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

2019; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41467-019-08492-8

2041-1723

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

Genetic Mapping and Diversity in Plants and Animals

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.