Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program

Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program Allan F. Moore 1 2 3 4 † , Kathleen A. Jablonski 5 , Jarred B. McAteer 1 4 , Richa Saxena 1 4 , Toni I. Pollin 6 , Paul W. Franks 7 , Robert L. Hanson 8 , Alan R. Shuldiner 6 , William C. Knowler 8 , David Altshuler 1 2 3 4 9 , Jose C. Florez 1 2 3 4 and for the Diabetes Prevention Program Research Group 1 Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 2 Diabetes Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts 4 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 5 The Biostatistics Center, George Washington University, Rockville, Maryland 6 Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 7 Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University Hospital, Umeå, Sweden 8 Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona 9 Department of Genetics, Harvard Medical School, Boston, Massachusetts Corresponding author: Jose C. Florez, dppmail{at}biostat.bsc.gwu.edu Abstract OBJECTIVE— Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo. RESEARCH DESIGN AND METHODS— We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2 , CDKAL1 , CDKN2A/B , IGF2BP2 , HHEX , LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year. RESULTS— None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baselin