In this project, we propose to use an integrative genomics approach to identify potentially functional regulatory variants in novel candidate genes for cardiovascular disease (CVD) risk. These objectively chosen candidate genes were obtained using large-scale transcriptional profiling of lymphocyte samples from 1,240 San Antonio Family Heart Study (SAFHS) participants. Target candidate loci were nominated based on the existence of significant correlations of quantitative gene expression levels with two major CVD risk factors, HDL-C levels and plasma triglyceride levels. Using our unique family-based resource of quantitative genome-wide transcriptional profiles, we will examine 50 novel candidate genes that exhibit both strong evidence for c/s-regulation of expression levels and significant correlations between expression levels and HDL-C or plasma triglyceride levels. Our prior linkage-based evidence for c/s-acting sequence variation can be exploited as a probabilistic causal anchor to maximize our chance for finding functional variation within proximal promoters. For each of these objectively chosen genes, we will (1) resequence approximately two kilobases of putative promoter region in 182 founder individuals to identify promoter variants; (2) genotype all detected promoter variation in the 1,240 SAFHS samples for which we have transcriptional profiles; (3) test whether promoter sequence variants are associated with gene expression levels of the appropriate candidate gene; (4) test for associations between promoter sequence variants and CVD-related phenotypes; (5) confirm observed associations in two independent samples, and (6) perform molecular functional analysis of the most likely regulatory variants The proposed integrative genomics research paradigm to be used in this project should increase the pace of discovery of the constituent genes of human quantitative trait loci (QTLs) influencing major risk factors for CVD risk. By focusing on genes whose transcripts show evidence for both c/s-regulatory variation and a strong relationship with the focal clinical phenotypes, we should maximize our probability for finding causal players in the CVD risk cascade.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Texas Biomedical Research Institute
San Antonio
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Kulkarni, Hemant; Mamtani, Manju; Wong, Gerard et al. (2017) Genetic correlation of the plasma lipidome with type 2 diabetes, prediabetes and insulin resistance in Mexican American families. BMC Genet 18:48
Mamtani, Manju; Kulkarni, Hemant; Wong, Gerard et al. (2016) Lipidomic risk score independently and cost-effectively predicts risk of future type 2 diabetes: results from diverse cohorts. Lipids Health Dis 15:67
Kulkarni, Hemant; Mamtani, Manju; Peralta, Juan Manuel et al. (2016) Lack of Association between SLC30A8 Variants and Type 2 Diabetes in Mexican American Families. J Diabetes Res 2016:6463214
Hanson, Robert L; Leti, Fatjon; Tsinajinnie, Darwin et al. (2016) The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3. Mol Genet Metab 118:128-37
Mamtani, Manju; Kulkarni, Hemant; Dyer, Thomas D et al. (2016) Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families. Clin Epigenetics 8:6
Kumar, Satish; Curran, Joanne E; Glahn, David C et al. (2016) Utility of Lymphoblastoid Cell Lines for Induced Pluripotent Stem Cell Generation. Stem Cells Int 2016:2349261
Chittoor, Geetha; Kent Jr, Jack W; Almeida, Marcio et al. (2016) GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans. BMC Genomics 17:276
Thameem, Farook; Voruganti, V Saroja; Blangero, John et al. (2015) Evaluation of neurotrophic tyrosine receptor kinase 2 (NTRK2) as a positional candidate gene for variation in estimated glomerular filtration rate (eGFR) in Mexican American participants of San Antonio Family Heart study. J Biomed Sci 22:23
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
Kulkarni, Hemant; Kos, Mark Z; Neary, Jennifer et al. (2015) Novel epigenetic determinants of type 2 diabetes in Mexican-American families. Hum Mol Genet 24:5330-44

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