Variants in ANRIL gene correlated with its expression contribute to myocardial infarction risk.

Jie Cheng,Sai-Sai Tang,Xinguang Liu,Xing-Dong Xiong,Meng-Yun Cai,Xi-Li Yang,Can Chen,Yu-Ning Chen,Zhi-Cheng Li

doi:10.18632/oncotarget.14721

Abstract

ANRIL (antisense non-coding RNA in the INK4 locus), located at the 9p21.3 locus, has been known to be closely associated with the risk of coronary artery disease (CAD). To date, studies of the 9p21.3 variants on CAD risk mainly focus on the non-coding region of ANRIL. However, the biological significance of the variants on ANRIL promoter and exons is still unknown. Here we investigate whether the variants on ANRIL promoter and exons have an effect on myocardial infarction (MI) risk, and further analyze the association of these variants with the expression of ANRIL transcript. We did not find any common variants with minor allele frequencies (MAF) larger than 5% in ANRIL promoter by sequencing 1.6kb upstream of the start codon. Unconditional logistic regression analysis revealed that two SNPs in ANRIL exons, rs10965215 and rs10738605, were significantly associated with MI risk. Further studies revealed that ANRIL transcript EU741058.1 expression levels of rs10965215 and rs10738605 risk genotypes were borderline lower than those of protective genotypes. Our data provide the evidence that the variants rs10965215 and rs10738605 in ANRIL exons contribute to MI risk in the Chinese Han population which might be correlated with the expression of its transcript EU741058.1.

Highlights

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide and in China [1, 2], which is ascribed to the combination of environmental and genetic factors
In the comparison of lipid profiles, serum triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDLC) were higher in the patients than in the controls (P < 0.001, P = 0.226, P < 0.001, respectively), whereas serum high density lipoprotein cholesterol (HDLC) levels were significantly higher among controls (P < 0.001)
Genome-wide association studies (GWAS) and many replication studies have demonstrated that variation at the 9p21.3 locus is a major genetic determinant for coronary artery disease (CAD) pathogenesis [4, 6,7,8, 10, 19, 24]

Summary

Introduction

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide and in China [1, 2], which is ascribed to the combination of environmental and genetic factors. It is generally accepted that chromosome 9p21.3 is a risk locus for coronary artery disease (CAD) [7,8,9]. This genomic interval spans 58 kb containing a gene for a long non-coding RNA (lncRNA) known as ANRIL (antisense non-coding RNA in the INK4 locus) [4, 6,7,8, 10]. ANRIL alters expression of these associated protein coding genes through multiple mechanisms, including RNA interference, gene silencing, chromatin remodeling, or DNA methylation [12]. ANRIL is expressed in endothelial cells, smooth muscle cells, and inflammatory cells known to be stimulated by atherosclerosis and consists of 20 exons www.impactjournals.com/oncotarget

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