Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma
Year: 2017
Type: review
Study design: Observational Study
Abstract: The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddx053
Institutions: University of Cambridge, Centre for Human Genetics, University of Oxford, University of Bergen, Brigham and Women's Hospital, Harvard University, Boston University, VA Boston Healthcare System, Wellcome Sanger Institute, British Heart Foundation, National Institute for Health and Care Research
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,671
Funders: U.S. Department of Veterans Affairs, Bayer, GlaxoSmithKline, Brigham and Women's Hospital, University of Minnesota, Johns Hopkins University, University of Pittsburgh, Temple University, National Jewish Health, Morehouse School of Medicine, National Institute for Health and Care Research, British Heart Foundation, Research Councils UK, University of Cambridge, European Commission, Cambridge University Hospitals, National Institutes of Health, University of California, San Diego, University of Texas Health Science Center at San Antonio, Anschutz Medical Campus, University of Colorado, Medical Research Council, NIHR Cambridge Biomedical Research Centre, National Heart, Lung, and Blood Institute, National Institute of Environmental Health Sciences
Awards: G1671907826, NIHR Senior Investigator Award, G1953244154, G2050459141, Identification of epigenetic markers underlying increased risk of T2D in South Asians, G226397431, G2474488143, G3217060148, G385907487, G3986547339, G4085921672, G4211044638, (2 of 2) Genetic Epidemiology of COPD, G4584873075, G4844870580, G5618924097, (1 of 2) Genetic Epidemiology of COPD, (2 of 2) Genetic Epidemiology of COPD, G567453067, G5790931794, The development and clinical applications of 111-Indium-labelled eosinophil scanning, Community Assist of Southern Arizona, EPIC-CVD: Individualised CVD risk assessment: tailoring targeted and cost-effective approaches to Europe's diverse populations, G6654704239, (1 of 2) Genetic Epidemiology of COPD, G6902171894, The BHF Chair of Epidemiology and Medicine, G7525999972, G754838926, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application (renewal). (Joint funding with MRC), G762219591, Using genetics to explore the pathophysiology of cerebral small vessel disease. 15, G7939076303, RENEWAL: Systematic approaches to the evaluation of emerging coronary risk markers. Large-scale epidemiological analyses of existing data and stored biological samples, G8585681489, G9000049958, G9000074745, G9000091268, G9000228787, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application
OpenAlex ID: W2590901505