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

Abstract

Background and Purpose 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. Methods 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. Results 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. Conclusion 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.

Role of Genetic Alterations in theNLRP3andCARD8Genes in Health and Disease

“…However, in a Chinese cohort, the rs2043211 was associated with ischemic stroke [53]. A study from Spanish cohort also showed that rs2043211 was not associated with risk of developing cardiovascular events in RA patients [79].…”

MALAT1 promotes colorectal cancer cell proliferation/migration/invasion via PRKA kinase anchor protein 9

“…Emerging evidences show that lncRNAs are associated with a spectrum of biological processes such as gene regulation on transcriptional and post-transcriptional levels [4, 5] , chromatin modification and epigenetics, alternative splicing, protein activity modulation, and protein localization, etc. Dysregulation of lncRNAs is also an important feature of many complex human diseases, including Alzheimer’s disease [6] ischemic diseases [7] , heart disease [8] and cancer [9, 10] . In fact, lncRNAs have been recognized as a hallmark of the onset and development of various tumors or tumor suppressor pathways [11, 12] .…”

The Association of <b><i>CARD8</i></b> rs2043211 Polymorphism with Preeclampsia in the Chinese Han Population

“…As a functional variant in CARD8, polymorphism of rs2043211 yields a truncated non-functional protein, resulting in the loss of CARD8-mediated inhibition of caspase-1 and apoptosis [35], which may influence the onset of PE. Several recent studies have indicated associations between the polymorphism of rs2043211 with different inflammatory diseases, including inflammatory bowel disease and rheumatoid arthritis [16,17,18]. …”

“…The mutation of CARD8 (p.C10X) (rs2043211) changes cysteine at codon 10 to a premature termination codon, thus yielding a premature, truncated protein [14,15], which influences the protein function in inflammasome-mediated processes and NF-κB suppression [13]. This variant was reported to have association with inflammatory bowel disease, rheumatoid arthritis and ischemic stroke [16,17,18]. …”