Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program

Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P?=?0.04–1×10^?17). Except for total HDL particles (r?=??0.03, P?=?0.26), all components of the lipid profile correlated with the GRS (partial |r|?=?0.07–0.17, P?=?5×10^?5–1×10^?19). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β?=?+0.87, SEE±0.22 mg/dl/allele, P?=?8×10^?5, P _interaction?=?0.02) in the lifestyle intervention group, but not in the placebo (β?=?+0.20, SEE±0.22 mg/dl/allele, P?=?0.35) or metformin (β?=??0.03, SEE±0.22 mg/dl/allele, P?=?0.90; P _interaction?=?0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β?=?+0.30, SEE±0.012 ln nmol/L/allele, P?=?0.01, P _interaction?=?0.01) but not in the placebo (β?=??0.002, SEE±0.008 ln nmol/L/allele, P?=?0.74) or metformin (β?=?+0.013, SEE±0.008 nmol/L/allele, P?=?0.12; P _interaction?=?0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss.