Genome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism

TLDR

Genome‑wide association studies have linked many genetic variants to BMI, but the genetic basis of effective weight loss from dietary interventions remains unclear. The study aims to identify genetic variants influencing weight loss by conducting a GWAS in two large low‑calorie diet intervention cohorts of obese individuals. The authors performed a genome‑wide association analysis on these cohorts to pinpoint variants associated with weight‑loss response. The analysis identified loci near NKX6.3/MIR486 and RBSG4 linked to weight‑loss efficacy, replicated across cohorts, and functional studies in Drosophila showed that NKX6.3 regulates triglyceride levels via oenocytes, implicating it in lipid metabolism and weight control.

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.