Haihua Zhang1,2, Tao Wang3,4, Zhifa Han5,6,7, Guiyou Liu8,9,10. 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. 5. School of Medicine, School of Pharmaceutical Sciences, THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China. 6. State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China. 7. Department of Pathophysiology, Peking Union Medical College, Beijing, China. 8. National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. liuguiyou1981@163.con. 9. Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China. liuguiyou1981@163.con. 10. Department of Neurology, Xuanwu Hospital, Capital Medical University, Room 1037, Donghuajinzuo, Guanganmennei Street, XiCheng District, Beijing, 100053, China. liuguiyou1981@163.con.
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.
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 humanIL-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.
Entities:
Keywords:
Genome-wide association study; Interleukin-6; Mendelian randomization; Multiple sclerosis; Tocilizumab
Authors: Luyan Gao; Kun Wang; Qing-Bin Ni; Hongguang Fan; Lan Zhao; Lei Huang; Mingfeng Yang; Huanming Li Journal: Front Genet Date: 2022-02-11 Impact factor: 4.599