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

Abstract

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.

Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia?

“…Evidence from randomized controlled trials of weight loss interventions show convincingly that weight loss lowers triglyceride concentrations, 40 whereas clinical trials focused on pharmacologically lowering triglyceride concentrations do not support a causal effect of triglycerides on body weight 41 ; thus, the causal direction between these variables is clear. It is possible though that lifestyle correlates of BMI might underlie (confound) the observed interaction; however, analyses conditioning on relevant lifestyle variables did not materially affect our results, and there was no evidence of WGRS TG ×lifestyle interactions.…”

Interactions of Lipid Genetic Risk Scores With Estimates of Metabolic Health in a Danish Population

“…10 Findings of a GRS based on 32 lipid-associated SNPs in a lifestyle intervention study of 2993 participants suggested that a high genetic burden predicts an attenuated response in LDL-C levels to both dietary and physical activity intervention and hence individuals in low genetic risk might benefit more from lifestyle intervention. 11 Identification of interactions between GRS and lifestyle factors may provide novel insight into the nature of dyslipidemia and may serve to identify individuals who are at higher risk of dyslipidemia and who may benefit from genotype-based targeted intervention. At present, it is unclear whether and how the identified genetic susceptibility loci collectively interact with lifestyle-related risk factors to influence risk of abnormal lipid levels.…”

Increasing insulin resistance accentuates the effect of triglyceride-associated loci on serum triglycerides during 5 years

“…One study performed prospective age-GRS interaction analyses and found that the effect of the triglyceride GRS on levels of triglycerides was stronger in younger (age: 45-54 years) participants than in older (age: 55-64 years) (12). Another study tested a combined LDL-cholesterol, HDL-cholesterol, and triglyceride GRS of 32 SNPs for a differential effect on lipid levels during one year in response to lifestyle or metformin treatment in the Diabetes Prevention Program (18). No genetic modulation of the triglyceride response was observed in this study for the combined lipid GRS.…”