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

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Armand Valsesia, Qiao-Ping Wang, Nele Gheldof, Jérôme Carayol, Hélène Ruffieux, Teleri Clark, Victoria Shenton, Lisa J Oyston, Gregory Lefebvre, Sylviane Metairon, Christian Chabert, Ondine Walter, Polina Mironova, Paulina Lau, Patrick Descombes, Nathalie Viguerie, Dominique Langin, Mary-Ellen Harper, Arne Astrup, Wim H Saris & 3 andre Robert Dent, Greg G Neely, Jörg Hager

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.

TidsskriftNature Communications
Antal sider10
StatusUdgivet - 2019

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CURIS 2019 NEXS 036

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