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

Abstract

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. 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. 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; P=0.05) and 1.60-fold (95% CI, 1.16-2.15; P=0.04) 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; P=0.005) and cardiovascular mortality (RR, 2.0; 95% CI, 1.26-3.18; P=0.003), 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; P=0.01) and recurrent stroke risk by 2.45-fold (95% CI, 1.56-3.86; P<0.0001) 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. Our findings indicated that the ANRIL may serve as a novel genetic marker for the risk of atherothrombotic and hemorrhagic stroke and their recurrence.