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.

通过使用观察性队列的全基因组关联研究（GWAS），数百种遗传变异与体重指数（BMI）相关联。然而，对饮食干预引起的有效减肥的遗传贡献仍然未知。我们在肥胖参与者的两个大型低热量饮食干预队列中进行了GWAS。在加拿大发现队列（n  = 1166）中鉴定出两个与NKX6.3 / MIR486和RBSG4接近的基因座，并在DiOGenes队列（n  = 789）中复制。果蝇中HGTX（NKX6.3直系同源物）水平的调节。导致甘油三酸酯水平显着改变。额外的组织特异性实验表明，通过调节脂质代谢的卵母细胞，苍蝇样肝细胞样细胞可发挥作用。我们的结果确定了与肥胖受试者体重减轻功效相关的遗传变异，并确定了NKX6.3在脂质代谢中的作用，从而可能在体重控制中发挥作用。