Variants on Chromosome 9p21.3 Correlated With ANRIL Expression Contribute to Stroke Risk and Recurrence in a Large Prospective Stroke Population

Abstract

Background and Purpose-ANRIL encodes a long antisense noncoding RNA in the INK4 locus. Although ANRIL has been proven to be associated with coronary heart disease, its roles in stroke are inconsistent, and sparse data are available regarding hemorrhagic stroke. Methods-A Chinese case-control study was conducted, comprising 1657 cases (724 atherothrombosis, 466 lacunar infarction, and 462 hemorrhagic strokes) and 1664 controls. Stroke patients were prospectively followed-up for a median of 4.5 (range, 0.1-6.0) years. Expression of ANRIL transcripts was examined in 42 human atherosclerotic plaques. Results-After adjustment for vascular risk factors and correction for multiple comparisons, subjects carrying the GG genotype of rs10757278 had 1.47-fold (95% CI, 1.11-1.89; Pϭ0.05) and 1.60-fold (95% CI, 1.16 -2.15; Pϭ0.04) increased risk for atherothrombotic and hemorrhagic strokes, respectively. During the follow-up, 317 recurrent strokes and 301 deaths from all causes were documented. Subjects carrying rs10757278GG had higher risk for stroke recurrence (relative risk [RR],1.56; 95% CI,1.15-2.12; Pϭ0.005) and cardiovascular mortality (RR, 2.0; 95% CI, 1.26 -3.18; Pϭ0.003), respectively. Rs10757274 was also associated with stroke risk and recurrence. Family history of stroke further increased the stroke risk by 2.37-fold (95% CI, 1.38 -4.06; Pϭ0.01) and recurrent stroke risk by 2.45-fold (95% CI, 1.56 -3.86; PϽ0.0001) respectively, when compared with those carrying none of G-alleles and without family history. Finally, rs10757278 was associated with differential expression of the ANRIL transcripts. Conclusions-Our findings indicated that the ANRIL may serve as a novel genetic marker for the risk of atherothrombotic and hemorrhagic stroke and their recurrence. (Stroke. 2012;43:14-21.)Key Words: chromosome 9p21.3 Ⅲ follow-up studies Ⅲ genetics Ⅲ risk factors S troke is a major cause of death and disability worldwide and in China. Survivors are often disabled, require long-term care, and are at high risk of recurrence. Among subtypes of stroke, hemorrhagic stroke accounts for 20% to 40% in the Chinese population; in contrast, the majority (80 -90%) of strokes are cerebral infarctions in most western populations. 1 The reasons for high risk of stroke, especially hemorrhagic stroke, among the Chinese, remain unknown. The contribution of genetic risk to stroke is still not completely understood.It is generally accepted that genetic variants on chromosome 9p21.3 are associated with the risk of coronary artery disease, 2-4 but its roles in stroke are inconsistent. [5][6][7][8][9][10][11][12] A recent meta-analysis 13 showed that the association of 9p21.3 with stroke is only confined to the subtype of large-vessel strokes. However, a recent genome-wide association study showed that the 9p21.3 region is also implicated in risk for intracranial aneurysm, in which atherosclerosis is not thought to play a major role. 14 Therefore, additional studies are needed to determine the mechanisms by which the 9p21.3 region affects vascular...

Epigenetic Mechanisms Underlying the Pathogenesis of Neurogenetic Diseases

“…For example, single nucleotide polymorphisms (SNPs) in BRD2, which encodes a chromatin-binding protein that recognizes acetylated histones, confer a significant degree of susceptibility to juvenile myoclonic epilepsy [24]. SNPs in the ANRIL/ CDKN2B-AS1 lncRNA gene on chromosome 9p21.3 are risk loci for a number of diseases, including ischemic and hemorrhagic stroke, intracranial aneurysms, plexiform neurofibromas, and Alzheimer disease (AD) [25,26]. By contrast, SNPs can influence miRNA-mediated gene regulation by creating, destroying, or otherwise modifying miRNA response elements in genes associated with nervous systems disease pathophysiology [e.g., AD, Parkinson disease (PD), multiple sclerosis (MS), schizophrenia, and depression] [27][28][29].…”

9p21 locus rs10757278 is associated with advanced carotid atherosclerosis in a gender-specific manner

“…17 Also, the rs10757278 genotypes were linked to differential expression of ANRIL splice variants, MTAP, and CDKN2A genes in CP tissue. 19 Atherosclerosis development and progression may be affected by differential expression of ANRIL splice variants that could interfere with gene expression in many processes, such as proliferation, remodeling of extracellular matrix, and response to inflammation. 20 The aim of this study was to analyze the possible association of 9p21 rs10757278 polymorphism with CP presence in patients with advanced atherosclerosis.…”

9p21 Polymorphisms increase the risk of peripheral artery disease in the Han Chinese population

“…Numerous genome-wide studies have shown that common sequence variants on chromosome 9p21 are closely associated with increased risk of atherosclerotic diseases including coronary artery disease (CAD), [1][2][3][4] myocardial infarction [5][6][7] and stroke, [8][9][10] with the single nucleotide polymorphisms (SNPs) rs10757274 and rs10757278…”

“…1,11,12 The homozygous GG genotype of rs10757278 is associated with CAD severity, extent and progression in Caucasian populations, 13 and both loci are also significantly associated with ischaemic stroke risk. 9,14 The increased risk of atherosclerosis is mediated via effects on the expression of cyclin-dependent kinase inhibitor 2 A (CDKN2A, also known as INK4/ARF). 9,15,16 Peripheral arterial disease (PAD) is a common form of atherosclerotic disease that has a similar aetiology and pathogenesis to CAD and ischaemic stroke.…”

“…9,14 The increased risk of atherosclerosis is mediated via effects on the expression of cyclin-dependent kinase inhibitor 2 A (CDKN2A, also known as INK4/ARF). 9,15,16 Peripheral arterial disease (PAD) is a common form of atherosclerotic disease that has a similar aetiology and pathogenesis to CAD and ischaemic stroke. 17 PAD increases the risk of disability, all-cause mortality and cardiovascular mortality.…”