Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases
Year: 2013
Type: article
Study design: Observational Study
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.
Source: PLoS Genetics
Authors: Ricardo C. Ferreira, Daniel F. Freitag, Antony J. Cutler, Joanna M. M. Howson, Daniel B. Rainbow, Deborah J. Smyth, Stephen Kaptoge, Pamela Clarke, Charlotte Boreham, Richard M. Coulson, Marcin L. Pekalski, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S. Rich, Adam S. Butterworth, Anders Malarstig, John Danesh, John A. Todd
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: Juvenile Diabetes Research Foundation International, Pfizer, GlaxoSmithKline, Wellcome Trust, National Institute for Health and Care Research, British Heart Foundation, Bupa Foundation, University of Cambridge, University of Leicester, European Commission, University of Bristol, Evelyn Trust, Merck Sharp and Dohme, Medical Research Council, Cambridge Institute for Medical Research, University of Cambridge, NIHR Cambridge Biomedical Research Centre, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, Fogarty International Center, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development
Awards: G1093531541, G1137313802, G119964413, Novel immunotherapies for type 1 diabetes, G1680531030, NIHR Senior Investigator Award, G2064885621, G2473961061, G2509851914, Diabetes and Inflammation Laboratory., Diabetes and Inflammation Laboratory., G2953502109, G3153491656, G3207356259, G3349769430, JDRF/WT Diabetes and Inflammation Laboratory., G393177772, G4273598029, G4733990475, Cellular Medicine at the Cambridge Institute for Medical Research., G5175381056, NIHR Senior Investigator Award, G5502349062, G5568298347, A national DNA control series for genetic case-control studies based on the British 1958 birth cohort, G5702163051, Type 1 Diabetes Genetics Consortium, G67356480, G690763772, G6991716568, G7627314639, RENEWAL: Systematic approaches to the evaluation of emerging coronary risk markers. Large-scale epidemiological analyses of existing data and stored biological samples, The genetics of weight, BMI, adiposity and obesity, Design and implementation of large-scale genetic association studies of commondiseases., Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application
OpenAlex ID: W1991747007