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Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases

Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with...

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Autores principales: Ferreira, Ricardo C., Freitag, Daniel F., Cutler, Antony J., Howson, Joanna M. M., Rainbow, Daniel B., Smyth, Deborah J., Kaptoge, Stephen, Clarke, Pamela, Boreham, Charlotte, Coulson, Richard M., Pekalski, Marcin L., Chen, Wei-Min, Onengut-Gumuscu, Suna, Rich, Stephen S., Butterworth, Adam S., Malarstig, Anders, Danesh, John, Todd, John A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617094/
https://www.ncbi.nlm.nih.gov/pubmed/23593036
http://dx.doi.org/10.1371/journal.pgen.1003444
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author Ferreira, Ricardo C.
Freitag, Daniel F.
Cutler, Antony J.
Howson, Joanna M. M.
Rainbow, Daniel B.
Smyth, Deborah J.
Kaptoge, Stephen
Clarke, Pamela
Boreham, Charlotte
Coulson, Richard M.
Pekalski, Marcin L.
Chen, Wei-Min
Onengut-Gumuscu, Suna
Rich, Stephen S.
Butterworth, Adam S.
Malarstig, Anders
Danesh, John
Todd, John A.
author_facet Ferreira, Ricardo C.
Freitag, Daniel F.
Cutler, Antony J.
Howson, Joanna M. M.
Rainbow, Daniel B.
Smyth, Deborah J.
Kaptoge, Stephen
Clarke, Pamela
Boreham, Charlotte
Coulson, Richard M.
Pekalski, Marcin L.
Chen, Wei-Min
Onengut-Gumuscu, Suna
Rich, Stephen S.
Butterworth, Adam S.
Malarstig, Anders
Danesh, John
Todd, John A.
author_sort Ferreira, Ricardo C.
collection PubMed
description Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10(−22)) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10(−22)). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10(−7)). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.
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spelling pubmed-36170942013-04-16 Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases Ferreira, Ricardo C. Freitag, Daniel F. Cutler, Antony J. Howson, Joanna M. M. Rainbow, Daniel B. Smyth, Deborah J. Kaptoge, Stephen Clarke, Pamela Boreham, Charlotte Coulson, Richard M. Pekalski, Marcin L. Chen, Wei-Min Onengut-Gumuscu, Suna Rich, Stephen S. Butterworth, Adam S. Malarstig, Anders Danesh, John Todd, John A. PLoS Genet Research Article Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10(−22)) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10(−22)). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10(−7)). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant. Public Library of Science 2013-04-04 /pmc/articles/PMC3617094/ /pubmed/23593036 http://dx.doi.org/10.1371/journal.pgen.1003444 Text en © 2013 Ferreira et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ferreira, Ricardo C.
Freitag, Daniel F.
Cutler, Antony J.
Howson, Joanna M. M.
Rainbow, Daniel B.
Smyth, Deborah J.
Kaptoge, Stephen
Clarke, Pamela
Boreham, Charlotte
Coulson, Richard M.
Pekalski, Marcin L.
Chen, Wei-Min
Onengut-Gumuscu, Suna
Rich, Stephen S.
Butterworth, Adam S.
Malarstig, Anders
Danesh, John
Todd, John A.
Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases
title Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases
title_full Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases
title_fullStr Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases
title_full_unstemmed Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases
title_short Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases
title_sort functional il6r 358ala allele impairs classical il-6 receptor signaling and influences risk of diverse inflammatory diseases
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617094/
https://www.ncbi.nlm.nih.gov/pubmed/23593036
http://dx.doi.org/10.1371/journal.pgen.1003444
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