Regulation of CARD8 Expression by ANRIL and Association of CARD8 Single Nucleotide Polymorphism rs2043211 (p.C10X) With Ischemic Stroke

• Published in: Stroke (1970) Vol. 45; no. 2; pp. 383 - 388
• Main Authors: YING BAI, SHAOFANG NIE, QIN YANG, QINGXIAN LI, YUE LI, YUNLONG XIA, YING LIU, JINQIU LIU, JIN QIAN, BIN LI, GANG WU, YANXIA WU, GUIQING JIANG, BINBIN WANG, XIANG CHENG, YANZONG YANG, TIE KE, HUI LI, XIANG REN, XU MA, YUHUA LIAO, CHENGQI XU, XIN TU, YINGCHAO ZHOU, WANG, Qing K, MENGCHEN ZHOU, YUANYUAN ZHAO, SISI LI, FAN WANG, QIULUN LV, YUFENG HUANG
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.02.2014
• Subjects: Adult; Aged; Aged, 80 and over; Asian Continental Ancestry Group; Biological and medical sciences; Brain Ischemia - epidemiology; Brain Ischemia - genetics; CARD Signaling Adaptor Proteins - genetics; Cardiology. Vascular system; China - epidemiology; Coronary Artery Disease - epidemiology; Coronary Artery Disease - genetics; Coronary heart disease; Female; Gene Expression - physiology; Genotype; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Heart; Humans; Male; Medical sciences; Middle Aged; Neoplasm Proteins - genetics; Nervous system (semeiology, syndromes); Neurology; Polymorphism, Single Nucleotide - genetics; Real-Time Polymerase Chain Reaction; RNA, Long Noncoding - genetics; Stroke - epidemiology; Stroke - genetics; Transfection; Vascular diseases and vascular malformations of the nervous system; China; coronary artery disease; Cerebral infarction; Stroke; Nervous system diseases; Cardiovascular disease; polymorphism; Case control study; Coronary heart disease; CARD8 gene; Cerebral disorder; Vascular disease; Central nervous system disease; Brain ischemia; single nucleotide; Single nucleotide polymorphism; Cerebrovascular disease; case-control studies; case–control studies; stroke; polymorphism, single nucleotide
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.113.003393

ANRIL has long been considered as the strongest candidate gene at the 9p21 locus, 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 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: 2 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 1 coronary artery disease cohort consisting of 772 patients and 873 controls. Expression quantitative loci 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. CARD8 is a downstream target gene regulated by ANRIL. Single nucleotide polymorphism rs2043211 in CARD8 is significantly associated with ischemic stroke. ANRIL may increase the risk of ischemic stroke through regulation of the CARD8 pathway.