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 {pipe}r{pipe} = 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,pinteraction = 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; pinteraction = 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,pinteraction = 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; pinteraction = 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. © 2012 pollin et al.