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IL6 receptor(358)Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis
OBJECTIVE: To test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (Asp(358)Ala, rs2228145, C allele) have associated increases in interleukin 6 (IL6) and IL6R levels in serum and CSF and faster disease progress...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865852/ https://www.ncbi.nlm.nih.gov/pubmed/31611269 http://dx.doi.org/10.1212/NXI.0000000000000631 |
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author | Wosiski-Kuhn, Marlena Robinson, Mac Strupe, Jane Arounleut, Phonepasong Martin, Matthew Caress, James Cartwright, Michael Bowser, Robert Cudkowicz, Merit Langefeld, Carl Hawkins, Gregory A. Milligan, Carol |
author_facet | Wosiski-Kuhn, Marlena Robinson, Mac Strupe, Jane Arounleut, Phonepasong Martin, Matthew Caress, James Cartwright, Michael Bowser, Robert Cudkowicz, Merit Langefeld, Carl Hawkins, Gregory A. Milligan, Carol |
author_sort | Wosiski-Kuhn, Marlena |
collection | PubMed |
description | OBJECTIVE: To test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (Asp(358)Ala, rs2228145, C allele) have associated increases in interleukin 6 (IL6) and IL6R levels in serum and CSF and faster disease progression than noncarriers. METHODS: An observational, case-control study of paired serum and CSF of 47 patients with ALS, 46 healthy, and 23 neurologic disease controls from the Northeastern ALS Consortium Biofluid Repository (cohort 1) was performed to determine serum levels of IL6, sIL6R, and soluble glycoprotein 130 and compared across groups and IL6R genotype. Clinical data regarding disease progression from a separate cohort of 35 patients with ALS from the Wake Forest ALS Center (cohort 2) were used to determine change in ALSFRS-R scores by genotype. RESULTS: Patients with ALS had increased CSF IL6 levels compared with healthy (p < 0.001) and neurologic (p = 0.021) controls. Patients with ALS also had increased serum IL6 compared with healthy (p = 0.040) but not neurologic controls. Additive allelic increases in serum IL6R were observed in all groups (average increase of 52% with the presence of the IL6R C allele; p < 0.001). However, only subjects with ALS had significantly increased CSF sIL6R levels compared with controls (p < 0.001). When compared across genotypes, only patients with ALS inheriting the IL6R C allele exhibit increased CSF IL6. ALSFRS-R scores decreased more in patients with ALS with the IL6R C allele than in those without (p = 0.019). CONCLUSIONS: Theses results suggest that for individuals inheriting the IL6R C allele, the cytokine exerts a disease- and location-specific role in ALS. Follow-up, prospective studies are necessary, as this subgroup of patients may be identified as ideally responsive to IL6 receptor–blocking therapies. |
format | Online Article Text |
id | pubmed-6865852 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-68658522019-12-13 IL6 receptor(358)Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis Wosiski-Kuhn, Marlena Robinson, Mac Strupe, Jane Arounleut, Phonepasong Martin, Matthew Caress, James Cartwright, Michael Bowser, Robert Cudkowicz, Merit Langefeld, Carl Hawkins, Gregory A. Milligan, Carol Neurol Neuroimmunol Neuroinflamm Article OBJECTIVE: To test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (Asp(358)Ala, rs2228145, C allele) have associated increases in interleukin 6 (IL6) and IL6R levels in serum and CSF and faster disease progression than noncarriers. METHODS: An observational, case-control study of paired serum and CSF of 47 patients with ALS, 46 healthy, and 23 neurologic disease controls from the Northeastern ALS Consortium Biofluid Repository (cohort 1) was performed to determine serum levels of IL6, sIL6R, and soluble glycoprotein 130 and compared across groups and IL6R genotype. Clinical data regarding disease progression from a separate cohort of 35 patients with ALS from the Wake Forest ALS Center (cohort 2) were used to determine change in ALSFRS-R scores by genotype. RESULTS: Patients with ALS had increased CSF IL6 levels compared with healthy (p < 0.001) and neurologic (p = 0.021) controls. Patients with ALS also had increased serum IL6 compared with healthy (p = 0.040) but not neurologic controls. Additive allelic increases in serum IL6R were observed in all groups (average increase of 52% with the presence of the IL6R C allele; p < 0.001). However, only subjects with ALS had significantly increased CSF sIL6R levels compared with controls (p < 0.001). When compared across genotypes, only patients with ALS inheriting the IL6R C allele exhibit increased CSF IL6. ALSFRS-R scores decreased more in patients with ALS with the IL6R C allele than in those without (p = 0.019). CONCLUSIONS: Theses results suggest that for individuals inheriting the IL6R C allele, the cytokine exerts a disease- and location-specific role in ALS. Follow-up, prospective studies are necessary, as this subgroup of patients may be identified as ideally responsive to IL6 receptor–blocking therapies. Lippincott Williams & Wilkins 2019-10-14 /pmc/articles/PMC6865852/ /pubmed/31611269 http://dx.doi.org/10.1212/NXI.0000000000000631 Text en Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Article Wosiski-Kuhn, Marlena Robinson, Mac Strupe, Jane Arounleut, Phonepasong Martin, Matthew Caress, James Cartwright, Michael Bowser, Robert Cudkowicz, Merit Langefeld, Carl Hawkins, Gregory A. Milligan, Carol IL6 receptor(358)Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis |
title | IL6 receptor(358)Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis |
title_full | IL6 receptor(358)Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis |
title_fullStr | IL6 receptor(358)Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis |
title_full_unstemmed | IL6 receptor(358)Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis |
title_short | IL6 receptor(358)Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis |
title_sort | il6 receptor(358)ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865852/ https://www.ncbi.nlm.nih.gov/pubmed/31611269 http://dx.doi.org/10.1212/NXI.0000000000000631 |
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