Title

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

Authors

Toni I. Pollin, University of Maryland School of Medicine
Tamara Isakova, University of Miami Leonard M. Miller School of Medicine
Kathleen A. Jablonski, The George Washington University
Paul I.W. de Bakker, Broad Institute
Andrew Taylor, Broad Institute
Jarred McAteer, Broad Institute
Qing Pan, The George Washington University
Edward S. Horton, Harvard Medical School
Edward S. Horton, Harvard Medical School
Linda M. Delahanty, Harvard Medical School
David Altshuler, Broad Institute
Alan R. Shuldiner, University of Maryland School of Medicine
Ronald B. Goldberg, University of Miami Leonard M. Miller School of Medicine
Jose C. Florez, Broad Institute
Paul W. Franks, Harvard T.H. Chan School of Public Health
George A. Bray, Pennington Biomedical Research Center
Iris W. Culbert, Pennington Biomedical Research Center
Catherine M. Champagne, Pennington Biomedical Research Center
Barbara Eberhardt, Pennington Biomedical Research Center
Frank Greenway, Pennington Biomedical Research Center
Fonda G. Guillory, Pennington Biomedical Research Center
April A. Herbert, Pennington Biomedical Research Center
Michael L. Jeffirs, Pennington Biomedical Research Center
Betty M. Kennedy, Pennington Biomedical Research Center
Jennifer C. Lovejoy, Pennington Biomedical Research Center
Laura H. Morris, Pennington Biomedical Research Center
Lee E. Melancon, Pennington Biomedical Research Center
Donna Ryan, Pennington Biomedical Research Center
Deborah A. Sanford, Pennington Biomedical Research Center
Kenneth G. Smith, Pennington Biomedical Research Center
Lisa L. Smith, Pennington Biomedical Research Center
Julia A. St. Amant, Pennington Biomedical Research Center

Document Type

Journal Article

Publication Date

8-1-2012

Journal

PLoS Genetics

Volume

8

Issue

8

DOI

10.1371/journal.pgen.1002895

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 {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.

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