comprehensively cover the 59-kb-long intron-1, eight additional tagging SNPs were selected from the HapMap. All the 19 SNPs were genotyped by TaqMan Assay in the entire data set (N = 670; 39 families). Association analyses between the SNPs and GFR and type 2 diabetes-related traits were performed using the measured genotype approach. Of the SNPs examined for association, only the Gly(972)Arg variant of IRS1 exhibited a significant association with GFR (P = 0.0006) and serum triglycerides levels (P = 0.003), after accounting for trait-specific covariate effects. Carriers of Arg972 had significantly decreased GFR values. Gly(972)Arg contributed to 26% of the linkage signal on 2q. Expression of IRS1 mutant Arg972 in human mesangial cells significantly reduced the insulin-stimulated phosphorylation of IRS1 and Akt kinase. Taken together, the data provide the first evidence that genetic variation in IRS1 may influence variation in GFR probably through impaired insulin receptor signaling.
  Diabetes 05/2012; 61(9):2385-93. · 8.29 Impact Factor
• Article: Wide disparity in genetic admixture among Mexican Americans from San Antonio, TX.

  Joke Beuten, Indrani Halder, Sharon P Fowler, Harald H H Groing, Ravindranath Duggirala, Rector Arya, Ian M Thompson, Robin J Leach, Donna M Lehman
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  ABSTRACT: We studied 706 participants of the San Antonio Family Diabetes Study (SAFDS) and 586 male samples from the San Antonio Center for Biomarkers of Risk of Prostate Cancer (SABOR) and used 64 ancestry informative markers to compare admixture proportions between both groups. Existence of population substructure was demonstrated by the excess association of unlinked markers. In the SAFDS sample, ancestral proportions were estimated at 50.2 ± 0.6% European, 46.4 ± 0.6% Native American, and 3.1 ± 0.2% West African. For the SABOR sample, the proportions were 58.9 ± 0.7%, 38.2 ± 0.7%, and 2.9 ± 0.2%, respectively. Additionally, in the SAFDS subjects a highly significant negative correlation was found between individual Native American ancestry and skin reflectance (R(2) = 0.07, P= 0.00006). The correlation was stronger in males than in females but clearly showed that ancestry only accounts for a small percentage of the variation in skin color and, conversely, that skin reflectance is not a robust surrogate for genetic admixture. Furthermore, a substantial difference in substructure is present in the two cohorts of Mexican American subjects from the San Antonio area in Texas, which emphasizes that genetic admixture estimates should be accounted for in association studies, even for geographically related subjects.
  Annals of Human Genetics 07/2011; 75(4):529-38. · 2.57 Impact Factor
• Article: Genome-wide linkage screen for systolic blood pressure in the Veterans Administration Genetic Epidemiology Study (VAGES) of Mexican-Americans and confirmation of a major susceptibility locus on chromosome 6q14.1.

  Sobha Puppala, Dawn K Coletta, Jennifer Schneider, Shirley L Hu, Vidya S Farook, Thomas D Dyer, Rector Arya, John Blangero, Ravindranath Duggirala, Ralph A DeFronzo, Christopher P Jenkinson
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  ABSTRACT: Hypertension or high blood pressure is a strong correlate of diseases such as obesity and type 2 diabetes. We conducted a genome-wide linkage screen to identify susceptibility genes influencing systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Mexican-Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). Using data from 1,089 individuals distributed across 266 families, we performed a multipoint linkage analysis to localize susceptibility loci for SBP and DBP by applying two models. In model 1, we added a sensible constant to the observed BP values in treated subjects [Tobin et al.; Stat Med 2005;24:2911-2935] to account for antihypertensive use (i.e. 15 and 10 mm Hg to SBP and DBP values, respectively). In model 2, we fixed values of 140 mm Hg for SBP and 90 mm Hg for DBP, if the treated values were less than the standard referenced treatment thresholds of 140/ 90 mm Hg for hypertensive status. However, if the observed treated BP values were found to be above these standard treatment thresholds, the actual observed treated BP values were retained in order not to reduce them by substitution of the treatment threshold values. The multipoint linkage analysis revealed strong linkage signals for SBP compared with DBP. The strongest evidence for linkage of SBP (model 1, LOD = 5.0; model 2, LOD = 3.6) was found on chromosome 6q14.1 near the marker D6S1031 (89 cM) in both models. In addition, some evidence for SBP linkage occurred on chromosomes 1q, 4p, and 16p. Most importantly, our major SBP linkage finding on chromosome 6q near marker D6S1031 was independently confirmed in a Caucasian population (LOD = 3.3). In summary, our study found evidence for a major locus on chromosome 6q influencing SBP levels in Mexican-Americans.
  Human Heredity 02/2011; 71(1):1-10. · 1.79 Impact Factor
• Source

  Available from: Liz Hare

  Article: Effects of covariates and interactions on a genome-wide association analysis of rheumatoid arthritis.

