Meyre D, Bouatia-Naji N, Tounian A, Samson C, Lecoeur C, Vatin V et al.. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet 37: 863-867

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
Nature Genetics (Impact Factor: 29.35). 08/2005; 37(8):863-7. DOI: 10.1038/ng1604
Source: PubMed


We identified a locus on chromosome 6q16.3-q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-->G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions.

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    • "use disease under certain circumstances . Although the community put a great deal of effort into genome - wide familial linkage studies during 10 years , only a few T2D putative linked regions were identified through this strategy : CAPN10 ( Hanis et al . , 1996 ) , ADIPOQ ( Vionnet et al . , 2000 ) , HNF4A ( Si - lander et al . , 2004 ) , ENPP1 ( Meyre et al . , 2005 ) , and TCF7L2 ( Grant et al . , 2006 ) . Yet , only the associations of HNF4A and TCF7L2 loci with T2D risk were subsequently replicated by GWAS analyses , casting doubt about the contribution of the others ( Figure 2 ) ( Kooner et al . , 2011 ; Sladek et al . , 2007 ) . Impor - tantly , the hypothesis of major genes involved in common"
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