The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region

• Type of Material: Article
• Authors: Wei Zhao, University of Michigan; Jennifer A Smith, University of Michigan; Guangmei Mao, University of Michigan; Myriam Fornage, Univ Texas Hlth Sci Ctr Houston; Patricia A. Peyser, University of Michigan; Yan Sun, Emory University; Stephen T Turner, Mayo Clinic; Sharon LR Kardia, University of Michigan
• Language: English
• Date: 2015-05-10
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Zhao et al.; licensee BioMed Central.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12920-015-0094-0
• Title of Journal or Parent Work: BMC Medical Genomics
• ISSN: 1755-8794
• Volume: 8
• Start Page: 21
• End Page: 21
• Grant/Funding Information: In addition, we are grateful for the generous support from the National Heart, Lung and Blood Institute (NHLBI) and the National Institute on Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) through grants HL100245, HL087660, HL119443 and NS041558.
• Keywords: DENSITY-LIPOPROTEIN; COMMON GENETIC-VARIANTS; ABDOMINAL AORTIC-ANEURYSM; GENOA; SNP; SINGLE NUCLEOTIDE POLYMORPHISMS; Life Sciences & Biomedicine; CHROMOSOME 9P21 LOCUS; Gene expression; HDL-CHOLESTEROL; Science & Technology; MYOCARDIAL-INFARCTION; GENOME-WIDE ASSOCIATION; NONCODING RNA; CAD; Chr9p21; Genetics & Heredity; HEART-DISEASE
• Research Categories: Health Sciences, Epidemiology; Biology, Genetics; Biology, Molecular

Abstract

Background Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression. Methods We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study. Results We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved. Conclusion These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms. Electronic supplementary material The online version of this article (doi:10.1186/s12920-015-0094-0) contains supplementary material, which is available to authorized users.