Genetic modulation of lipid profiles following lifestyle modification or metformin treatment: the Diabetes Prevention Program

PLoS Genet. 2012;8(8):e1002895. doi: 10.1371/journal.pgen.1002895. Epub 2012 Aug 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cardiovascular Diseases* / drug therapy
  • Cardiovascular Diseases* / genetics
  • Cardiovascular Diseases* / prevention & control
  • Cholesterol, HDL / genetics
  • Cholesterol, LDL / genetics
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Dyslipidemias / genetics*
  • Dyslipidemias / metabolism
  • Female
  • Genetic Association Studies
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Life Style
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / genetics*
  • Lipoproteins / analysis
  • Lipoproteins / genetics
  • Magnetic Resonance Spectroscopy
  • Male
  • Metformin / administration & dosage
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Triglycerides / blood
  • Triglycerides / genetics
  • Weight Loss / genetics
  • Weight Loss / physiology

Substances

  • Cholesterol, HDL
  • Cholesterol, LDL
  • Hypoglycemic Agents
  • Lipoproteins
  • Triglycerides
  • Metformin