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Comprehensive Association Study of Type 2 Diabetes and Related Quantitative Traits with 222 Candidate Genes

¹Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
²Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI
³Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD
⁴Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
⁵Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore MD
⁶Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
⁷Department of Public Health, University of Helsinki, Helsinki, Finland
⁸South Ostrobothnia Central Hospital, Seinäjoki, Finland
⁹Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA

Objective: Type 2 diabetes (T2D) is a common complex disorder with environmental and genetic components. We used a candidate gene-based approach to identify single nucleotide polymorphism (SNP) variants in 222 candidate genes that influence susceptibility to T2D.

Research Design and Method: In a case-control study of 1,161 T2D and 1,174 normal glucose tolerant (NGT) control Finns, we genotyped 3,531 tagSNPs and annotation-based SNPs and imputed an additional 7,498 SNPs, providing 99.9% coverage of common HapMap variants in the 222 candidate genes. Selected SNPs were genotyped in an additional 1,211 T2D cases and 1,259 NGT controls, also from Finland.

Results: Using SNP and gene-based analysis methods, we replicated previously reported SNP- T2D associations in PPARG, KCNJ11, and SLC2A2, identified significant SNPs in genes with previously reported associations, ENPP1 (rs2021966, p=.00026) and NRF1 (rs1882095, p=.00096), and implicated novel genes in T2D susceptibility including RAPGEF1 (rs4740283, p=.00013) and TP53 (rs1042522; Arg72Pro, p=.00086).

Conclusion: Our study provides an effective gene-based approach to association study design and analysis. One or more of the newly implicated genes may contribute to T2D pathogenesis; analysis of additional samples will be necessary to determine their effect on susceptibility.

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Stephen S. Rich, Jill M. Norris, and Jerome I. Rotter
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				S. S. Rich, J. M. Norris, and J. I. Rotter Genes Associated With Risk of Type 2 Diabetes Identified by a Candidate-Wide Association Scan: As a Trickle Becomes a Flood Diabetes, November 1, 2008; 57(11): 2915 - 2917. [Full Text] [PDF]