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
  • Wim H Saris
  • 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.

Original languageEnglish
Article number540
JournalNature Communications
Number of pages10
Publication statusPublished - 2019

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