THE ENPP1 K121Q POLYMORPHISM IS ASSOCIATED WITH TYPE 2 DIABETES IN EUROPEAN POPULATIONS: EVIDENCE FROM AN UPDATED META-ANALYSIS IN 42,042 SUBJECTS
- Jarred B. McAteer1,,2,
- Sabrina Prudente3,,4,
- Simonetta Bacci5,
- Helen N. Lyon2,,6,,7,
- Joel N. Hirschhorn2,,6,,7,
- Vincenzo Trischitta3,,4,,5,,8 and
- Jose C. Florez (jcflorez{at}partners.org) for the ENPP1 Consortium1,,2,,9
- From the 1Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
- 2 the Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- 3 Research Unit of Diabetes and Endocrine Diseases, CSS Scientific Institute, San Giovanni Rotondo, Italy
- 4 CSS-Mendel Institute, Rome, Italy
- 5 Unit of Endocrinology, CSS Scientific Institute, San Giovanni Rotondo, Italy
- 6 Divisions of Genetics and Endocrinology, Children's Hospital Boston, Boston, Massachusetts
- 7 Department of Genetics, Harvard Medical School, Boston, Massachusetts
- 8 Department of Clinical Sciences, Sapienza University of Rome, Rome, Italy; and
- 9 Department of Medicine, Harvard Medical School, Boston, Massachusetts
Abstract
Objective: Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase 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 We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes.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 cases and 26,241 controls. 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 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 controls: this association was stronger in studies in which controls 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 which appears to be modulated by BMI.
Footnotes
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- Received September 19, 2007.
- Accepted November 30, 2007.
- Copyright © American Diabetes Association
