Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke.
Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke.
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ANRIL 对 CARD8 表达的调节以及 CARD8 单核苷酸多态性 rs2043211 (p.C10X) 与缺血性中风的关联
DOI：
10.1161/strokeaha.113.003393
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发表时间：
2014-02
期刊：
影响因子：
8.3
通讯作者：
Wang QK
中科院分区：
文献类型：
--
作者：
Bai Y;Nie S;Jiang G;Zhou Y;Zhou M;Zhao Y;Li S;Wang F;Lv Q;Huang Y;Yang Q;Li Q;Li Y;Xia Y;Liu Y;Liu J;Qian J;Li B;Wu G;Wu Y;Wang B;Cheng X;Yang Y;Ke T;Li H;Ren X;Ma X;Liao Y;Xu C;Tu X;Wang QK
ANRIL一直被认为是9 p21位点上最强的候选基因，与中风和冠状动脉疾病（CAD）密切相关。然而，潜在的分子机制仍然未知。本研究试图阐明这种机制。利用eQTL分析，我们确定了潜在的基因，其表达可能受到ANRIL遗传变异的影响。为了验证鉴定的基因，在HUVEC和HepG 2细胞中评估ANRIL的敲低和过表达。然后在3个中国汉族人群中，在证实由ANRIL介导的基因中评价缺血性卒中和CAD风险;两个缺血性卒中人群，包括华中队列（903例病例和873例对照）和北方队列（816例病例和879例对照），以及一个CAD队列，包括772例患者和873例对照。eQTL分析鉴定了CARD 8等，其中ANRIL表达的敲低降低CARD 8表达，ANRIL的过表达增加CARD 8表达。在两个独立的中风队列中，发现先前鉴定的CARD 8变体（rs 2043211）的次要T等位基因与隐性模型下缺血性中风的保护作用显著相关。未发现rs 2043211与CAD之间存在显著关联。CARD 8是受ANRIL调控的下游靶基因。CARD 8中的SNP rs 2043211与缺血性卒中显著相关。ANRIL可能通过调节CARD 8通路增加缺血性卒中的风险。
ANRIL has long been considered as the strongest candidate gene at the 9p21 locus, robustly associated with stroke and coronary artery disease (CAD). However, the underlying molecular mechanism remains unknown. The present study works to elucidate such a mechanism. Utilizing eQTL analysis we identified potential genes whose expression may be influenced by genetic variation in ANRIL. To verify the identified gene(s), knockdown and over-expression of ANRIL was evaluated in HUVECs and HepG2 cells. Ischemic stroke and CAD risk was then evaluated in the gene(s) demonstrated to be mediated by ANRIL in 3 populations of Chinese Han ancestry; two ischemic stroke populations including the Central China cohort (903 cases and 873 controls) and the Northern China cohort (816 cases and 879 controls), and one CAD cohort consisting of 772 patients and 873 controls. eQTL analysis identified CARD8 among others, with knockdown of ANRIL expression decreasing CARD8 expression and over-expression 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 two independent stroke cohorts. No significant association was found between rs2043211 and CAD. CARD8 is a downstream target gene regulated by ANRIL. SNP rs2043211 in CARD8 is significantly associated with ischemic stroke. ANRIL may increase the risk of ischemic stroke through regulation of the CARD8 pathway.