title: Functional analysis of the TRIB1 associated locus linked to plasma triglycerides and coronary artery disease.
abstract: BACKGROUND
  The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease in humans. The lipid-associated single nucleotide polymorphisms (SNPs), identified by genome-wide association studies, are located ≈30 kb downstream from TRIB1, suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits.
  
  
  RESULTS
  Characterization of the risk locus reveals that it encompasses a gene, TRIB1-associated locus (TRIBAL), composed of a well-conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and resequencing identified a single SNP, rs2001844, within the promoter region that associates with increased plasma triglycerides and reduced high-density lipoprotein cholesterol and coronary artery disease risk. Further, correction for triglycerides as a covariate indicated that the genome-wide association studies association is largely dependent on triglycerides. In addition, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs, including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes.
  
  
  CONCLUSIONS
  These studies demonstrate an interplay between a novel locus, TRIBAL, and TRIB1. TRIBAL is located in the genome-wide association studies identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression, and associates with plasma triglyceride concentrations.
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada (A.D., S., T.N., A.M., M.N., R.M.P.).
authors.forename: Adrianna
authors.initials: A
authors.lastname: Douvris
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada (A.D., S., T.N., A.M., M.N., R.M.P.).
authors.forename: Sébastien
authors.initials: S
authors.lastname: Soubeyrand
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada (A.D., S., T.N., A.M., M.N., R.M.P.).
authors.forename: Thet
authors.initials: T
authors.lastname: Naing
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada (A.D., S., T.N., A.M., M.N., R.M.P.).
authors.forename: Amy
authors.initials: A
authors.lastname: Martinuk
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada (A.D., S., T.N., A.M., M.N., R.M.P.).
authors.forename: Majid
authors.initials: M
authors.lastname: Nikpay
authors.affiliation: Environmental Health Science and Research Bureau, Ottawa, Canada (A.W., J.B., C.Y.).
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: Environmental Health Science and Research Bureau, Ottawa, Canada (A.W., J.B., C.Y.).
authors.forename: Julie
authors.initials: J
authors.lastname: Buick
authors.affiliation: Environmental Health Science and Research Bureau, Ottawa, Canada (A.W., J.B., C.Y.).
authors.forename: Carole
authors.initials: C
authors.lastname: Yauk
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada (A.D., S., T.N., A.M., M.N., R.M.P.) Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada (R.M.P.).
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
mesh_terms: D000818:Animals; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D005260:Female; D020555:GTP-Binding Protein Regulators / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D056945:Hep G2 Cells / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood*
chemical_list: D020555:GTP-Binding Protein Regulators; D047908:Intracellular Signaling Peptides and Proteins; C493170:TRIB1 protein, human; D014280:Triglycerides; D017346:Protein Serine-Threonine Kinases
keywords: cardiovascular diseases; lipids; lipoproteins; liver