IL-6R protective variant rs7529229 reduces interleukin-6 signaling and contributes to decreased ischemic stroke risk [post]

Haihua Zhang, Wenbo Zhao, Bian Liu, Tao Wang, Zhifa Han, Xunming Ji, Guiyou Liu
2020 unpublished
BackgroundInterleukin-6 (IL-6) signaling is associated with the increased risk of coronary artery disease (CAD) and ischemic stroke (IS). Growing evidence shows that the minor allele of IL-6R rs7529229 variant could significantly increase the soluble IL-6 receptor levels and reduce CAD risk. However, it is largely unknown about the role of rs7529229 in IS, which promotes us to perform a comprehensive analysis. MethodsIn stage 1, we performed a meta-analysis of three GWAS datasets from
more » ... , UK Biobank, and Million Veteran Program to evaluate the association of rs7529229 with IS. In stage 2, we conducted an expression quantitative trait loci analysis to examine the effects of rs7529229 on IL-6R expression in neuropathologically normal individuals from UK Brain Expression Consortium, GTEx project and eQTLGen Consortium. In stage 3, a tissue-specific gene expression analysis is used to evaluate the potential difference of IL-6R expression across the human tissues using gene expression data from GTEx. In stage 4, a case-control gene expression analysis is used to explore the potentially differential expression of IL-6R in IS and healthy controls in whole blood. ResultsOur results show that (1) rs7529229 minor allele could significantly reduce the risk of IS (OR=0.97, 95% CI 0.95-0.99, P=2.30E-03); (2) rs7529229 minor allele could significantly reduce IL-6R expression in relevant tissues especially in blood vessels and whole blood; (3) IL-6R is mainly expressed in skeletal muscle and whole blood; (4) expression of IL-6R is significantly reduced in healthy controls compared with IS cases in whole blood. Importantly, the biological senses in stage 1-4 are all convergent. ConclusionsCollectively, these findings indicate that rs7529229 minor allele may first reduce IL-6R expression in relevant tissues, further reduce IL-6 signaling, and eventually reduce the IS risk. Hence, IL-6R may be a potential therapeutic target, and blocking IL-6 signaling might be effective in treatment of IS.
doi:10.21203/rs.3.rs-37472/v1 fatcat:y2ga3cdg3zb2vk2znal7u53npi