Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program
- Kathleen A. Jablonski1,
- Jarred B. McAteer2,3,
- Paul I.W. de Bakker3,4,5,
- Paul W. Franks6,
- Toni I. Pollin7,
- Robert L. Hanson8,
- Richa Saxena2,3,
- Sarah Fowler1,
- Alan R. Shuldiner7,9,
- William C. Knowler8,
- David Altshuler2,3,4,10,11,
- Jose C. Florez2,3,4,11 and
- for the Diabetes Prevention Program Research Group*
- 1The Biostatistics Center, George Washington University, Rockville, Maryland;
- 2Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts;
- 3Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts;
- 4Department of Medicine, Harvard Medical School, Boston, Massachusetts;
- 5Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
- 6Genetic Epidemiology and Clinical Research Group, the Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University Hospital, Umeå, Sweden, and the Department of Clinical Sciences, Lund University, Malmö, Sweden;
- 7Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland;
- 8Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona;
- 9Geriatrics Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland;
- 10Department of Genetics, Harvard Medical School, Boston, Massachusetts;
- 11Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
- Corresponding author: Jose C. Florez, .
OBJECTIVE Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions.
RESEARCH DESIGN AND METHODS We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates.
RESULTS We replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09–1.40, P = 7 × 10−4). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates.
CONCLUSIONS We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples.
*A list of the Diabetes Prevention Program Research Group investigators is provided in the online appendix, available at http://diabetes.diabetesjournals.org/cgi/content/full/db10-0543/DC1.
The opinions expressed in this article are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies.
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- Received April 18, 2010.
- Accepted July 18, 2010.
- © 2010 by the American Diabetes Association.
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