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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.
Highlights
Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts
Genome-wide association studies (GWAS) from the GIANT consortium have identified about 100 loci associated with body mass index (BMI) variability in the general population[9]
Those candidate obesity loci were investigated in two lifestyle interventions: the Diabetes Prevention Program (DPP)[10,11] and Look AHEAD12,13
Summary
Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. 10 Department of Human Biology, NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+(MUMC+), 6211 Maastricht, The Netherlands These authors contributed : Armand Valsesia, Qiao-Ping Wang. Genome-wide association studies (GWAS) from the GIANT consortium have identified about 100 loci associated with body mass index (BMI) variability in the general population[9] Those candidate obesity loci were investigated in two lifestyle interventions: the Diabetes Prevention Program (DPP)[10,11] and Look AHEAD12,13. We present results from a genome-wide association (GWA) study for weight loss using two large low-caloric diet interventions: the Canadian Optifast900® meal replacement program[16] and the DiOGenes clinical trial[17,18]. Our study provides evidence for a weight loss locus on chromosome 8p11 and knock out experiments in Drosophila melanogaster suggest the NKX6.3 gene in the region as a potential functional candidate
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