Abstract
Background Interleukin-6 (IL-6) signaling is associated with an increased risk of coronary artery disease (CAD) and ischemic stroke (IS). Growing evidence shows that the minor alleles of IL-6 receptor gene (IL-6R) variants rs2228145, rs7529229, and rs4129267 significantly increase soluble IL-6R levels and reduce CAD risk. However, the role of IL-6R variants in IS is largely unknown, prompting us to perform a comprehensive analysis. Methods In stage 1 of this study, we performed a meta-analysis of three genome-wide association study datasets from MEGASTROKE, UK Biobank, and the 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 healthy individuals from the UK Brain Expression Consortium, GTEx project, and the eQTLGen Consortium. In stage 3, we used a tissue-specific gene expression analysis to evaluate differences in IL-6R expression across human tissues using gene expression data from GTEx. In stage 4, we conducted a case–control gene expression analysis to explore the differential expression of IL-6R in the whole blood of IS patients and healthy controls. Results We found that: (1) the rs7529229 minor allele significantly reduced the risk of developing IS (odds ratio=0.97, 95% confidence interval 0.95–0.99, P=2.30E-03); (2) the rs7529229 minor allele significantly reduced IL-6R expression in relevant tissues especially in blood vessels and whole blood; (3) IL-6R was mainly expressed in skeletal muscle and whole blood; and (4) IL-6R expression was significantly reduced in the whole blood of healthy controls compared with IS patients. Importantly, the biological senses in stages 1–4 were all convergent. Conclusions Taken together, our findings indicate that the rs7529229 minor allele decreases IL-6R expression in relevant tissues, diminishes IL-6 signaling, and eventually reduces the IS risk. Hence, IL-6R may be a potential therapeutic target for IS. Tocilizumab, a monoclonal antibody that blocks both membrane-bound and circulating IL-6R, might be effective in treating IS or lowering its risk of development, so warrants further testing in suitably powered randomized controlled trials.
Gene expression analysis of peripheral blood leukocytes from discordant sib-pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches