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

David Meyre^1, 2, Nabila Bouatia-Naji¹, Agnès Tounian³, Chantal Samson¹, Cécile Lecoeur^1, 2, Vincent Vatin¹, Maya Ghoussaini¹, Christophe Wachter¹, Serge Hercberg⁴, Guillaume Charpentier⁵, Wolfgang Patsch⁶, François Pattou⁷, Marie-Aline Charles⁸, Patrick Tounian⁹, Karine Clément³, Béatrice Jouret¹⁰, Jacques Weill¹¹, Betty A Maddux¹², Ira D Goldfine¹², Andrew Walley², Philippe Boutin¹, Christian Dina¹ & Philippe Froguel^1, 2

¹  CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.

²  Section of Genomic Medicine and Genome Centre, Hammersmith Campus, Du Cane Road, Imperial College London, London W12 0NN, UK.

³  EA3502, Hôtel-Dieu Hospital, Paris, France.

⁴  INSERM U557/INRA U1125, ISTNA, Paris, France.

⁵  Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, France.

⁶  Paracelsus Private Medical School, Salzburg, Austria.

⁷  INSERM ERIT-M 0106, University of Lille 2, Lille, France.

⁸  INSERM, U258-IFR69, Paris Sud Faculty of Medicine, Villejuif, France.

⁹  Department of Pediatric Gastroenterology and Nutrition, Trousseau Hospital, Paris, France.

¹⁰  INSERM U563, Children's Hospital, Toulouse, France.

¹¹  Pediatric Endocrine Unit, Jeanne de Flandre Hospital, Lille, France.

¹²  Department of Medicine and Diabetes Center, University of California San Francisco, San Francisco, California, USA.

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^{1, 2, 3, 4, 5, 6, 7, 8}. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance^{9, 10}, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT−11 and AG+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 AG+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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