The association of ENPP1 K121Q with diabetes incidence is abolished by lifestyle modification in the diabetes prevention program.

Moore, Allan F; Jablonski, Kathleen A; Mason, Clinton C; McAteer, Jarred B; Arakaki, Richard F; Goldstein, Barry J; Kahn, Steven E; Kitabchi, Abbas E; Hanson, Robert L; Knowler, William C; Florez, Jose C; Diabetes Prevention Program Research Group

<bold>Context: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.

TYPE 2 diabetes prevention; BEHAVIOR; BENZOPYRANS; COMBINED modality therapy; COMPARATIVE studies; DISEASE susceptibility; ESTERASES; EXERCISE therapy; GENES; GENETIC polymorphisms; GENETICS; GLUTAMIC acid; HYDROLASES; HYPOGLYCEMIC agents; LYSINE; RESEARCH methodology; MEDICAL cooperation; TYPE 2 diabetes; RESEARCH; RESEARCH funding; EVALUATION research; RANDOMIZED controlled trials; DISEASE incidence; METFORMIN; THIAZOLIDINEDIONES

Journal of Clinical Endocrinology & Metabolism, 2009, Vol 94, Issue 2, p449

0021-972X

Academic Journal

10.1210/jc.2008-1583