  Rector Arya, Elizabeth Hare, Inmaculada Del Rincon, Christopher P Jenkinson, Ravindranath Duggirala, Laura Almasy, Agustin Escalante
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  ABSTRACT: ABSTRACT : While genetic and environmental factors and their interactions influence susceptibility to rheumatoid arthritis (RA), causative genetic variants have not been identified. The purpose of the present study was to assess the effects of covariates and genotype x sex interactions on the genome-wide association analysis (GWAA) of RA using Genetic Analysis Workshop 16 Problem 1 data and a logistic regression approach as implemented in PLINK. After accounting for the effects of population stratification, effects of covariates and genotype x sex interactions on the GWAA of RA were assessed by conducting association and interaction analyses. We found significant allelic associations, covariate, and genotype x sex interaction effects on RA. Several top single-nucleotide polymorphisms (SNPs) (~22 SNPs) showed significant associations with strong p-values (p < 1 x 10-4 - p < 1 x 10-24). Only three SNPs on chromosomes 4, 13, and 20 were significant after Bonferroni correction, and none of these three SNPs showed significant genotype x sex interactions. Of the 30 top SNPs with significant (p < 1 x 10-4 - p < 1 x 10-6) interactions, ~23 SNPs showed additive interactions and ~5 SNPs showed only dominance interactions. Those SNPs showing significant associations in the regular logistic regression failed to show significant interactions. In contrast, the SNPs that showed significant interactions failed to show significant associations in models that did not incorporate interactions. It is important to consider interactions of genotype x sex in addition to associations in a GWAA of RA. Furthermore, the association between SNPs and RA susceptibility varies significantly between men and women.
  BMC proceedings 01/2009; 3 Suppl 7:S84.
• Source

  Available from: John Blangero

  Article: Genome-wide linkage scan for genes influencing plasma triglyceride levels in the Veterans Administration Genetic Epidemiology Study.

  Dawn K Coletta, Jennifer Schneider, Shirley L Hu, Thomas D Dyer, Sobha Puppala, Vidya S Farook, Rector Arya, Donna M Lehman, John Blangero, Ralph A DeFronzo, Ravindranath Duggirala, Christopher P Jenkinson
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  ABSTRACT: Elevated plasma triglyceride concentration is a component of the insulin resistance syndrome and is commonly associated with type 2 diabetes, obesity, and coronary heart disease. The goal of our study was to perform a genome-wide linkage scan to identify genetic regions that influence variation in plasma triglyceride levels in families that are enriched with individuals with type 2 diabetes. We used phenotypic and genotypic data from 1,026 individuals distributed across 294 Mexican-American families, who were ascertained for type 2 diabetes, from the Veterans Administration Genetic Epidemiology Study (VAGES). Plasma triglyceride values were transformed, and a variance-components technique was used to conduct multipoint linkage analysis. After adjusting for the significant effects of sex and BMI, heritability for plasma triglycerides was estimated as 46 +/- 7% (P < 0.0001). Multipoint linkage analysis yielded the strongest evidence for linkage of plasma triglycerides near marker D12S391 on chromosome 12p (logarithm of odds [LOD] = 2.4). Our linkage signal on chromosome 12p provides independent replication of a similar finding in another Mexican-American sample from the San Antonio Family Diabetes Study (SAFDS). Combined multipoint linkage analysis of the VAGES and SAFDS data yielded significant evidence for linkage of plasma triglycerides to a genetic location between markers GATA49D12 and D12S391 on 12p (LOD = 3.8, empirical P value = 2.0 x 10(-5)). This region on 12p harbors the gene-encoding adiponectin receptor 2 (AdipoR2), where we previously have shown that multiple single nucleotide polymorphisms are associated with plasma triglyceride concentrations in the SAFDS. In the present study, we provided suggestive evidence in favor of association for rs929434 with triglyceride concentrations in the VAGES. Collectively, these results provide strong evidence for a major locus on chromosome 12p that influences plasma triglyceride levels in Mexican Americans.
  Diabetes 10/2008; 58(1):279-84. · 8.29 Impact Factor
• Article: Association of genetic variation in ENPP1 with obesity-related phenotypes.

