The objective of Project 1 is to detect, map and characterize genes that contribute to variation in risk of cardiovascular disease (CVD). The focus in this Program Project (the San Antonio Family Heart Study, SAFHS) is on extended Mexican American families ascertained without regard to disease status. Each of the -1400 family members has been genotyped for >400 microsatellite markers in an 8 centimorgan map. In the current grant period significant evidence has been obtained for QTLs that influence HDL-C and other lipoprotein measures; phenotypes related to metabolic syndrome, diabetes, and insulin; obesity-related traits; phenotypes related to blood pressure and its change with age; and several novel CVD-related phenotypes, including risk of infection with Chlamydia pneumoniae. Identification of the functional alleles for a few of the best characterized of these genes will be pursued in Projects 2 and 3, and novel candidate genes will be identified in Project 4. In Project 1, taking advantage of the resource of extensive genotypic and phenotypic data that has been created in the past 15 years as well as a wealth of newly generated expression data and a 550K SNP panel currently being genotyped under other funding, we will (1) utilize the longitudinal data to investigate the genetic basis of phenotypic change, and in particular, to ask whether QTLs identified through analyses of cross-sectional data also influence change over time. (2) perform multivariate analyses of newly available transcript data that yield more than 20,000 quantitative expression phenotypes, and a set of carefully selected CVD risk factors and environmental variables to generate hypotheses concerning gene action. (3) conduct genome-wide association screens with a 550K SNP panel for clinically important traits with significant heritabilities for which no QTLs have yet been localized in the SAFHS. (4) use association with a dense set of SNPs, drawn from the 550K SNP panel, to follow-up suggestive linkage peaks from the current grant period. Thus, Project 1 will be devoted to follow-up of intriguing findings from the current grant period; detection of new QTLs in analyses of newly-available data; genetic analyses of age-related changes in risk factors; and genetic analysis of new risk factors, including information on levels of 20,000+ transcripts.

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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