Dataset Information

Long Noncoding RNA ANRIL: Lnc-ing Genetic Variation at the Chromosome 9p21 Locus to Molecular Mechanisms of Atherosclerosis.

ABSTRACT: Ever since the first genome-wide association studies (GWAS) on coronary artery disease (CAD), the Chr9p21 risk locus has emerged as a top signal in GWAS of atherosclerotic cardiovascular disease, including stroke and peripheral artery disease. The CAD risk SNPs on Chr9p21 lie within a stretch of 58 kilobases of non-protein-coding DNA, containing the gene body of the long noncoding RNA (lncRNA) antisense non coding RNA in the INK4 locus (ANRIL). How risk is affected by the Chr9p21 locus in molecular detail is a matter of ongoing research. Here we will review recent advances in the understanding that ANRIL serves as a key risk effector molecule of atherogenesis at the locus. One focus of this review is the shift in understanding that genetic variation at Chr9p21 not only affects the abundance of ANRIL, and in some cases expression of the adjacent CDKN2A/B tumor suppressors, but also impacts ANRIL splicing, such that 3'-5'-linked circular noncoding ANRIL RNA species are produced. We describe how the balance of linear and circular ANRIL RNA, determined by the Chr9p21 genotype, regulates molecular pathways and cellular functions involved in atherogenesis. We end with an outlook on how manipulating circular ANRIL abundance may be exploited for therapeutic purposes.

SUBMITTER: Holdt LM

PROVIDER: S-EPMC6232298 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Long Noncoding RNA ANRIL: Lnc-ing Genetic Variation at the Chromosome 9p21 Locus to Molecular Mechanisms of Atherosclerosis.

Holdt Lesca M LM Teupser Daniel D

Frontiers in cardiovascular medicine 20181106

Ever since the first genome-wide association studies (GWAS) on coronary artery disease (CAD), the Chr9p21 risk locus has emerged as a top signal in GWAS of atherosclerotic cardiovascular disease, including stroke and peripheral artery disease. The CAD risk SNPs on Chr9p21 lie within a stretch of 58 kilobases of non-protein-coding DNA, containing the gene body of the long noncoding RNA (lncRNA) antisense non coding RNA in the INK4 locus (ANRIL). How risk is affected by the Chr9p21 l ...[more]

PMID: 30460243

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Project description:BackgroundCase-control Genome-Wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). The locus does not contain a clear candidate gene. Hence, the results of GWAS have raised an intense interest in delineating the basis for the observed association. We analyzed association of 4 SNPs at the 9p21 locus with the severity and progression of coronary atherosclerosis, as determined by serial quantitative coronary angiograms (QCA) in the well-characterized Lipoprotein Coronary Atherosclerosis Study (LCAS) population. The LCAS is a randomized placebo-control longitudinal follow-up study in patients with CAD conducted to test the effects of fluvastatin on progression or regression of coronary atherosclerosis.MethodsExtensive plasma lipid levels were measured at the baseline and 2 1/2 years after randomization. Likewise serial QCA was performed at the baseline and upon completion of the study. We genotyped the population for 4 SNPs, previously identified as the susceptibility SNPs for CAD in GWAS, using fluorogenic 5' nuclease assays. We reconstructed the haplotypes using Phase 2, analyzed SNP and haplotype effects using the Thesias software as well as by the conventional statistical methods.ResultsOnly Caucasians were included since they comprised 90% of the study population (332/371 with available DNA sample). The 4 SNPs at the 9p21 locus were in tight linkage disequilibrium, leading to 3 common haplotypes in the LCAS population. We found no significant association between quantitative indices of severity of coronary atherosclerosis, such as minimal lumen diameter and number of coronary lesions or occlusions and the 9p21 SNPs and haplotypes. Likewise, there was no association between quantitative indices of progression of coronary atherosclerosis and the SNPs or haplotypes. Similarly, we found no significant SNP or haplotype effect on severity and progression of coronary atherosclerosis.ConclusionWe conclude the 4 SNPs at the 9p21 locus analyzed in this study do not impart major effects on the severity or progression of coronary atherosclerosis. The effect size may be very modest or the observed association of the CAD with SNPs at the 9p21 locus in the case-control GWAS reflect involvement of vascular mechanisms not directly related to the severity or progression of coronary atherosclerosis.

Dataset Information

Long Noncoding RNA ANRIL: Lnc-ing Genetic Variation at the Chromosome 9p21 Locus to Molecular Mechanisms of Atherosclerosis.

Publications

Long Noncoding RNA <i>ANRIL</i>: Lnc-ing Genetic Variation at the Chromosome 9p21 Locus to Molecular Mechanisms of Atherosclerosis.

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