  Christopher P Jenkinson, Dawn K Coletta, Marion Flechtner-Mors, Shirley L Hu, Marcel J Fourcaudot, Lenore M Rodriguez, Jennifer Schneider, Rector Arya, Michael P Stern, John Blangero, Ravindranath Duggirala, Ralph A DeFronzo
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  ABSTRACT: Ectonucleotide pyrophosphatase phosphodiesterase (ENPP1) is a positional candidate gene at chromosome 6q23 where we previously detected strong linkage with fasting-specific plasma insulin and obesity in Mexican Americans from the San Antonio Family Diabetes Study (SAFDS). We genotyped 106 single-nucleotide polymorphisms (SNPs) within ENPP1 in all 439 subjects from the linkage study, and measured association with obesity and metabolic syndrome (MS)-related traits. Of 72 polymorphic SNPs, 24 were associated, using an additive model, with at least one of eight key metabolic traits. Three traits were associated with at least four SNPs. They were high-density lipoprotein cholesterol (HDL-C), leptin, and fasting plasma glucose (FPG). HDL-C was associated with seven SNPs, of which the two most significant P values were 0.0068 and 0.0096. All SNPs and SNP combinations were analyzed for functional contribution to the traits using the Bayesian quantitative-trait nucleotide (BQTN) approach. With this SNP-prioritization analysis, HDL-C was the most strongly associated trait in a four-SNP model (P=0.00008). After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to our previous linkage peak with MS-related traits in Mexican Americans. However, these results indicate that ENPP1 is a genetic determinant of these traits in this population, and are consistent with multiple positive association findings in independent studies in diverse human populations.
  Obesity 08/2008; 16(7):1708-13. · 4.28 Impact Factor
• Article: Autosomal genome-wide linkage analysis to identify loci for gallbladder wall thickness in Mexican Americans.

  Narahari Samudrala, Vidya S Farook, Gerald D Dodd, Sobha Puppala, Jennifer Schneider, Sharon Fowler, Richard Granato, Thomas D Dyer, Rector Arya, Laura Almasy, Christopher P Jenkinson, Andrew K Diehl, John Blangero, Ravindranath Duggirala
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  ABSTRACT: The significance of gallbladder wall thickness (GBWT) in regard to gallbladder disease (GBD) is not completely understood. Thickening of the gallbladder wall has been observed in patients with acute calculous and acalculous cholecystitis and chronic cholecystitis. However, various pathologic processes, such as gallbladder cancer and nonbiliary disorders such as liver cirrhosis and viral hepatitis, could also cause thickening of the gallbladder wall. To date, there is no report available on the genetic factors influencing GBWT. Therefore we sought to estimate the heritability (h2) of GBWT and to perform a genome-wide search to identify the susceptibility genes for GBWT, using data from the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), a family study of Mexican Americans. GBWT was measured by ultrasound. After adjusting for the significant effects of age, sex, GBD (i.e., asymptomatic gallstones), metabolic syndrome, and duration of type 2 diabetes (T2DM), GBWT was found to be under significant and appreciable additive genetic influences (h2 +/- SE = 0.38 +/- 0.09, P < 0.0001). The strongest evidence for linkage occurred between markers D11S912 and D11S968 on chromosome 11q24-q25 (LOD = 2.7), where we have already shown suggestive evidence for linkage of GBD (LOD = 2.7) in a subset of our SAFDGS data. Potential evidence for linkage occurred at markers D1S1728 (1p31.1; LOD = 1.4) and D16S748 (16p13.1; LOD = 1.4), respectively. In conclusion, our study provides suggestive evidence for linkage of GBWT on chromosome 11q in Mexican Americans, and future tasks of mapping susceptibility gene(s) for GBD and its related traits, such as GBWT, in this chromosomal region can be fruitful.
  Human Biology 02/2008; 80(1):11-28. · 1.31 Impact Factor
• Article: Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans.

