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, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 ( P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in β-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment ( P = 0.01) and possibly lifestyle modification ( P = 0.05). CONCLUSIONS— We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B . Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 10 June 2008. Clinical trial reg. no. NCT00004992, clinicaltrials.gov. A complete list of Diabetes Prevention Program Research Group investigators is provided in the online appendix available at http://dx.doi.org/10.2337/db08-0284 . † † Dr. Allan F. Moore passed away on 24 July 2008. This article, to which he contributed his privileged intellect and unwavering enthusiasm, is dedicated to his memory. His colleagues and peers will miss him. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 1, 2008. Received February 28, 2008. DIABETES