Functional Analysis of the TRIB1 Associated Locus Linked to Plasma Triglycerides and Coronary Artery Disease
- DOI
- Language of the publication
- English
- Date
- 2014-06-03
- Type
- Article
- Author(s)
- Douvris, Adrianna
- Soubeyrand, Sébastien
- Naing, Thet
- Martinuk, Amy
- Nikpay, Majid
- Williams, Andrew
- Buick, Julie
- Yauk, Carole
- McPherson, Ruth
- Publisher
- Wiley Open Access
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. 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.
Plain language summary
WHY: Dietary, environmental and genetic factors contribute to changes in lipid levels that can place individuals at increased risk of coronary artery disease. Previous research has shown that a relatively commonly occurring change in the DNA sequence (called a polymorphism) near a gene called TRIB1 in humans is associated with high levels of triglycerides (a blood lipid). High levels of triglycerides are a risk factor for heart disease and stroke. In this study, detailed molecular investigations were conducted to examine the role of the TRIB1 polymorphism in controlling lipid levels in order to increase our understanding of why some individuals are at increased risk of coronary artery disease. WHAT: Computational and genomics methodologies were applied to fully characterize the DNA sequence near the TRIB1 gene. The sequence revealed the genetic code for another gene (called TRIBAL) and a specific polymorphism that was associated with increased triglyceride levels. The data suggested that the polymorphism can affect the product abundance of both TRIB1 and TRIBAL, and that these genes interact. SO WHAT: These findings will be used to develop an understanding of the polymorphisms that exist in the human population that contribute to increased susceptibility to coronary artery disease in some populations. NOW WHAT: The interaction of gene polymorphisms, environmental factors (drugs, diet, environmental chemicals etc.) and health outcomes of exposures will be the focus of future work in this field.
Subject
- Health,
- Health and safety