Open AccessFunctional Analysis of the TRIB 1 Associated Locus Linked to Plasma Triglycerides and Coronary Artery Disease
Author(s) -
Douvris Adrianna,
Soubeyrand Sébastien,
Naing Thet,
Martinuk Amy,
Nikpay Majid,
Williams Andrew,
Buick Julie,
Yauk Carole,
McPherson Ruth
Publication year - 2014
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.114.000884
Subject(s) - locus (genetics) , single nucleotide polymorphism , genome wide association study , expression quantitative trait loci , gene , genetic association , genetics , biology , snp , quantitative trait locus , gene knockdown , medicine , genotype
Background The TRIB 1 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 ( SNP s), identified by genome‐wide association studies, are located ≈30 kb downstream from TRIB 1, 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 SNP s at the TRIB 1 locus and plasma lipid traits. Methods and 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.