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The Association of ENPP1 K121Q with Diabetes Incidence Is Abolished by Lifestyle Modification in the Diabetes Prevention Program

Center for Human Genetic Research and Department of Medicine (A.F.M., J.B.M., J.C.F.), Massachusetts General Hospital, Boston, Massachusetts 02114-2622; Program in Medical and Population Genetics (A.F.M., J.B.M., J.C.F.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142; Department of Medicine (A.F.M., J.C.F.), Harvard Medical School, Boston, Massachusetts 02115; The Biostatistics Center (K.A.J.), George Washington University, Rockville, Maryland 20852; The National Institute of Diabetes and Digestive and Kidney Diseases (C.C.M., R.L.H., W.C.K.), Phoenix, Arizona 85014; Department of Medicine, Diabetes, and Endocrinology (R.F.A.), University of Hawaii, Honolulu, Hawaii 96813; Division of Endocrinology, Diabetes and Metabolic Diseases (B.J.G.), Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine (S.E.K.), University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98195-5502; and Division of Endocrinology, Diabetes, and Metabolism, University of Tennessee Health Science Center (A.E.K.), Memphis, Tennessee 38163

Address all correspondence and requests for reprints to: Jose C. Florez, M.D., Ph.D., Diabetes Prevention Program Coordinating Center, George Washington University, 6110 Executive Boulevard, Suite 750, Rockville, Maryland 20852. E-mail: dppmail{at}biostat.bsc.gwu.edu and jcflorez{at}partners.org.

Context: Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes.

Objective and Intervention: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP).

Design, Setting, Participants, and Outcome: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence.

Results: Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08–1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99–1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92–1.45), P = 0.20, respectively] but did not reach statistical significance.

Conclusions: ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.

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