Cited by 317Cytokine Signaling Pathways and InteractionsGenetic Associations and EpidemiologyRheumatoid Arthritis Research and Therapies

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

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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.·2013·PLoS Genetics

DOI 10.1371/journal.pgen.1003444PMC PMC3617094

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Abstract

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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Authors: Ferreira, R. C., Freitag, D. F., Cutler, A. J., Howson, J. M. M., Rainbow, D. B., Smyth, D. J., Kaptoge, S., Clarke, P., Boreham, C., Coulson, R. M., Pekalski, M. L., Chen, W.-M., Onengut-Gumuscu, S., Rich, S. S., Butterworth, A. S., Malarstig, A., Danesh, J., & Todd, J. A.
Affiliations: University of Cambridge (GB)
University of Virginia (US)
Corresponding author: Todd, John A.
ORCID: Ferreira, Ricardo C.
Cutler, Antony J.
Howson, Joanna M. M.
Rainbow, Daniel B.
Smyth, Deborah J.
Kaptoge, Stephen
Chen, Wei-Min
Rich, Stephen S.
Butterworth, Adam S.
Danesh, John
Todd, John A.
Venue: PLoS Genetics
Publisher: Public Library of Science (PLoS)
Published: 2013-04-04
Volume: 9
Issue: 4
Pages: e1003444
ISSN: 1553-7390 (ISSN-L)
1553-7404
DOI: 10.1371/journal.pgen.1003444
PMC: PMC3617094
OpenAlex: W1991747007
Cited by: 316
References: 56
Citations by year: 2026: 23 · 2025: 34 · 2024: 19 · 2023: 32 · 2022: 30 · 2021: 27 · 2020: 26 · 2019: 26 · 2018: 19 · 2017: 26 · 2016: 18 · 2015: 15 · 2014: 13 · 2013: 8
FWCI: 9.65
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS Genetics (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Figshare (submittedVersion, cc-by)
Funders: Juvenile Diabetes Research Foundation International (9-2011-253, U01 DK062418, 068545/Z/02)
Pfizer
GlaxoSmithKline
Wellcome Trust (068545/Z/02), FP7/2007–2013, 091157, 096388, G0000934, 061858, 100140, 068545, 9-2011-253, 076113, 076113/C/04/Z)
National Institute for Health and Care Research (NF-SI-0512-10165, FP7/2007–2013, G0000934, NF-SI-0508-10275)
British Heart Foundation (FS/09/050, RG/08/014, 068545/Z/02, G0000934, RG/08/014/24067)
Bupa Foundation
University of Cambridge
University of Leicester
European Commission (241447, 2007–2013, FP7 2007-2013, FP7/2007)
University of Bristol
Evelyn Trust
Merck Sharp and Dohme
Medical Research Council (FP7/20072013, MR/L003120/1, 068545/Z/02, G0000934)
Cambridge Institute for Medical Research, University of Cambridge (100140)
NIHR Cambridge Biomedical Research Centre
National Heart, Lung, and Blood Institute (068545/Z/02, G0000934)
National Human Genome Research Institute
National Institute of Allergy and Infectious Diseases
Fogarty International Center
National Institute of Diabetes and Digestive and Kidney Diseases (DK062418, U01DK062418)
National Institute of Child Health and Human Development
Topics: Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords: IL-6 receptor, rs2228145, soluble IL-6 receptor, IL-6 signaling, type 1 diabetes, STAT3 phosphorylation, STAT1 phosphorylation, CD4+ T cells, monocytes, peripheral blood mononuclear cells, coronary artery disease, rheumatoid arthritis, atrial fibrillation, abdominal aortic aneurysm, asthma
MeSH terms: Alleles, Diabetes Mellitus, Type 1, Humans, Inflammation, Leukocytes, Mononuclear, Mutation, Phosphorylation, Risk Factors, Signal Transduction, Amino Acid Substitution, Receptors, Interleukin-6, Protein Isoforms, Genetic Association Studies

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

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