Type 2 diabetes is now considered one of the main threats to human health in the 21st century. In this project, we propose to use an integrative genomics approach to identify potentially functional regulatory variants in novel candidate genes for diabetes risk, in a large family based study. These objectively chosen candidate genes were obtained using large-scale transcriptional profiling of lymphocyte samples from 1,240 San Antonio Family Heart Study participants. Target candidate loci were nominated based on the existence of significant correlations of quantitative gene expression levels with fasting glucose levels, a major diabetes risk factor, plus one or more diabetes risk factors including fasting insulin and composite diabetes risk index. Using our unique family-based resource of quantitative genome-wide transcriptional profiles, we will examine 100 novel candidate genes that exhibit both strong evidence for cis-regulation of expression levels and significant correlations between expression levels and diabetes risk phenotypes. Our prior linkage-based evidence for cis-acting sequence variation can be exploited as a probabilistic causal anchor that should 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 each of the 100 candidate genes in the 1,240 SAFHS samples for whom 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 diabetes risk phenotypes;and 5) confirm observed associations in two independent sample populations. The estimated economic burden of diabetes in the United States alone is approximately $100 billion per year, making this disease of major public health importance. The knowledge gained by this project will help contribute to the understanding of the genetics of type 2 diabetes through the identification of novel and potentially functional candidate genes, assisting in the development of new preventative measures and/or therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079169-05
Application #
8089438
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Mckeon, Catherine T
Project Start
2007-08-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$329,294
Indirect Cost
Name
Texas Biomedical Research Institute
Department
Type
DUNS #
007936834
City
San Antonio
State
TX
Country
United States
Zip Code
78245
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
Mamtani, Manju; Meikle, Peter J; Kulkarni, Hemant et al. (2014) Plasma dihydroceramide species associate with waist circumference in Mexican American families. Obesity (Silver Spring) 22:950-6
Mamtani, Manju; Kulkarni, Hemant; Dyer, Thomas D et al. (2014) Increased waist circumference is independently associated with hypothyroidism in Mexican Americans: replicative evidence from two large, population-based studies. BMC Endocr Disord 14:46
Kulkarni, Hemant; Meikle, Peter J; Mamtani, Manju et al. (2014) Plasma lipidome is independently associated with variability in metabolic syndrome in Mexican American families. J Lipid Res 55:939-46
Bellis, Claire; Kulkarni, Hemant; Mamtani, Manju et al. (2014) Human plasma lipidome is pleiotropically associated with cardiovascular risk factors and death. Circ Cardiovasc Genet 7:854-863
Mamtani, M; Kulkarni, H; Dyer, T D et al. (2014) Waist circumference is genetically correlated with incident Type 2 diabetes in Mexican-American families. Diabet Med 31:31-5
Mamtani, Manju; Kulkarni, Hemant; Dyer, Thomas D et al. (2013) Waist circumference independently associates with the risk of insulin resistance and type 2 diabetes in mexican american families. PLoS One 8:e59153
Meikle, Peter J; Wong, Gerard; Barlow, Christopher K et al. (2013) Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PLoS One 8:e74341
Kulkarni, Hemant; Meikle, Peter J; Mamtani, Manju et al. (2013) Variability in associations of phosphatidylcholine molecular species with metabolic syndrome in Mexican-American families. Lipids 48:497-503
Weir, Jacquelyn M; Wong, Gerard; Barlow, Christopher K et al. (2013) Plasma lipid profiling in a large population-based cohort. J Lipid Res 54:2898-908

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