Variation in Interleukin 6 Receptor Gene Associates With Risk of Crohn’s Disease and Ulcerative Colitis

Abstract

Interleukin 6 (IL6) is an inflammatory cytokine; signaling via its receptor (IL6R) is believed to contribute to development of inflammatory bowel diseases (IBD). The single nucleotide polymorphism rs2228145 in IL6R associates with increased levels of soluble IL6R (s-IL6R), as well as reduced IL6R signaling and risk of inflammatory disorders; its effects are similar to those of a therapeutic monoclonal antibody that blocks IL6R signaling. We used the effect of rs2228145 on s-IL6R level as an indirect marker to investigate whether reduced IL6R signaling associates with risk of ulcerative colitis (UC) or Crohn’s disease (CD). In a genome-wide meta-analysis of 20,550 patients with CD, 17,647 patients with UC, and more than 40,000 individuals without IBD (controls), we found that rs2228145 (scaled to a 2-fold increase in s-IL6R) was associated with reduced risk of CD (odds ratio 0.876; 95% confidence interval 0.822–0.933; P = .00003) or UC (odds ratio 0.932; 95% confidence interval 0.875–0.996; P = .036). These findings indicate that therapeutics designed to block IL6R signaling might be effective in treatment of IBD.

Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

“…As the instruments used in the current setting were not identified based on established biological effects, but solely on the basis of their statistical associations with CRP levels, in an additional sensitivity analysis, we restricted our genetic instrument to a single SNP (rs2228145) within the IL6R gene with well-established biological effects leading to a downregulation of the IL-6 signaling. 20,34,38,39 To disentangle the effects of IL-6 signaling from the respective effects of CRP, we selected SNPs associated with CRP levels at genome-wide significance (p<5x10 -8 ) throughout the genome and clumped them to r 2 < 0.1. We then performed MR analyses using all these SNPs as instruments, and performed 10,000 permutations for each outcome using 7 randomly selected SNPs (the same number as those used as instruments for IL-6 signaling).…”

“…29,30 Hence, MR has become a powerful strategy to prioritize interventions for exploration in clinical trials. 28 Here, leveraging data from large genome-wide association studies (GWASs) [31][32][33] and applying MR analyses, we aimed to: (i) identify genetic proxies for downregulated IL-6 signaling on the basis of their effects on CRP levels, a well-established IL-6 signaling downstream effector, 13,20,34 (ii) validate their utility by comparing the consistency of their effects on upstream regulators and downstream effectors of the IL-6 signaling pathway with the effects of pharmacological IL-6R inhibition, as derived from clinical trials, (iii) explore associations of genetic predisposition to downregulated IL-6 signaling with the risk of ischemic stroke and coronary artery disease, (iv) examine associations with major etiological subtypes of ischemic stroke (large artery, cardioembolic, and small vessel stroke), and (v) examine associations with a broad range of other cardiovascular phenotypes. To derive clinically meaningful effect sizes that would be comparable to those derived from potential future clinical trials, we weighted our instruments based on the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R.…”

Reply

“…I read with interest the recent publication of the pair of phase III trials for the use of avatrombopag before invasive procedures in patients with chronic liver disease and severe thrombocytopenia. 1 Given the increase in portal vein thrombosis that occurred in trials in a similar group of patients receiving the once-promising eltrombopag, the investigators were bold in this endeavor. 2 Learning from the 2012 ELEVATE trial, the ADAPT trials were more conservative in design, treating patients with the thrombopoietinreceptor agonist for 5 days (compared with 14 days) to mitigate the potential for portal vein thrombosis.…”

“…2 Learning from the 2012 ELEVATE trial, the ADAPT trials were more conservative in design, treating patients with the thrombopoietinreceptor agonist for 5 days (compared with 14 days) to mitigate the potential for portal vein thrombosis. 1,2 The authors acknowledge in the introduction of the article that there is no universal consensus for the safe level of platelet count in this patient population-an important point to take into account given the composite primary endpoint of the need for platelet transfusion or rescue procedure for bleeding. The trial did meet its primary composite end point, but the investigators do not provide the breakdown of the composite end point-platelet transfusion or rescue procedure for bleeding.…”

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

“…Interleukin-6 (IL-6) is an important in ammatory cytokine, and could exert its effect via classic signaling and trans-signaling [1]. In classic signaling, IL-6 binds to membrane-bound IL-6 receptor (IL-6R), forms IL-6-IL-6R complex, and then recruits glycoprotein 130 (gp130) [2][3].…”