  Sobha Puppala, Rector Arya, Farook Thameem, Nedal H Arar, Kusum Bhandari, Donna M Lehman, Jennifer Schneider, Sharon Fowler, Vidya S Farook, Vincent P Diego, Laura Almasy, John Blangero, Michael P Stern, Ravindranath Duggirala, Hanna E Abboud
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  ABSTRACT: Glomerular filtration rate (GFR) is used to assess the progression of renal disease. We performed linkage analysis to localize genes that influence GFR using estimated GFR data from the San Antonio Family Diabetes/Gallbladder Study. We also examined the effect of genotype by diabetes interaction (G x DM) on the detection of linkage to address whether genetic effects on GFR differ in diabetic and nondiabetic subjects. GFR (N = 453) was estimated using the recently recalculated Cockcroft-Gault (GFR-CGc) and the simplified Modification of Diet in Renal Disease (GFR-4VMDRD) formulae. Both estimates of GFR exhibited significant heritabilities, but only GFR-CGc showed significant G x DM interaction. We therefore performed multipoint linkage analyses on both GFR measures using models that did not include G x DM interaction effects (Model 1) and that included G x DM interaction effects (Model 2, in the case of GFR-CGc). The strongest evidence for linkage (Model 1) of both GFR-CGc (logarithm of odds [LOD] 2.9) and GFR-4VMDRD (LOD 2.6) occurred between markers D9S922 and D9S1120 on chromosome 9q. However, using Model 2, the strongest evidence for linkage of GFR-CGc on chromosome 2q was found near marker D2S427 (corrected LOD score [LOD(C)] 3.3) compared with the LOD score of 2.7 based on Model 1. Potential linkages (LOD or LOD(C) >or=1.2) were found only for GFR-CGc on chromosomes 3p, 3q, 4p, 8q, 11q, and 14q. We found a major locus on chromosome 2q that differentially influences GFR in diabetic and nondiabetic environments in the Mexican-American population.
  Diabetes 11/2007; 56(11):2818-28. · 8.29 Impact Factor
• Article: Meta-analysis of genome-wide linkage studies in BMI and obesity.

  Catherine L Saunders, Benedetta D Chiodini, Pak Sham, Cathryn M Lewis, Victor Abkevich, Adebowale A Adeyemo, Mariza de Andrade, Rector Arya, Gerald S Berenson, John Blangero, [......], Markus Perola, R Arlen Price, Susan Redline, Sathanur R Srinivasan, Michael P Stern, Steven Stone, Heather Stringham, Stephen Turner, Cisca Wijmenga, David A Collier
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  ABSTRACT: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.
  Obesity 09/2007; 15(9):2263-75. · 4.28 Impact Factor
• Article: Meta-analysis of genome-wide linkage studies of quantitative lipid traits in families ascertained for type 2 diabetes.

  Alka Malhotra, Steven C Elbein, Maggie C Y Ng, Ravindranath Duggirala, Rector Arya, Giuseppina Imperatore, Adebowale Adeyemo, Toni I Pollin, Wen-Chi Hsueh, Juliana C N Chan, Charles Rotimi, Robert L Hanson, Sandra J Hasstedt, Johanna K Wolford
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  ABSTRACT: Dyslipidemia is a major risk factor for coronary heart disease, which is the predominant cause of mortality in individuals with type 2 diabetes. To date, nine linkage studies for quantitative lipid traits have been performed in families ascertained for type 2 diabetes, individually yielding linkage results that were largely nonoverlapping. Discrepancies in linkage findings are not uncommon and are typically due to limited sample size and heterogeneity. To address these issues and increase the power to detect linkage, we performed a meta-analysis of all published genome scans for quantitative lipid traits conducted in families ascertained for type 2 diabetes. Statistically significant evidence (i.e., P < 0.00043) for linkage was observed for total cholesterol on 7q32.3-q36.3 (152.43-182 cM; P = 0.00004), 19p13.3-p12 (6.57-38.05 cM; P = 0.00026), 19p12-q13.13 (38.05-69.53 cM; P = 0.00001), and 19q13.13-q13.43 (69.53-101.1 cM; P = 0.00033), as well as LDL on 19p13.3-p12 (P = 0.00041). Suggestive evidence (i.e., P < 0.00860) for linkage was also observed for LDL on 19p12-q13.13, triglycerides on 7p11-q21.11 (63.72-93.29 cM), triglyceride/HDL on 7p11-q21.11 and 19p12-q13.13, and LDL/HDL on 16q11.2-q24.3 (65.2-130.4 cM) and 19p12-q13.13. Linkage for lipid traits has been previously observed on both chromosomes 7 and 19 in several unrelated studies and, together with the results of this meta-analysis, provide compelling evidence that these regions harbor important determinants of lipid levels in individuals with type 2 diabetes.
  Diabetes 03/2007; 56(3):890-6. · 8.29 Impact Factor
• Article: P2 promoter variants of the hepatocyte nuclear factor 4alpha gene are associated with type 2 diabetes in Mexican Americans.

