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

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Title: Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases.
Authors: Zhang, Haihua (AUTHOR), Wang, Tao (AUTHOR), Han, Zhifa (AUTHOR), Liu, Guiyou (AUTHOR)
Source: Neurological Sciences. Oct2020, Vol. 41 Issue 10, p2875-2882. 8p. 1 Diagram, 1 Chart.
Subjects: Rubella, Neurodegeneration, Interleukin-6, Amyotrophic lateral sclerosis, Alzheimer's disease, Interleukins, Cellular signal transduction
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. [ABSTRACT FROM AUTHOR]
Copyright of Neurological Sciences is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases.
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  Data: <searchLink fieldCode="AR" term="%22Zhang%2C+Haihua%22">Zhang, Haihua</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wang%2C+Tao%22">Wang, Tao</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Han%2C+Zhifa%22">Han, Zhifa</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Liu%2C+Guiyou%22">Liu, Guiyou</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Neurological+Sciences%22">Neurological Sciences</searchLink>. Oct2020, Vol. 41 Issue 10, p2875-2882. 8p. 1 Diagram, 1 Chart.
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  Data: <searchLink fieldCode="DE" term="%22Rubella%22">Rubella</searchLink><br /><searchLink fieldCode="DE" term="%22Neurodegeneration%22">Neurodegeneration</searchLink><br /><searchLink fieldCode="DE" term="%22Interleukin-6%22">Interleukin-6</searchLink><br /><searchLink fieldCode="DE" term="%22Amyotrophic+lateral+sclerosis%22">Amyotrophic lateral sclerosis</searchLink><br /><searchLink fieldCode="DE" term="%22Alzheimer's+disease%22">Alzheimer's disease</searchLink><br /><searchLink fieldCode="DE" term="%22Interleukins%22">Interleukins</searchLink><br /><searchLink fieldCode="DE" term="%22Cellular+signal+transduction%22">Cellular signal transduction</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: <bold>Background: </bold>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.<bold>Methods: </bold>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).<bold>Results: </bold>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).<bold>Conclusion: </bold>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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Neurological Sciences is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1007/s10072-020-04381-x
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      – SubjectFull: Interleukin-6
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      – SubjectFull: Interleukins
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      – SubjectFull: Cellular signal transduction
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      – TitleFull: Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases.
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              Text: Oct2020
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