The incidence of type 2 diabetes (T2DM) continues to rise and increasingly affects individuals of all ages across all ethnic groups; however, individuals from certain ethnic groups including Mexican Americans have an increased propensity towards developing T2DM. The increased risk of T2DM in Mexican Americans may indicate an increased genetic susceptibility. Hence, we performed a genome-wide linkage scan to localize those genes in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), an extended pedigree study comprised of 39 Mexican Americans families with 906 individuals. Using follow-up data which used each subject's most recent diabetic status, we observed significant evidence for linkage of the traits diabetes and diabetes age-of-onset to a genetic region on chromosome 3p (empirical multipoint LOD score of 3.76, p=0.000016). This region has previously been implicated by numerous independent studies to be linked to diabetes and related traits. In addition, we have recently observed the expression profiles of known and novel transcripts from this region to be highly correlated with diabetes risk in an independent, large study of Mexican Americans. Therefore, there is growing evidence that this region may harbor a gene influencing susceptibility to T2DM and deserves exploration. The 1.5-LOD support interval around our peak spans an approximately 15 Mb region and harbors approximately 59 identified genes and ESTs. A number of these genes appear to have biologic relevance to the pathophysiology of diabetes, whereas the function of many is still unknown. This proposal aims to identify the gene(s) in this region that influences diabetes susceptibility and/or diabetes age-of-onset by identifying DNA sequence variants that are associated with diabetes and account for the observed linkage signal. In order to efficiently and thoroughly investigate this locus, we will conduct association tests for variants at intervals of approximately 1 per 1.6 kilobases (Specific Aim 1). We will also conduct comprehensive analyses of candidate genes in the region (Specific Aim 2). In addition, the utilization of a novel statistical functional genomic analysis (BQTN) in the 3rd specific aim of this proposal should enhance the final stage of identifying the specific variants involved. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK070746-02
Application #
7477192
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Mckeon, Catherine T
Project Start
2007-08-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$442,052
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Winnier, Deidre A; Fourcaudot, Marcel; Norton, Luke et al. (2015) Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). PLoS One 10:e0119941
Blackburn, August; Almeida, Marcio; Dean, Angela et al. (2015) Effects of copy number variable regions on local gene expression in white blood cells of Mexican Americans. Eur J Hum Genet 23:1229-35
Farook, Vidya S; Coletta, Dawn K; Puppala, Sobha et al. (2013) Linkage of type 2 diabetes on chromosome 9p24 in Mexican Americans: additional evidence from the Veterans Administration Genetic Epidemiology Study (VAGES). Hum Hered 76:36-46
Blackburn, August; Goring, Harald H H; Dean, Angela et al. (2013) Utilizing extended pedigree information for discovery and confirmation of copy number variable regions among Mexican Americans. Eur J Hum Genet 21:404-9
Beuten, Joke; Halder, Indrani; Fowler, Sharon P et al. (2011) Wide disparity in genetic admixture among Mexican Americans from San Antonio, TX. Ann Hum Genet 75:529-38
Puppala, Sobha; Coletta, Dawn K; Schneider, Jennifer et al. (2011) 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. Hum Hered 71:1-10
Coletta, Dawn K; Schneider, Jennifer; Hu, Shirley L et al. (2009) Genome-wide linkage scan for genes influencing plasma triglyceride levels in the Veterans Administration Genetic Epidemiology Study. Diabetes 58:279-84