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

Medical Department III (Y.B., B.E., M.S., P.K.), University Hospital for Children and Adolescents (A.K., W.K.), University of Leipzig, D-04103 Leipzig, Germany; and Vestische Hospital for Children and Adolescents Datteln (T.R.), University of Witten/Herdecke, D- 45711 Datteln, Germany

Address all correspondence and requests for reprints to: Peter Kovacs, Ph.D., Medical Department III, University of Leipzig, Philipp-Rosenthal-Strasse 27, D-04103 Leipzig, Germany. E-mail: peter.kovacs{at}medizin.uni-leipzig.de.

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.

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