학술논문
Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program
Document Type
article
Author
Pollin, Toni I; Isakova, Tamara; Jablonski, Kathleen A; de Bakker, Paul IW; Taylor, Andrew; McAteer, Jarred; Pan, Qing; Horton, Edward S; Delahanty, Linda M; Altshuler, David; Shuldiner, Alan R; Goldberg, Ronald B; Florez, Jose C; Franks, Paul W; Bray, George A; Culbert, Iris W; Champagne, Catherine M; Eberhardt, Barbara; Greenway, Frank; Guillory, Fonda G; Herbert, April A; Jeffirs, Michael L; Kennedy, Betty M; Lovejoy, Jennifer C; Morris, Laura H; Melancon, Lee E; Ryan, Donna; Sanford, Deborah A; Smith, Kenneth G; Smith, Lisa L; St. Amant, Julia A; Tulley, Richard T; Vicknair, Paula C; Williamson, Donald; Zachwieja, Jeffery J; Polonsky, Kenneth S; Tobian, Janet; Ehrmann, David; Matulik, Margaret J; Clark, Bart; Czech, Kirsten; DeSandre, Catherine; Hilbrich, Ruthanne; McNabb, Wylie; Semenske, Ann R; Caro, Jose F; Watson, Pamela G; Goldstein, Barry J; Smith, Kellie A; Mendoza, Jewel; Liberoni, Renee; Pepe, Constance; Spandorfer, John; Donahue, Richard P; Prineas, Ronald; Rowe, Patricia; Calles, Jeanette; Cassanova-Romero, Paul; Florez, Hermes J; Giannella, Anna; Kirby, Lascelles; Larreal, Carmen; McLymont, Valerie; Mendez, Jadell; Ojito, Juliet; Perry, Arlette; Saab, Patrice; Haffner, Steven M; Montez, Maria G; Lorenzo, Carlos; Martinez, Arlene; Hamman, Richard F; Nash, Patricia V; Testaverde, Lisa; Anderson, Denise R; Ballonoff, Larry B; Bouffard, Alexis; Calonge, B Ned; Delve, Lynne; Farago, Martha; Hill, James O; Hoyer, Shelley R; Jortberg, Bonnie T; Lenz, Dione; Miller, Marsha; Price, David W; Regensteiner, Judith G; Seagle, Helen; Smith, Carissa M; Steinke, Sheila C; VanDorsten, Brent; Lawton, Kathleen E; Arky, Ronald A; Bryant, Marybeth; Burke, Jacqueline P; Caballero, Enrique; Callaphan, Karen M; Ganda, Om P
Source
PLOS Genetics. 8(8)
Subject
Language
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.