Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program
Year: 2012
Type: article
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.
Source: PLoS Genetics
Institutions: University of Maryland, Baltimore, University of Miami, George Washington University, Broad Institute, Brigham and Women's Hospital, Harvard University, University Medical Center Utrecht, Massachusetts Institute of Technology, Massachusetts General Hospital, Baltimore VA Medical Center, Veterans Administration, Lund University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: American Diabetes Association, Doris Duke Charitable Foundation, Bristol-Myers Squibb, Henry M. Jackson Foundation, Pfizer, AstraZeneca, Massachusetts General Hospital, University of Miami, Northwestern University, University of Washington, Joslin Diabetes Center, University of Pittsburgh, Daiichi-Sankyo, Eisai, Hjärt-Lungfonden, Novo Nordisk, Vetenskapsrådet, Novo Nordisk Fonden, National Institutes of Health, Centers for Disease Control and Prevention, Feinberg School of Medicine, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development, National Center for Research Resources, Office of Research on Women's Health, National Center for Advancing Translational Sciences
Awards: University of New Mexico Clinical and Translational Science Center, 14/22 Limited Competition for the Continuation of the Diabetes Prevention Program Outcomes Study (DPPOS) Clinical Center, G1996713209, A Human-Centered Pharmacogenomic Screen of Metformin Action, UNM HSC Clinical and Translational Science Center, Calcium Handling and Secondary Hyperparathyroidism in Chronic Kidney Disease, JHU-UMD Diabetes Research Center, Diabetes Research Center, G970309226
OpenAlex ID: W2163675915