Coronary Heart Disease (CHD) is a leading cause of morbidity and mortality in the United States and the world. The broad, long-term goal of our research is to dissect the complex genetic architecture of Coronary Heart Disease (CHD), which will subsequently lead to better prediction and treatment of this devastating disease. We hypothesize that amino acid variants, their interactions with each other, and with the environment will play an important role in the complex etiology of CHD. We expect that in order to unravel the genetic architecture of CHD, we must go beyond the additive model. To determine the role of amino acid variants in CHD, we will use a novel approach to acquire genotype data for a comprehensive set of uncommon (0.010.01) amino acid variants in the full ARIC study. We will use whole- exome sequence data in a subset of 1500 ((1000 EA, ~500 AA) participants from the Atherosclerosis Risk in Communities (ARIC) study and an additional 7500 from the NHLBI Exome Sequencing Project (ESP) and the CHARGE-S project in conjunction with GWAS data to impute a comprehensive set of amino acid variants in the entire ARIC cohort. To analytically dissect the complex architecture of lipid profiles and CHD in this subset of SNPs, we will go beyond the simple models used in GWAS screening into more sophisticated models that fall into three categories. First, a single locus model that is generalized to allow the full range of genetic effects (not just additive). Second, two locus models that test for gene-by-gene interactions. Third, test for genotype- by-sex interactions. Sequence uncertainty and imputation probability will be incorporated into each analysis. Using this novel approach, for the first time, a comprehensive set of uncommon to common amino acid variants will be analyzed in a large sample and in multiple ethnic populations for their association with lipid profiles and incident CHD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL105502-03
Application #
8575544
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Hasan, Ahmed AK
Project Start
2011-08-15
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$238,269
Indirect Cost
$68,131
Name
George Washington University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Cao, Ying; Wei, Peng; Bailey, Matthew et al. (2014) A versatile omnibus test for detecting mean and variance heterogeneity. Genet Epidemiol 38:51-9
Xue, Cheng; Liu, Xiaoming; Gong, Yun et al. (2013) Significantly fewer protein functional changing variants for lipid metabolism in Africans than in Europeans. J Transl Med 11:67