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Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases

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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.

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Data availability

All relevant data are within the paper. The authors confirm that all data underlying the findings are either fully available without restriction through consortia websites or may be made available from consortia upon request. Social Science Genetic Association Consortium (SSGAC): https://www.thessgac.org/data; type 2 diabetes from DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium: http://diagram-consortium.org/downloads.html; Tobacco and Genetics Consortium (TGC): http://www.med.unc.edu/pgc/downloads; Ukbiobank: http://www.ukbiobank.ac.uk/scientists-3/genetic-data/;https://sites.google.com/broadinstitute.org/ukbbgwasresults/home?authuser=0;http://geneatlas.roslin.ed.ac.uk; International MS Genetics Consortium (IMSGC): http://imsgc.net/publications/.

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Acknowledgments

We thank International Multiple Sclerosis Genetics Consortium, International Genomics of Alzheimer’s Project (IGAP), International Parkinson’s Disease Genomics Consortium, Tobacco and Genetics Consortium, and the SUNLIGHT consortium for the GWAS summary statistics. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. We thank Longcai Wang and Yan Zhang for their contribution to this revision.

Funding

The i-Select chips was funded by the French National Foundation on AD and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2, and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant no. 503480), Alzheimer’s Research UK (Grant no. 503176), the Wellcome Trust (Grant no. 082604/2/07/Z), and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no. 01GI0102, 01GI0711, and 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG-12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer’s Association grant ADGC-10-196728.

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Authors and Affiliations

  1. National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China

    Haihua Zhang & Guiyou Liu

  2. Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China

    Haihua Zhang & Guiyou Liu

  3. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Tao Wang

  4. Chinese Institute for Brain Research, Beijing, China

    Tao Wang

  5. School of Medicine, School of Pharmaceutical Sciences, THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China

    Zhifa Han

  6. State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China

    Zhifa Han

  7. Department of Pathophysiology, Peking Union Medical College, Beijing, China

    Zhifa Han

  8. Department of Neurology, Xuanwu Hospital, Capital Medical University, Room 1037, Donghuajinzuo, Guanganmennei Street, XiCheng District, Beijing, 100053, China

    Guiyou Liu

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  1. Haihua Zhang
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Contributions

GYL and HHZ conceived and initiated the project. GYL and HHZ analyzed the data and wrote the first draft of the manuscript. All authors contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.

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Correspondence to Guiyou Liu.

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The authors declare that they have no competing interests.

Ethics approval and consent to participate

This article contains human participants collected by several studies performed by previous studies. All participants gave informed consent in all the corresponding original studies, as described in the “Materials and methods” section. Here, our study is based on the publicly available, large-scale GWAS summary datasets, and not the individual-level data. Hence, ethical approval was not sought.

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Zhang, H., Wang, T., Han, Z. et al. Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases. Neurol Sci 41, 2875–2882 (2020). https://doi.org/10.1007/s10072-020-04381-x

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