The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations

OBJECTIVE—Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) may confer susceptibility to insulin resistance; genetic evidence on its effect on type 2 diabetes, however, has been conflicting. We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes. RESEARCH DESIGN AND METHODS—After a systematic review of the literature, we evaluated the effect of ENPP1 K121Q on diabetes risk under three genetic models using a random-effects approach. Our primary analysis consisted of 30 studies comprising 15,801 case and 26,241 control subjects. Due to considerable heterogeneity and large differences in allele frequencies across populations, we limited our meta-analysis to those of self-reported European descent and, when available, included BMI as a covariate. RESULTS—We found a modest increase in risk of type 2 diabetes for QQ homozygotes in white populations (combined odds ratio [OR] 1.38 [95% CI 1.10–1.74], P = 0.005). There was no evidence of publication bias, but we noted significant residual heterogeneity among studies (P = 0.02). On meta-regression, 16% of the effect was accounted for by the mean BMI of control subjects. This association was stronger in studies in which control subjects were leaner but disappeared after adjustment for mean control BMI (combined OR 0.93 [95% CI 0.75–1.15], P = 0.50). CONCLUSIONS—The ENPP1 Q121 variant increases risk of type 2 diabetes under a recessive model of inheritance in whites, an effect that appears to be modulated by BMI.