title: Genome-wide association study of triglyceride response to a high-fat meal among participants of the NHLBI Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).
abstract: OBJECTIVE
  The triglyceride (TG) response to a high-fat meal (postprandial lipemia, PPL) affects cardiovascular disease risk and is influenced by genes and environment. Genes involved in lipid metabolism have dominated genetic studies of PPL TG response. We sought to elucidate common genetic variants through a genome-wide association (GWA) study in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).
  
  
  METHODS
  The GOLDN GWAS discovery sample consisted of 872 participants within families of European ancestry. Genotypes for 2,543,887 variants were measured or imputed from HapMap. Replication of our top results was performed in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 843). PPL TG response phenotypes were constructed from plasma TG measured at baseline (fasting, 0 hour), 3.5 and 6 hours after a high-fat meal, using a random coefficient regression model. Association analyses were adjusted for covariates and principal components, as necessary, in a linear mixed model using the kinship matrix; additional models further adjusted for fasting TG were also performed. Meta-analysis of the discovery and replication studies (n = 1715) was performed on the top SNPs from GOLDN.
  
  
  RESULTS
  GOLDN revealed 111 suggestive (p < 1E-05) associations, with two SNPs meeting GWA significance level (p < 5E-08). Of the two significant SNPs, rs964184 demonstrated evidence of replication (p = 1.20E-03) in the HAPI Heart Study and in a joint analysis, was GWA significant (p = 1.26E-09). Rs964184 has been associated with fasting lipids (TG and HDL) and is near ZPR1 (formerly ZNF259), close to the APOA1/C3/A4/A5 cluster. This association was attenuated upon additional adjustment for fasting TG.
  
  
  CONCLUSIONS
  This is the first report of a genome-wide significant association with replication for a novel phenotype, namely PPL TG response. Future investigation into response phenotypes is warranted using pathway analyses, or newer genetic technologies such as metabolomics.
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO. Electronic address: mwojczynski@wustl.edu.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Wojczynski
authors.affiliation: Nutrition and Genomics Laboratory, Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Parnell
authors.affiliation: Program in Personalized and Genomic Medicine, and Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
authors.affiliation: Nutrition and Genomics Laboratory, Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
authors.forename: Chao Q
authors.initials: CQ
authors.lastname: Lai
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Feitosa
authors.affiliation: Program in Personalized and Genomic Medicine, and Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Jeff R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX.
authors.forename: Alexis C
authors.initials: AC
authors.lastname: Frazier-Wood
authors.affiliation: Program in Personalized and Genomic Medicine, and Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Quince
authors.initials: Q
authors.lastname: Gibson
authors.affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: Program in Personalized and Genomic Medicine, and Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Ryan
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
authors.affiliation: Section on Statistical Genetics, Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.affiliation: Nutrition and Genomics Laboratory, Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.affiliation: Program in Personalized and Genomic Medicine, and Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD; Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, MD.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
mesh_terms: D000328:Adult; D000368:Aged; D059305:Diet, High-Fat; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008297:Male; D062407:Meals; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D054555:National Heart, Lung, and Blood Institute (U.S.); D020641:Polymorphism, Single Nucleotide; D019518:Postprandial Period / Q000187:drug effects / Q000235:genetics; D014280:Triglycerides / Q000097:blood*; D014481:United States
chemical_list: D000960:Hypolipidemic Agents; D008055:Lipids; D014280:Triglycerides
keywords: Genetics; Gwas; Postprandial lipemia; Triglyceride