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

J Clin Endocrinol Metab. 2009 Feb;94(2):449-55. doi: 10.1210/jc.2008-1583. Epub 2008 Nov 18.


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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Chromans / administration & dosage
  • Combined Modality Therapy
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Exercise Therapy
  • Female
  • Gene Frequency
  • Genetic Linkage
  • Genetic Predisposition to Disease / epidemiology*
  • Genetic Predisposition to Disease / prevention & control*
  • Glutamic Acid / genetics
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Incidence
  • Lysine / genetics
  • Male
  • Metformin / administration & dosage
  • Middle Aged
  • Phosphoric Diester Hydrolases / genetics*
  • Polymorphism, Single Nucleotide
  • Pyrophosphatases / genetics*
  • Risk Reduction Behavior*
  • Thiazolidinediones / administration & dosage
  • Troglitazone


  • Chromans
  • Hypoglycemic Agents
  • Thiazolidinediones
  • Glutamic Acid
  • Metformin
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases
  • Troglitazone
  • Lysine