  Donna M Lehman, Dawn K Richardson, Chris P Jenkinson, Kelly J Hunt, Thomas D Dyer, Robin J Leach, Rector Arya, Hanna E Abboud, John Blangero, Ravindranath Duggirala, Michael P Stern
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  ABSTRACT: Common and rare variants of the hepatocyte nuclear factor 4alpha (HNF4A) gene have been associated with type 2 diabetes and related traits in several populations suggesting the involvement of this transcription factor in diabetes pathogenesis. Single nucleotide polymorphisms (SNPs) within a large haplotype block surrounding the alternate P2 promoter, located approximately 45 kb upstream from the coding region, have been investigated in several populations of varying ethnicity with inconsistent results. Additionally, SNPs located within the P1 promoter and coding region have also been inconsistently associated with type 2 diabetes. Characterization of variation across this gene region in Mexican-American populations has not been reported. We therefore examined polymorphisms across the HNF4A gene in a cohort of Mexican-American pedigrees and assessed their association with type 2 diabetes. We observed evidence for association of SNPs in the P2 promoter region with type 2 diabetes (P = 0.003) and its age at diagnosis (P = 0.003). The risk allele frequency (53%) was intermediate to that reported in Caucasian populations (20-27%) and Pima Indians (83%). No other SNPs were associated with either trait. These results support the possibility that a variant in the P2 promoter region of HNF4A, or variants in linkage disequilibrium within this region, contributes to susceptibility to type 2 diabetes in many ethnic populations including Mexican Americans.
  Diabetes 03/2007; 56(2):513-7. · 8.29 Impact Factor
• Article: Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans.

  Donna M Lehman, Kelly J Hunt, Robin J Leach, Jeanette Hamlington, Rector Arya, Hanna E Abboud, Ravindranath Duggirala, John Blangero, Harald H H Göring, Michael P Stern
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  ABSTRACT: TCF7L2 acts as both a repressor and transactivator of genes, as directed by the Wnt signaling pathway. Recently, several highly correlated sequence variants located within a haplotype block of the TCF7L2 gene were observed to associate with type 2 diabetes in three Caucasian cohorts. We previously reported linkage of type 2 diabetes in the San Antonio Family Diabetes Study (SAFADS) cohort consisting of extended pedigrees of Mexican Americans to the region of chromosome 10q harboring TCF7L2. We therefore genotyped 11 single nucleotide polymorphisms (SNPs) from nine haplotype blocks across the gene in 545 SAFADS subjects (178 diabetic) to investigate their role in diabetes pathogenesis. We observed nominal association between four SNPs (rs10885390, rs7903146, rs12255372, and rs3814573) in three haplotype blocks and type 2 diabetes, age at diagnosis, and 2-h glucose levels (P = 0.001-0.055). Furthermore, we identified a common protective haplotype defined by these four SNPs that was significantly associated with type 2 diabetes and age at diagnosis (P = 4.2 x 10(-5), relative risk [RR] 0.69; P = 6.7 x 10(-6), respectively) and a haplotype that confers diabetes risk that contains the rare alleles at SNPs rs10885390 and rs12255372 (P = 0.02, RR 1.64). These data provide evidence that variation in the TCF7L2 genomic region may affect risk for type 2 diabetes in Mexican Americans, but the attributable risk may be lower than in Caucasian populations.
  Diabetes 03/2007; 56(2):389-93. · 8.29 Impact Factor
• Article: A quantitative trait locus (QTL) on chromosome 6q influences birth weight in two independent family studies.

  Rector Arya, Ellen Demerath, Christopher P Jenkinson, Harald H H Göring, Sobha Puppala, Vidya Farook, Sharon Fowler, Jennifer Schneider, Richard Granato, Roy G Resendez, [......], Laura Almasy, Anthony G Comuzzie, Roger M Siervogel, Benjamin Bradshaw, Ralph A DeFronzo, Jean MacCluer, Michael P Stern, Bradford Towne, John Blangero, Ravindranath Duggirala
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  ABSTRACT: Low birth weight is an important cause of infant mortality and morbidity worldwide. Birth weight has been shown to be inversely correlated with adult complex diseases such as obesity, type-2 diabetes and cardiovascular disease. However, little is known about the genetic factors influencing variation in birth weight and its association with diseases that occur in later life. We, therefore, have performed a genome-wide search to identify genes that influence birth weight in Mexican-Americans using the data from the San Antonio Family Birth Weight Study participants (n=840). Heritability of birth weight was estimated as 72.0+/-8.4% (P<0.0001) after adjusting for the effects of sex and term. Multipoint linkage analysis yielded the strongest evidence for linkage of birth weight (LOD=3.7) between the markers D6S1053 and D6S1031 on chromosome 6q. This finding has been replicated (LOD=2.3) in an independent European-American population. Together, these findings provide substantial evidence (LOD(adj)=4.3) for a major locus influencing variation in birth weight. This region harbors positional candidate genes such as chorionic gonadotropin, alpha chain; collagen, type XIX, alpha-1; and protein-tyrosine phosphatase, type 4A, 1 that may play a role in fetal growth and development. In addition, potential evidence for linkage (LOD>or=1.2) was found on chromosomes 1q, 2q, 3q, 4q, 9p, 19p and 19q with LODs ranging from 1.3 to 2.7. Thus, we have found strong evidence for a major gene on chromosome 6q that influences variation in birth weight in both Mexican- and European-Americans.
  Human Molecular Genetics 05/2006; 15(10):1569-79. · 7.64 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: A genomewide search finds major susceptibility loci for gallbladder disease on chromosome 1 in Mexican Americans.

