The goal of this proposal is to identify genes that contribute to cardiovascular disease (CVD) in people with diabetes. Diabetes is a profound influence on CVD development. The focus of this study is subclinical measures of CVD: vascular calcified plaque and carotid atherosclerosis. In the first phase of the Diabetes Heart Study we successfully recruited and extensively phenotyped 1443 subjects in 564 families with multiple type 2 diabetes (T2DM) affected subjects. This created a unique data resource for the study of CVD and other related traits in a diabetes-enriched (85%) population. Extensive genetic and epidemiological analyses were performed. These results provide a strong foundation for the proposed identification of important genes using a Genome Wide Association Study (GWAS) approach.
Specific Aims are: 1). GWAS genotyping and analysis of subjects from the Diabetes Heart Study. The entire European American sample will be genotyped on the Affymetrix SNP Array 6.0 platform. A comprehensive analysis of the genotypic data will be carried out to identify loci/genes associated with the primary measures of subclinical CVD of vascular calcified plaque and carotid wall thickness. 2). Replication and meta analyses of coronary calcified plaque and carotid wall thickness. A meta analysis of European American samples with GWAS data for coronary calcified plaque and, where possible, carotid wall thickness, will be performed in the Framingham Heart Study, Genetic Epidemiology Network of Arteriopathy (GENOA), Amish Family Calcification Study (AFCS), and the Diabetes Heart Study. 3). High scoring polymorphisms from Aims 2 will be evaluated for replication in other study samples to further test for association with: a) prevalent CVD in European Americans, b) subclinical CVD in other ethnicities/races, and c) prevalent CVD in other ethnicities/races. 4). Intensive molecular genetic analysis, novel analytic, and bioinformatic approaches will be used to identify trait influencing variants. The best replicated loci from the Aims 2 &3 will be subjected to additional genotyping (if appropriate) and resequencing to clearly define risk loci. Innovative analysis approaches will be used to define trait associated variants. We have assembled an experienced, highly productive, interdisciplinary team to perform this promising study.

Public Health Relevance

In this research study, genes which contribute to heart disease in people with diabetes will be identified.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092301-04
Application #
8441612
Study Section
Special Emphasis Panel (ZRG1-PSE-A (02))
Program Officer
Jaquish, Cashell E
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$630,209
Indirect Cost
$204,392
Name
Wake Forest University Health Sciences
Department
Biochemistry
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Cox, Amanda J; Azeem, Amir; Yeboah, Joseph et al. (2014) Heart rate-corrected QT interval is an independent predictor of all-cause and cardiovascular mortality in individuals with type 2 diabetes: the Diabetes Heart Study. Diabetes Care 37:1454-61
Cox, Amanda J; Hsu, Fang-Chi; Ng, Maggie C Y et al. (2014) Genetic risk score associations with cardiovascular disease and mortality in the Diabetes Heart Study. Diabetes Care 37:1157-64
Cox, Amanda J; Hugenschmidt, Christina E; Raffield, Laura M et al. (2014) Heritability and genetic association analysis of cognition in the Diabetes Heart Study. Neurobiol Aging 35:1958.e3-1958.e12
Cox, Amanda J; Hsu, Fang-Chi; Freedman, Barry I et al. (2014) Contributors to mortality in high-risk diabetic patients in the Diabetes Heart Study. Diabetes Care 37:2798-803
Raffield, Laura M; Agarwal, Subhashish; Cox, Amanda J et al. (2014) Cross-sectional analysis of calcium intake for associations with vascular calcification and mortality in individuals with type 2 diabetes from the Diabetes Heart Study. Am J Clin Nutr 100:1029-35
Adams, Jeremy N; Raffield, Laura M; Freedman, Barry I et al. (2014) Analysis of common and coding variants with cardiovascular disease in the Diabetes Heart Study. Cardiovasc Diabetol 13:77
Cox, Amanda J; Hsu, Fang-Chi; Carr, J Jeffrey et al. (2013) Glomerular filtration rate and albuminuria predict mortality independently from coronary artery calcified plaque in the Diabetes Heart Study. Cardiovasc Diabetol 12:68
Agarwal, Subhashish; Cox, Amanda J; Herrington, David M et al. (2013) Coronary calcium score predicts cardiovascular mortality in diabetes: diabetes heart study. Diabetes Care 36:972-7
Cox, Amanda J; Hugenschmidt, Christina E; Wang, Patty T et al. (2013) Usefulness of biventricular volume as a predictor of mortality in patients with diabetes mellitus (from the Diabetes Heart Study). Am J Cardiol 111:1152-8
Raffield, Laura M; Cox, Amanda J; Hsu, Fang-Chi et al. (2013) Impact of HDL genetic risk scores on coronary artery calcified plaque and mortality in individuals with type 2 diabetes from the Diabetes Heart Study. Cardiovasc Diabetol 12:95

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