Genome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism.
Armand Valsesia,Qiao-Ping Wang,Qiao-Ping Wang,Nele Gheldof,Jérôme Carayol,Hélène Ruffieux,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,Dominique Langin,Mary-Ellen Harper,Arne Astrup,Wim H. M. Saris,Robert Dent,G. Gregory Neely,Joerg Hager +25 more
TLDR
Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort and replicated in the DiOGenes cohort and taken forward for Bayesian fine-mapping and functional assessment in flies.Abstract:
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. Individuals show large variability in their capacity to lose weight and maintain this weight. Here, the authors perform GWAS in two weight loss intervention cohorts and identify two genetic loci associated with weight loss that are taken forward for Bayesian fine-mapping and functional assessment in flies.read more
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