ACDC/Adiponectin Polymorphisms Are Associated With Severe Childhood and Adult Obesity

ACDC/Adiponectin Polymorphisms Are Associated With Severe Childhood and Adult Obesity Nabila Bouatia-Naji 1 , David Meyre 1 , Stéphane Lobbens 1 , Karin Séron 1 , Frédéric Fumeron 2 , Beverley Balkau 3 , Barbara Heude 3 , Béatrice Jouret 4 , Philipp E. Scherer 5 , Christian Dina 1 , Jacques Weill 6 and Philippe Froguel 1 7 1 Centre National de la Recherche Scientifique UMR8090, Pasteur Institute of Lille, Lille, France 2 Institut National de la Santé et de la Recherche Médicale (INSERM) U695, Faculty of Medicine Xavier Bichat, Paris, France 3 INSERM, U258-IFR69, Faculty of Medicine Paris Sud, Villejuif, France 4 INSERM U563, Children’s Hospital, Toulouse, France 5 Department of Cell Biology and Diabetes Research and Training Centre, Albert Einstein College of Medicine, Bronx, New York 6 Pediatric Endocrine Unit, Jeanne de Flandre Hospital, Lille, France 7 Genomic Medicine and Genome Centre, Hammersmith Campus, Imperial College, London, U.K Address correspondence and reprint requests to Philippe Froguel, Genomic Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, U.K. E-mail: p.froguel{at}imperial.ac.uk Abstract Common single nucleotide polymorphisms (SNPs) in the ACDC adiponectin encoding gene have been associated with insulin resistance and type 2 diabetes in several populations. Here, we investigate the role of SNPs −11,377C>G, −11,391G>A, +45T>G, and +276G>T in 2,579 French Caucasians (1,229 morbidly obese and 1,350 control subjects). We found an association between severe forms of obesity and −11,377C (odds ratio 1.23, P = 0.001) and +276T (1.19, P = 0.006). Surprisingly, alternative alleles −11,377G and +276G have been previously reported as risk factors for type 2 diabetes. Transmission disequilibrium tests showed a trend in overtransmission (56.7%) of a risk haplotype 1 (C) -1 (G) -1 (T) -2 (T) including −11,377C and +276T in 634 obesity trios ( P = 0.097). Family-based analysis in 400 trios from the general population indicated association between obesity haplotype and higher adiponectin levels, suggesting a role of hyperadiponectinemia in weight gain. However, experiments studying the putative roles of SNPs −11,377C>G and +276G>T on ACDC functionality were not conclusive. In contrast, promoter SNP −11,391G>A was associated with higher adiponectin levels in obese children ( P = 0.005) and in children from the general population (0.00007). In vitro transcriptional assays showed that −11,391A may increase ACDC acti