  Sobha Puppala, Gerald D Dodd, Sharon Fowler, Rector Arya, Jennifer Schneider, Vidya S Farook, Richard Granato, Thomas D Dyer, Laura Almasy, Christopher P Jenkinson, Andrew K Diehl, Michael P Stern, John Blangero, Ravindranath Duggirala
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  ABSTRACT: Gallbladder disease (GBD) is one of the major digestive diseases. Its risk factors include age, sex, obesity, type 2 diabetes, and metabolic syndrome (MS). The prevalence of GBD is high in minority populations, such as Native and Mexican Americans. Ethnic differences, familial aggregation of GBD, and the identification of susceptibility loci for gallstone disease by use of animal models suggest genetic influences on GBD. However, the major susceptibility loci for GBD in human populations have not been identified. Using ultrasound-based information on GBD occurrence and a 10-cM gene map, we performed multipoint variance-components analysis to localize susceptibility loci for GBD. Phenotypic and genotypic data from 715 individuals in 39 low-income Mexican American families participating in the San Antonio Family Diabetes/Gallbladder Study were used. Two GBD phenotypes were defined for the analyses: (1) clinical or symptomatic GBD, the cases of cholecystectomies due to stones confirmed by ultrasound, and (2) total GBD, the clinical GBD cases plus the stone carriers newly diagnosed by ultrasound. With use of the National Cholesterol Education Program/Adult Treatment Panel III criteria, five MS risk factors were defined: increased waist circumference, hypertriglyceredemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. The MS risk-factor score (range 0-5) for a given individual was used as a single, composite covariate in the genetic analyses. After accounting for the effects of age, sex, and MS risk-factor score, we found stronger linkage signals for the symptomatic GBD phenotype. The highest LOD scores (3.7 and 3.5) occurred on chromosome 1p between markers D1S1597 and D1S407 (1p36.21) and near marker D1S255 (1p34.3), respectively. Other genetic locations (chromosomes 2p, 3q, 4p, 8p, 9p, 10p, and 16q) across the genome exhibited some evidence of linkage (LOD >or=1.2) to symptomatic GBD. Some of these chromosomal regions corresponded with the genetic locations of Lith loci, which influence gallstone formation in mouse models. In conclusion, we found significant evidence of major genetic determinants of symptomatic GBD on chromosome 1p in Mexican Americans.
  The American Journal of Human Genetics 03/2006; 78(3):377-92. · 10.60 Impact Factor
• Source

  Available from: PubMed Central

  Article: Effect of genotype x alcoholism interaction on linkage analysis of an alcoholism-related quantitative phenotype.

  Rector Arya, Thomas D Dyer, Diane M Warren, Christopher P Jenkinson, Ravindranath Duggirala, Laura Almasy
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  ABSTRACT: Studies have shown that genetic and environmental factors and their interactions affect several alcoholism phenotypes. Genotype x alcoholism (GxA) interaction refers to the environmental (alcoholic and non-alcoholic) influences on the autosomal genes contributing to variation in an alcoholism-related quantitative phenotype. The purpose of this study was to examine the effects of GxA interaction on the detection of linkage for alcoholism-related phenotypes. We used phenotypic and genotypic data from the Collaborative Study on the Genetics of Alcoholism relating to 1,388 subjects as part of Genetic Analysis Workshop 14 problem 1. We analyzed the MXDRNK phenotype to detect GxA interaction using SOLAR. Upon detecting significant interaction, we conducted variance-component linkage analyses using microsatellite marker data. For maximum number of drinks per a 24 hour period, the highest LODs were observed on chromosomes 1, 4, and 13 without GxA interaction. Interaction analysis yielded four regions on chromosomes 1, 4, 13, and 15. On chromosome 4, a maximum LOD of 1.5 at the same location as the initial analysis was obtained after incorporating GxA interaction effects. However, after correcting for extra parameters, the LOD score was reduced to a corrected LOD of 1.1, which is similar to the LOD observed in the non-interaction analysis. Thus, we see little differences in LOD scores, while some linkage regions showed large differences in the magnitudes of estimated quantitative trait loci heritabilities between the alcoholic and non-alcoholic groups. These potential hints of differences in genetic effect may influence future analyses of variants under these linkage peaks.
  BMC Genetics 01/2006; 6 Suppl 1:S120. · 2.47 Impact Factor
• Article: Genome-wide linkage analyses of type 2 diabetes in Mexican Americans: the San Antonio Family Diabetes/Gallbladder Study.

