title: Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program.
abstract: BACKGROUND
  We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial.
  
  
  RESULTS
  We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3×10-4>P>1.1×10-16) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (β=-0.11 µmol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5×10-3; Pinteraction=1×10-3for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits.
  
  
  CONCLUSIONS
  Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.
  
  
  BACKGROUND
  URL: https://www.clinicaltrials.gov. Unique Identifier: NCT00004992.
authors: Dept of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund Univ, Malmö, Sweden.
authors: Tibor V
authors: TV
authors: Varga
authors: Division of Endocrinology, Diabetes & Nutrition, Dept of Medicine & Program in Genetics & Genomic Medicine, Univ of Maryland School of Medicine, Baltimore.
authors: Alexandra H
authors: AH
authors: Winters
authors: The Biostatistics Center, George Washington Univ, Rockville, MD.
authors: Kathleen A
authors: KA
authors: Jablonski
authors: Dept of Medicine, Harvard Medical School.|Joslin Diabetes Center, Boston, MA.
authors: Edward S
authors: ES
authors: Horton
authors: Washington Univ, St. Louis, MO.
authors: Prajakta
authors: P
authors: Khare-Ranade
authors: Diabetes Epidemiology & Clinical Research Section, NIDDK, Phoenix, AZ.
authors: William C
authors: WC
authors: Knowler
authors: Northwest Lipid Metabolism & Diabetes Research Laboratories, Univ of Washington, Seattle, WA.
authors: Santica M
authors: SM
authors: Marcovina
authors: Dept of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund Univ, Malmö, Sweden.|Dept of Biobank Research, Umeå Univ, Umeå, Sweden.
authors: Frida
authors: F
authors: Renström
authors: Dept of Medicine, UCLA School of Medicine, CA.
authors: Karol E
authors: KE
authors: Watson
authors: Lipid Disorders Clinic, Division of Endocrinology, Diabetes & Metabolism, Leonard M. Miller School of Medicine, Univ of Miami, Miami, FL.|The Diabetes Research Institute, Leonard M. Miller School of Medicine, Univ of Miami, Miami, FL.
authors: Ronald
authors: R
authors: Goldberg
authors: Dept of Medicine, Harvard Medical School.|Program in Medical & Population Genetics, Broad Institute of Harvard & MIT, Cambridge.|Center for Human Genetic Research, Diabetes Unit, MGH.|Diabetes Research Center, Diabetes Unit, MGH.
authors: José C
authors: JC
authors: Florez
authors: Division of Endocrinology, Diabetes & Nutrition, Dept of Medicine & Program in Genetics & Genomic Medicine, Univ of Maryland School of Medicine, Baltimore.
authors: Toni I
authors: TI
authors: Pollin
authors: Dept of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund Univ, Malmö, Sweden.|Dept of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.|Dept of Public Health & Clinical Medicine, Umeå Univ, Umeå, Sweden.
authors: Paul W
authors: PW
authors: Franks
mesh_terms: D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D050171:Dyslipidemias / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy*; D059647:Gene-Environment Interaction; D056426:Genetic Loci; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood*; D008687:Metformin / Q000627:therapeutic use*; D010316:Particle Size; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011236:Prediabetic State / Q000097:blood / Q000453:epidemiology / Q000628:therapy*; D018570:Risk Assessment; D012307:Risk Factors; D040242:Risk Reduction Behavior; D014280:Triglycerides / Q000097:blood; D014481:United States / Q000453:epidemiology
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005819:Genetic Markers; D007004:Hypoglycemic Agents; D008055:Lipids; D014280:Triglycerides; D008687:Metformin
keywords: clinical trial; genetics; lifestyle; lipids; lipoproteins; molecular epidemiology; polymorphism, genetic