Genome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism

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Valsesia, Armand | Wang, Qiao-Ping | Gheldof, Nele | Carayol, Jérôme | Ruffieux, Hélène | Clark, Teleri | Shenton, Victoria | Oyston, Lisa, J | Lefebvre, Gregory | Metairon, Sylviane | Chabert, Christian | Walter, Ondine | Mironova, Polina | Lau, Paulina | Descombes, Patrick | Viguerie, Nathalie | Langin, Dominique | Harper, Mary-Ellen | Astrup, Arne | Saris, Wim, H | Dent, Robert | Neely, Greg, G | Hager, Jörg

Edité par CCSD ; Nature Publishing Group -

International audience. Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention remains unknown. We perform a GWAS in two large low-caloric diet intervention cohorts of obese participants. Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort (n = 1166) and replicated in the DiOGenes cohort (n = 789). Modulation of HGTX (NKX6.3 ortholog) levels in Drosophila melanogaster leads to significantly altered triglyceride levels. Additional tissue-specific experiments demonstrate an action through the oenocytes, fly hepatocyte-like cells that regulate lipid metabolism. Our results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control.

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