  Kelly J Hunt, Donna M Lehman, Rector Arya, Sharon Fowler, Robin J Leach, Harald H H Göring, Laura Almasy, John Blangero, Tom D Dyer, Ravindranath Duggirala, Michael P Stern
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  ABSTRACT: The San Antonio Family Diabetes/Gallbladder Study was initiated to identify susceptibility genes for type 2 diabetes. Evidence was previously reported of linkage to diabetes on 10q with suggestive evidence on 3p and 9p in a genome-wide scan of 440 individuals from 27 pedigrees ascertained through a single diabetic proband. Subsequently, the study was expanded to include 906 individuals from 39 extended Mexican-American pedigrees, two additional examination cycles approximately 5.3 and 7.6 years after baseline, and genotypes for a new set of genome-wide markers. Therefore, we completed a second genome-wide linkage scan. Using information from a participant's most recent exam, the prevalence of diabetes in nonprobands was 21.8%. We performed genome-wide variance components-based genetic analysis on the discrete trait diabetes using a liability model and on the quantitative Martingale residual obtained from modeling age of diabetes diagnosis using Cox proportional hazard models. Controlling for age and age(2), our strongest evidence for linkage to the trait diabetes and the quantitative Martingale residual was on chromosome 3p at marker D3S2406 with multipoint empirical logarithm of odds scores of 1.87 and 3.76, respectively. In summary, we report evidence for linkage to diabetes on chromosome 3p in a region previously identified in at least three independent populations.
  Diabetes 10/2005; 54(9):2655-62. · 8.29 Impact Factor
• Article: Cardiovascular calcification in Hispanic Americans (HA) with chronic kidney disease (CKD) due to type 2 diabetes.

  Wajeh Y Qunibi, Fadi Abouzahr, Mohammad R Mizani, Charles R Nolan, Rector Arya, Kelly J Hunt
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  ABSTRACT: Cardiovascular calcification (CVC) is common and severe in patients with end-stage renal disease on dialysis. However, the prevalence and severity of CVC is less well documented in patients with chronic kidney disease (CKD) not yet on dialysis. Fifty-eight nondialyzed HA with type 2 diabetes and CKD were enrolled. They comprise 29 patients with stages 1 and 2 CKD (early CKD group) and 26 patients with stages 4 and 5 CKD (advanced CKD group). Coronary artery calcification (CAC) was measured by ultrafast spiral computed tomography, while peripheral artery calcification (PAC) was evaluated by plain x-ray of the chest, pelvis, thighs, and lower extremities. The prevalence of CAC and PAC were significantly higher in the advanced CKD group compared to the early CKD group (73% vs. 38%; P < 0.01 and 85% vs. 35%; P < 0.0001, respectively). The median CAC scores were 18-fold greater in the advanced CKD group (138.9 vs. 7.8, respectively). By linear regression analysis, a strong association was found between the level of renal function and ln total volume of CAC. Our data indicate that CAC and PAC are common and severe in HA diabetic patients with CKD not previously treated with dialysis, calcium-based phosphate binders, or vitamin D analogues. Lower level of renal function is associated with increased burden of vascular calcification in predialysis patients with CKD.
  Kidney International 07/2005; 68(1):271-7. · 6.61 Impact Factor
• Article: A single nucleotide polymorphism in MGEA5 encoding O-GlcNAc-selective N-acetyl-beta-D glucosaminidase is associated with type 2 diabetes in Mexican Americans.

  Donna M Lehman, Dong-Jing Fu, Angela B Freeman, Kelly J Hunt, Robin J Leach, Teresa Johnson-Pais, Jeanette Hamlington, Thomas D Dyer, Rector Arya, Hanna Abboud, Harald H H Göring, Ravindranath Duggirala, John Blangero, Robert J Konrad, Michael P Stern
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  ABSTRACT: Excess O-glycosylation of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) may be involved in the pathogenesis of type 2 diabetes. The enzyme O-GlcNAc-selective N-acetyl-beta-d glucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10q24.1-q24.3 reverses this modification by catalyzing the removal of O-GlcNAc. We have previously reported the linkage of type 2 diabetes and age at diabetes onset to an overlapping region on chromosome 10q in the San Antonio Family Diabetes Study (SAFADS). In this study, we investigated menangioma-expressed antigen-5 (MGEA5) as a positional candidate gene. Twenty-four single nucleotide polymorphisms (SNPs), identified by sequencing 44 SAFADS subjects, were genotyped in 436 individuals from 27 families whose data were used in the original linkage report. Association tests indicated significant association of a novel SNP with the traits diabetes (P = 0.0128, relative risk = 2.77) and age at diabetes onset (P = 0.0017). The associated SNP is located in intron 10, which contains an alternate stop codon and may lead to decreased expression of the 130-kDa isoform, the isoform predicted to contain the O-GlcNAcase activity. We investigated whether this variant was responsible for the original linkage signal. The variance attributed to this SNP accounted for approximately 25% of the logarithm of odds. These results suggest that this variant within the MGEA5 gene may increase diabetes risk in Mexican Americans.
  Diabetes 05/2005; 54(4):1214-21. · 8.29 Impact Factor
• Article: Bivariate linkage analysis of the insulin resistance syndrome phenotypes on chromosome 7q.

