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Genome-wide association studies (GWASs) have identified many genomic variants that contribute to common,late-onset diseases such as coronary artery disease and stroke.However,these variants contribute to only a small proportion of the heritability of each disease.Thus,it is important to identify new genomic variants that can account for the rest of the heritability.The ANRIL gene has long been considered as the strongest candidate gene at the 9p21 locus,which was robustly associated with stroke and coronary artery disease.However,the underlying molecular mechanism remains unknown.The present study works to elucidate such a mechanism.Using expression quantitative loci (eQTL) analysis,we identified potential genes whose expression may be influenced by genetic variation in ANRIL.To verify the identified gene(s),knockdown and overexpression of ANRIL were evaluated in human umbilical vein endothelial cells and HepG2 cells.Ischemic stroke and coronary artery disease risk were then evaluated in the gene(s) demonstrated to be mediated by ANRIL in 3 populations of Chinese Han ancestry:two ischemic stroke populations consisting of the Central China cohort (903 cases and 873 controls) and the Northern China cohort (816 cases and 879 controls) and one coronary artery disease cohort consisting of 772 patients and 873 controls.The eQTL analysis identified CARD8 among others,with knockdown of ANRIL expression decreasing CARD8 expression and overexpression of ANRIL increasing CARD8 expression.The minor T allele of a previously identified CARD8 variant (rs2043211) was found to be significantly associated with a protective effect of ischemic stroke under the recessive model in 2 independent stroke cohorts.No significant association was found between rs2043211 and coronary artery disease.We conclude that CARD8 is a downstream target gene regulated by ANRI,single nucleotide polymorphism rs2043211 in CARD8 is significantly associated with ischemic stroke and ANRIL may increase the risk of ischemic stroke through regulation of the CARD8 pathway.