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

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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.

authors

  • Meyre, David Jean-Claude
  • 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

publication date

  • August 2005