  Donna M Lehman, Rector Arya, John Blangero, Laura Almasy, Sobha Puppala, Thomas D Dyer, Robin J Leach, Peter O'Connell, Michael P Stern, Ravindranath Duggirala
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  ABSTRACT: Metabolic abnormalities of the insulin resistance syndrome (IRS) have been shown to aggregate in families and to exhibit trait-pair correlations, suggesting a common genetic component. A broad region on chromosome 7q has been implicated in several studies to contain loci that cosegregate with IRS-related traits. However, it is not clear whether such loci have any common genetic (pleiotropic) influences on the correlated traits. Also, it is not clear whether the chromosomal regions contain more than one locus influencing the IRS-related phenotypes. In this study we present evidence for linkage of five IRS-related traits [body mass index (BMI), waist circumference (WC), In split proinsulin (LSPI), In triglycerides (LTG), and high-density lipoprotein cholesterol (HDLC)] to a region at 7q11.23. Subsequently, to gain further insight into the genetic component(s) mapping to this region, we explored whether linkage of these traits is due to pleiotropic effects using a bivariate linkage analytical technique, which has been shown to localize susceptibility regions with precision. Four hundred forty individuals from 27 Mexican American families living in Texas were genotyped for 19 highly polymorphic markers on chromosome 7. Multipoint variance component linkage analysis was used to identify genetic location(s) influencing IRS-related traits of obesity (BMI and WC), dyslipidemia (LTG and HDLC), and insulin levels (LSPI); the analysis identified a broad chromosomal region spanning approximately 24 cM. To gain more precision in localization, we used a bivariate linkage approach for each trait pair. These analyses suggest localization of most of these bivariate traits to an approximately 6-cM region near marker D7S653 [7q11.23, 103-109 cM; a maximum bivariate LOD of 4.51 was found for the trait pair HDLC and LSPI (the LODeq score is 3.94)]. We observed evidence of pleiotropic effects in this region on obesity and insulin-related trait pairs.
  Human Biology 05/2005; 77(2):231-46. · 1.31 Impact Factor
• Article: Effect of genotype × alcoholism interaction on linkage analysis of an alcoholism-related quantitative phenotype

  Rector Arya, Thomas Dyer, Diane Warren, Christopher Jenkinson, Ravindranath Duggirala, Laura Almasy
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  ABSTRACT: Abstract Studies have shown that genetic and environmental factors and their interactions affect several alcoholism phenotypes. Genotype × alcoholism (G×A) interaction refers to the environmental (alcoholic and non-alcoholic) influences on the autosomal genes contributing to variation in an alcoholism-related quantitative phenotype. The purpose of this study was to examine the effects of G×A interaction on the detection of linkage for alcoholism-related phenotypes. We used phenotypic and genotypic data from the Collaborative Study on the Genetics of Alcoholism relating to 1,388 subjects as part of Genetic Analysis Workshop 14 problem 1. We analyzed the MXDRNK phenotype to detect G×A interaction using SOLAR. Upon detecting significant interaction, we conducted variance-component linkage analyses using microsatellite marker data. For maximum number of drinks per a 24 hour period, the highest LODs were observed on chromosomes 1, 4, and 13 without G×A interaction. Interaction analysis yielded four regions on chromosomes 1, 4, 13, and 15. On chromosome 4, a maximum LOD of 1.5 at the same location as the initial analysis was obtained after incorporating G×A interaction effects. However, after correcting for extra parameters, the LOD score was reduced to a corrected LOD of 1.1, which is similar to the LOD observed in the non-interaction analysis. Thus, we see little differences in LOD scores, while some linkage regions showed large differences in the magnitudes of estimated quantitative trait loci heritabilities between the alcoholic and non-alcoholic groups. These potential hints of differences in genetic effect may influence future analyses of variants under these linkage peaks.
  BMC Genetics. 01/2005;