We investigated whether a 1-year intensive lifestyle intervention (ILI) for weight loss would avert the unfavorable cardiometabolic effects associated with GCKR Leu446Pro when compared with a diabetes mellitus support and education arm in overweight/obese individuals with type 2 diabetes mellitus with triglyceride (n=3214) and CRP (n=1411) data participating in a randomized lifestyle intervention study for weight loss, Action for Health in Diabetes Mellitus (Look AHEAD).
Here we show that adiposity significantly amplifies the effect of three sequence variants (encoding PNPLA3 p.I148M, TM6SF2 p.E167K, and GCKR p.P446L) associated with nonalcoholic fatty liver disease (NAFLD).
Results of logistic regression revealed that, despite higher triglyceride levels, the carriers of the GCKR variants were more protected against the development of obesity; the adjusted models confirmed the lower risk of obesity for both variants (rs1260326: OR, 0.46; 95% CI, 0.25-0.83; rs780094: OR, 0.41; 95% CI, 0.23-0.74).