Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes

We identified a childhood obesity locus on chromosome 6q16.3-q24.21 that includes 2.4 Mb common to eight genome scans for Type 2 diabetes (T2D) or obesity1-8. Analysis of the ENPP1 (PC-1) gene, a candidate for insulin resistance9,10 in 6,147 subjects revealed association between a three allele risk...

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Main Authors: Meyre, David, Bouatia-Naji, Nabila, Tounian, Agnès, Samson, Chantal, Lecoeur, Cécile, Vatin, Vincent, Ghoussaini, Maya, Wachter, Christophe, Hercberg, Serge, Charpentier, Guillaume, Patsch, Wolfgang, Pattou, François, Charles, Marie-Aline, Tounian, Patrick, Clément, Karine, Jouret, Béatrice, Weill, Jacques, Maddux, Betty A., Goldfine, Ira D., Walley, Andrew, Boutin, Philippe, Dina, Christian, Froguel, Philippe
Formato: Artigo
Idioma:English
Publicado em: 2005
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Article
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC2000804/
https://ncbi.nlm.nih.gov/pubmed/16025115
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1038/ng1604
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Resumo:We identified a childhood obesity locus on chromosome 6q16.3-q24.21 that includes 2.4 Mb common to eight genome scans for Type 2 diabetes (T2D) or obesity1-8. Analysis of the ENPP1 (PC-1) gene, a candidate for insulin resistance9,10 in 6,147 subjects revealed association between a three allele risk haplotype (K121Q/IVS20 delT-11/A>G +1044 TGA, QdelTG) and childhood obesity (OR=1.69, p=0.0006), and in adults with morbid or moderate obesity (OR= 1.50, p= 0.006, OR= 1.37, p= 0.02) and also with T2D (OR=1.56, p=0.00002). The Genotype IBD Sharing Test suggested a contribution of this obesity-associated ENPP1 risk haplotype to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and to 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 +1044 TGA SNP, was found to be specific for pancreatic islet beta-cells, adipocytes and liver. These findings suggest a primary role for several variants of ENPP1 in mediating insulin-resistance, in the development of both obesity and type 2 diabetes, suggesting an underlying molecular mechanism common to both widespread afflictions.