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.

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@inproceedings{Pollin2012GeneticMO, title={Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program}, author={Toni Pollin and Tamara Isakova and Kathleen A. Jablonski and Paul I W de Bakker and Andrew T Taylor and Jarred B. McAteer and Qing Pan and Edward S. Horton and Linda M. Delahanty and David Altshuler and Alan R. Shuldiner and Ronald B . Goldberg and Jose C Florez and Paul W Franks and George A . Bray and Iris W. Culbert and Catherine M Champagne and Barbara Eberhardt and Frank L. Greenway and Fonda G. Guillory and April A. Herbert and Michael L. Jeffirs and Betty Monroe Kennedy and Jennifer C. Lovejoy and Laura H. Morris and Lee E. Melancon and Donna H. Ryan and Deborah A. Sanford and Kenneth G. C. Smith and Lisa L. Smith and Julia A. St. Amant and Richard T. Tulley and Paula C. Vicknair and Donald A. Williamson and Jeffery J. Zachwieja and Kenneth S. Polonsky and Janet Ash Tobian and David A. 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