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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

CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
Nature Genetics (Impact Factor: 29.65). 08/2005; 37(8):863-7. DOI: 10.1038/ng1604
Source: PubMed

ABSTRACT 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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    • "In addition to rs1044498, other ENPP1/PC-1 variants have been reported to modulate insulin resistance-related metabolic disturbances. In a large study [29], a threepolymorphism " risk haplotype " of the ENPP1 gene has been described to be associated with obesity and T2D in both children and adults. This haplotype included the previously reported Q121 allele variant and two functionally uncharacterized noncoding polymorphisms: rs1799774-/T and rs7754561A/G, the latter being located in the 3 í® í° UTR, which might be involved in the modulation of gene expression . "
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