Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases
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ORIGINAL ARTICLE
Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases Haihua Zhang 1,2 & Tao Wang 3,4 & Zhifa Han 5,6,7 & Guiyou Liu 1,2,8 Received: 23 October 2019 / Accepted: 27 March 2020 # Fondazione Società Italiana di Neurologia 2020
Abstract Background Multiple sclerosis (MS) is a complex neurological disease and chronic inflammatory disease. Until now, observational studies have reported positive association between serum interleukin-6 (IL-6) levels and MS risk. In order to develop effective therapies, we should establish the causal link between IL-6 signaling and MS. However, it is currently unknown whether IL-6 signaling is causally associated with the risk of MS. Methods Here, we selected the increased soluble IL-6R (s-IL-6R) levels as the indirect markers for reduced IL-6 signaling, and performed a Mendelian randomization (MR) study using the rs2228145 variant as the instrumental variable to evaluate and quantify the effect of IL-6 signaling on the risk of MS. To be a comparison, we also evaluated the causal association of IL-6 signaling with the risk of other three neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Results We found that the increased s-IL-6R levels (per 1 standard deviation) were significantly associated with decreased MS risk (OR = 0.96, 95% CI 0.94–0.98, P = 1.69E-04), but not associated with the risk of AD (OR = 1.01, 95% CI 0.92–1.11, P = 0.835), PD (OR = 0.94, 95% CI 0.84–1.05, P = 0.261), or ALS (OR = 1.00, 95% CI 0.92–1.10, P = 0.9411). Conclusion Our findings have the similar directional effects to an existing humanized anti-IL-6R monoclonal antibody Tocilizumab which could bind to the IL-6 binding site of human IL-6R and competitively inhibit IL-6 signaling. Hence, we provided genetic evidence that inhibiting the IL-6 signaling such as tocilizumab treatment might represent a novel therapy for MS. Keywords Multiple sclerosis . Tocilizumab . Interleukin-6 . Genome-wide association study . Mendelian randomization
Introduction Multiple sclerosis (MS) is a complex neurological disease and chronic inflammatory disease [1]. It is reported that MS is caused by both genetic and environmental factors [2–4]. Interleukin-6 (IL-6) is an important inflammatory cytokine involved in inflammatory diseases, which could exert its effect via classic signaling
* Guiyou Liu [email protected] 1
National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
2
Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
3
Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
4
Chinese Institute for Brain Research, Beijing, China
and trans-signaling [5, 6]. 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) [7, 8]. In
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