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No Evidence of Association of ENPP1 Variants With Type 2 Diabetes or Obesity in a Study of 8,089 U.K. Caucasians

¹ Department of Diabetes Research and Vascular Medicine, Peninsula Medical School, Exeter, U.K
² Centre of Diabetes and Metabolic Medicine, Barts and the London, Queen Mary School of Medicine and Dentistry, University of London, London, U.K
³ Department of Medicine, School of Medicine, Newcastle upon Tyne, U.K
⁴ Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, U.K

Address correspondence and reprint requests to Dr. Tim Frayling, Molecular Genetics, Peninsula Medical School, Barrack Road, Exeter, EX2 5DW, U.K. E-mail: t.m.frayling{at}exeter.ac.uk

Abbreviations: SNP, single nucleotide polymorphism

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) is an inhibitor of insulin-induced activation of the insulin receptor. There is strong evidence from several previous studies that a common coding variant of ENPP1 (K121Q) and a three-marker haplotype (Q121, IVS20delT-11, and G+1044TGA) are associated with type 2 diabetes and obesity. We examined the impact of ENPP1 variation on type 2 diabetes and obesity in a large U.K. genetic association study. We genotyped the three previously associated polymorphisms in 2,363 type 2 diabetic case and 4,045 control subjects, as well as 1,681 subjects from 529 type 2 diabetic families. We used the same subjects for morbid and moderate obesity association studies. For type 2 diabetes, moderate and morbid obesity, and for both the Q121 and three-marker haplotype, our results exclude with >95% confidence the effect sizes from previous studies (Q121 allele: odds ratio 1.02 [95% CI 0.93–1.12], P = 0.61; 1.00 [0.85–1.18], P = 0.99; and 0.92 [0.70–1.20], P = 0.41; three-marker haplotype: 1.10 [0.96–1.26], P = 0.17; 0.97 [0.77–1.23], P = 0.81; and 0.86 [0.57–1.30], P = 0.46 for type 2 diabetes, moderate, and morbid obesity, respectively). A K121Q type 2 diabetes meta-analysis of all previously published studies remained significant after the inclusion of this study (1.25 [1.10–1.43], P = 0.0007), although there was some evidence of publication bias. In conclusion, we find no evidence that previously associated variants of ENPP1 are associated with type 2 diabetes or obesity in the U.K. population.

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