Type 2 diabetes is a major clinical and public health problem, especially in African Americans. The overall objective of this application is to identify novel loci that may partially account for excess risk of type 2 diabetes in African Americans compared to whites. We will employ Mapping by Admixture Linkage Disequilibrium (MALD) analysis, a specialized form of linkage disequilibrium mapping, to perform a genome-wide MALD analysis in a case-control study nested within the Atherosclerosis Risk in Communities (ARIC) study, a community-based prospective cohort study of the natural history of atherosclerosis. For the proposed MALD analysis, cases will be all African-American ARIC participants with type 2 diabetes (N = 1,238), and controls will be 1,238 age-matched African-American ARIC participants without type 2 diabetes. We hypothesize that some susceptibility alleles for type 2 diabetes are present at a higher frequency in African Americans than in whites and that specific regions of the genome in African Americans contain marker alleles that are in admixture linkage disequilibrium with type 2 diabetes susceptibility alleles. To test this hypothesis, we will: (1) genotyping 1,536 highly informative African-American MALD markers (~2 cM average spacing) in DNA from 2,476 African-American ARIC participants using the Center for Inherited Disease Research (CIDR) Human Custom Single Nucleotide Polymorphism (SNP) Genotyping Facility; (2) perform a genome-wide MALD analysis using the aforementioned scan to identify regions that are in admixture linkage disequilibrium with type 2 diabetes; and (3) follow up and confirm the most promising putative chromosomal regions with more densely-spaced SNPs. The proposed genetic analyses are innovative and complementary to the more traditional linkage and candidate gene techniques. The Principal Investigator has assembled a team of experts in all components of this research. This application explores the utility of MALD, a novel mapping technique, to identify type 2 diabetes susceptibility genes. Although this methodology is high risk, it also holds high promise for future genetics studies of type 2 diabetes and other complex traits. Detection of susceptibility genes for type 2 diabetes is a daunting challenge. Findings from this study will not only provide key insights into a new methodology for mapping genes, but will also lead to a better understanding of the genes that control type 2 diabetes susceptibility, a problem with high relevance in African Americans. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK073482-01
Application #
7015679
Study Section
Special Emphasis Panel (ZRG1-HOP-N (90))
Program Officer
Mckeon, Catherine T
Project Start
2006-02-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$238,396
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Foster, Meredith C; Coresh, Josef; Fornage, Myriam et al. (2013) APOL1 variants associate with increased risk of CKD among African Americans. J Am Soc Nephrol 24:1484-91
Cheng, Ching-Yu; Reich, David; Haiman, Christopher A et al. (2012) African ancestry and its correlation to type 2 diabetes in African Americans: a genetic admixture analysis in three U.S. population cohorts. PLoS One 7:e32840
Maruthur, Nisa M; Kao, W H Linda; Clark, Jeanne M et al. (2011) Does genetic ancestry explain higher values of glycated hemoglobin in African Americans? Diabetes 60:2434-8
Deo, Rahul C; Wilson, James G; Xing, Chao et al. (2011) Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans. PLoS One 6:e14581
Cheng, Ching-Yu; Reich, David; Wong, Tien Y et al. (2010) Admixture mapping scans identify a locus affecting retinal vascular caliber in hypertensive African Americans: the Atherosclerosis Risk in Communities (ARIC) study. PLoS Genet 6:e1000908
Cheng, Ching-Yu; Reich, David; Coresh, Josef et al. (2010) Admixture mapping of obesity-related traits in African Americans: the Atherosclerosis Risk in Communities (ARIC) Study. Obesity (Silver Spring) 18:563-72
Reich, David; Nalls, Michael A; Kao, W H Linda et al. (2009) Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet 5:e1000360
Cheng, Ching-Yu; Kao, W H Linda; Patterson, Nick et al. (2009) Admixture mapping of 15,280 African Americans identifies obesity susceptibility loci on chromosomes 5 and X. PLoS Genet 5:e1000490
Kottgen, Anna; Hsu, Charles C; Coresh, Josef et al. (2008) The association of podocin R229Q polymorphism with increased albuminuria or reduced estimated GFR in a large population-based sample of US adults. Am J Kidney Dis 52:868-75