title: 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.
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, and Program in Genetics and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
authors.forename: Tamara
authors.initials: T
authors.lastname: Isakova
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Jablonski
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Andrew
authors.initials: A
authors.lastname: Taylor
authors.forename: Jarred
authors.initials: J
authors.lastname: McAteer
authors.forename: Qing
authors.initials: Q
authors.lastname: Pan
authors.forename: Edward S
authors.initials: ES
authors.lastname: Horton
authors.forename: Linda M
authors.initials: LM
authors.lastname: Delahanty
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Goldberg
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
mesh_terms: D000328:Adult; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control; D008076:Cholesterol, HDL / Q000235:genetics; D008078:Cholesterol, LDL / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control*; D050171:Dyslipidemias / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D008019:Life Style; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008074:Lipoproteins / Q000032:analysis / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008687:Metformin / Q000008:administration & dosage; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood / Q000235:genetics; D015431:Weight Loss / Q000235:genetics / Q000502:physiology
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D007004:Hypoglycemic Agents; D008074:Lipoproteins; D014280:Triglycerides; D008687:Metformin