Nestlé Institute of Health Sciences, 1015, Lausanne, Switzerland.
Functional Genomics group, Charles Perkins Centre, University of Sydney, 2006, Sydney, NSW, Australia.
Nat Commun. 2019 Feb 1;10(1):540. doi: 10.1038/s41467-019-08492-8.
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.
通过使用观察队列的全基因组关联研究（GWAS），已经发现了数百种与体重指数（BMI）相关的遗传变异。然而，对于饮食干预下有效减肥的遗传贡献仍不清楚。我们在两个大型低热量饮食干预肥胖参与者队列中进行了 GWAS。在加拿大发现队列（n=1166）中确定了两个接近 NKX6.3/MIR486 和 RBSG4 的基因座，并在 DiOGenes 队列（n=789）中得到了复制。果蝇中 HGTX（NKX6.3 同源物）水平的调节导致甘油三酯水平显著改变。其他组织特异性实验表明，该基因通过调节脂质代谢的果蝇脂肪体细胞发挥作用。我们的研究结果确定了与肥胖受试者减肥效果相关的遗传变异，并确定了 NKX6.3 在脂质代谢中的作用，从而可能控制体重。
