ANRIL Expression Is Associated With Atherosclerosis Risk at Chromosome 9p21

Abstract

Objective-We tested the hypothesis that expression of transcripts adjacent to the chromosome 9p21 (Chr9p21) locus of coronary artery disease was affected by the genotype at this locus and associated with atherosclerosis risk. Methods and Results-We replicated the locus for coronary artery disease (Pϭ0.007; ORϭ1.28) and other manifestations of atherosclerosis such as carotid plaque (Pϭ0.003; ORϭ1.31) in the Leipzig Heart Study, a cohort of 1134 patients with varying degree of angiographically assessed coronary artery disease. Expression analysis in peripheral blood mononuclear cells (nϭ1098) revealed that transcripts EU741058 and NR_003529 of antisense noncoding RNA in the INK4 locus (ANRIL) were significantly increased in carriers of the risk haplotype (Pϭ2.1ϫ10 Ϫ12 and Pϭ1.6ϫ10 Ϫ5 , respectively). In contrast, transcript DQ485454 remained unaffected, suggesting differential expression of ANRIL transcripts at Chr9p21. Results were replicated in whole blood (nϭ769) and atherosclerotic plaque tissue (nϭ41). Moreover, expression of ANRIL transcripts was directly correlated with severity of atherosclerosis (EU741058 and NR_003529; Pϭ0.02 and Pϭ0.001, respectively). No consistent association of Chr9p21 or atherosclerosis was found with expression of other genes such as CDKN2A, CDKN2B, C9orf53, and MTAP. Conclusion-Our data provide robust evidence for an association of ANRIL but not CDKN2A, CDKN2B, C9orf53, and MTAP, with atherosclerosis and Chr9p21 genotype in a large cohort. (Arterioscler Thromb Vasc Biol. 2010;30:620-627.)Key Words: atherosclerosis Ⅲ blood cells Ⅲ coronary artery disease Ⅲ gene expression Ⅲ peripheral arterial disease G enome-wide association studies have independently led to the identification of a susceptibility locus of coronary artery disease (CAD) on human chromosome (Chr) 9p21. [1][2][3] Until now, the locus has been replicated in a large number of additional studies 4 -7 and can be considered the most robust genetic marker of atherosclerotic cardiovascular disease.Despite these advances, the pathophysiology underlying this locus is currently not understood. Chr9p21 is not associated with known cardiovascular risk factors such as hyperlipidemia and hypertension. 7 Moreover, no known proteincoding genes reside within the haplotype block except for a long noncoding transcript of unknown function, designated antisense noncoding RNA in the INK4 locus (ANRIL). 8 In the absence of annotated genes at the immediate locus, adjacent ones such as the cyclin-dependent kinase inhibitors CDKN2A, CDKN2B, and methyl-thioadenosine phosphorylase (MTAP) have been regarded as potential candidate genes for atherosclerosis susceptibility at Chr9p21. However, the role of these genes in atherogenesis is not clear even though there is a wealth of data about their function in cancer, cell-cycle control, apoptosis, and aging. 9 -11 In addition, data from recent genome-wide association studies have revealed single nucleotide polymorphisms (SNPs) at Chr9p21 associated with the risk for glioma and skin cancers. 12,...

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

“…The chromosome 9p21 locus is a prominent example: whereas initial studies focused on the two genes situated at the locus, CDKN2A and CDKN2B, current studies rather point to radically new disease mechanisms. Indeed, it appears that the risk/non‐risk alleles at the 9p21 locus relate to different isoforms of ANRIL and subsequently to preferred synthesis of non‐circular/circular forms of this long non‐coding RNA, which affect via ribosomal function the expression of multiple genes leading ultimately to opposing effects on cell proliferation and apoptosis (Holdt et al , 2010, 2013). …”

miRNAs and lncRNAs in vascular injury and remodeling

“…rysms, hypertension, stroke and peripheral artery disease. Recent work has shown that antisense non-coding RNA in the INK4 locus (ANRIL) is transcribed from the Chr9p21 locus and acts as an epigenetic regulator to modulate cardiovascular risks [70]. Functional studies have shown that this lncRNA may be involved in atherosclerotic process, therefore inducing ischemic and hemorrhagic stroke.…”

Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-κB pathway

“…The chromosome 9p21 CAD risk haplotype containing multiple single nucleotide polymorphisms (SNP) in tight linkage disequilibrium resides at the 3 0 end of ANRIL gene and exhibits a clear association with ANRIL expression. [15][16][17][18][19] Based on these genetics studies, ANRIL is currently considered as a prime candidate gene for the chromosome 9p21 CAD locus. Subsequently ANRIL is found to be associated with periodontitis, diabetes, open angle glaucoma and various cancers.…”