ENPP1 Variants and Haplotypes Predispose to Early Onset Obesity and Impaired Glucose and Insulin Metabolism in German Obese Children

Abstract

Context:ENPP1 (nucleotide pyrophosphatase/phosphodiesterase-1) encodes a membrane-bound glycoprotein that inhibits the insulin-receptor tyrosine kinase activity, resulting in reduced insulin sensitivity. Hence, variants in this gene may be related to obesity and insulin resistance.

Objective: Therefore, in this study, we aimed to explore the role of ENPP1 genetic variants in obesity and related traits in a representative population of Caucasian children and in cohorts of obese children with detailed metabolic characteristics including oral glucose tolerance test.

Design: We genotyped the K121Q, IVS20delT-11, and A/G+1044TGA ENPP1 genetic variants for association analyses in 712 schoolchildren (346 boys and 366 girls; mean age 12 ± 3 yr; mean body mass index-sd score 0.09 ± 0.04) and in independent cohorts of 205 obese children from Leipzig and 195 obese children from Datteln, Germany.

Results: We identified a significantly increased risk of obesity in Leipzig children carrying the 121Q variant (adjusted odds ratio, 1.82; 95% confidence interval, 1.30–2.56; P = 0.0005) or the [Q-delT-G] haplotype [1.75 (1.17–2.62), P = 0.006] as compared with a lean control group. This was replicated in another independent obesity/overweight cohort from Leipzig as well as obese children from Datteln. In addition, obese children from Leipzig with the [Q-delT-G] haplotype were characterized by impaired glucose metabolism, whereas the [K-delT-G] and [K-insT-A] haplotypes were significantly associated with improved insulin sensitivity and glucose metabolism (all P < 0.05 after adjusting for age, gender, and body mass index).

Conclusions: In conclusion, our study suggests a potential role of the K121Q polymorphism or derived ENPP1 haplotypes in increased susceptibility to obesity and early impairment of glucose and insulin metabolism in children.