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

David Meyre 1 Nabila Bouatia-Naji 2 Agnès Tounian 3 Chantal Samson 1, 4, 5 Cécile Lecoeur 1 Vincent Vatin 1 Maya Ghoussaini 1 Christophe Wachter 2 Serge Hercberg 6 Guillaume Charpentier 7 Wolfgang Patsch 8 François Pattou 9 Marie-Aline Charles 10, 11, 12 Patrick Tounian 13 Karine Clément 1, 14, 15, 16, 17 Béatrice Jouret 9 Jacques Weill 18, 19 Betty A Maddux 20 Ira D Goldfine 20 Andrew Walley 21 Philippe Boutin 1 Christian Dina 1 Philippe Froguel 1, 22, 23 
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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Submitted on : Tuesday, January 25, 2022 - 3:41:14 PM
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David Meyre, Nabila Bouatia-Naji, Agnès Tounian, Chantal Samson, Cécile Lecoeur, et al.. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nature Genetics, 2005, 37 (8), pp.863-7. ⟨10.1038/ng1604⟩. ⟨hal-00174474⟩



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