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dc.contributor.authorFarahi, Nedaen
dc.contributor.authorPaige, Een
dc.contributor.authorBalla, Jen
dc.contributor.authorPrudence, Een
dc.contributor.authorFerreira, RCen
dc.contributor.authorSouthwood, Men
dc.contributor.authorAppleby, SLen
dc.contributor.authorBakke, Pen
dc.contributor.authorGulsvik, Aen
dc.contributor.authorLitonjua, AAen
dc.contributor.authorSparrow, Den
dc.contributor.authorSilverman, EKen
dc.contributor.authorCho, MHen
dc.contributor.authorDanesh, Johnen
dc.contributor.authorPaul, Dirken
dc.contributor.authorFreitag, DFen
dc.contributor.authorChilvers, Edwinen
dc.date.accessioned2017-04-28T17:00:45Z
dc.date.available2017-04-28T17:00:45Z
dc.date.issued2017-02-17en
dc.identifier.issn0964-6906
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/263899
dc.description.abstractThe 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.
dc.description.sponsorshipThis work was supported by the UK Medical Research Council [MR/L003120/1 and MR/J00345X/1]; the British Heart Foundation [RG/13/13/30194]; the UK National Institute for Health Research Cambridge Biomedical Research Centre; and the Cambridge NIHR BRC Cell Phenotyping Hub. The Cardiovascular Epidemiology Unit at the University of Cambridge is supported by the UK Medical Research Council [G0800270]; the British Heart Foundation [SP/09/002]; and the UK National Institute for Health Research Cambridge Biomedical Research Centre. The ECLIPSE study is supported by GlaxoSmithKline [SCO104960]. The COPDGene study was supported by National Institutes of Health [R01 HL089897 and R01 HL089856]. The Norway GenKOLS study is supported by GlaxoSmithKline [RES11080]. The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, MA. Funding to pay the Open Access publication charges for this article was provided by University of Cambridge block grants from the Research Councils UK and the Charity Open Access Fund.
dc.languageengen
dc.language.isoenen
dc.publisherOxford University Press
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectallelesen
dc.subjectchronic obstructive airway diseaseen
dc.subjectpulmonary arteryen
dc.subjectsignal transductionen
dc.subjectendothelial cellsen
dc.subjectlungen
dc.subjectasthmaen
dc.subjectgenesen
dc.subjecthomozygoteen
dc.subjectmonocyte chemoattractant protein-1en
dc.subjectneutrophilen
dc.subjectinterleukin 6 receptoren
dc.subjectrespiration disordersen
dc.subjectinterleukin-6en
dc.subjectextrinsic asthmaen
dc.subjectin vitro studyen
dc.subjectsquamous intraepithelial lesionen
dc.subjectpmel17en
dc.subjecttocilizumaben
dc.subjectbiobanksen
dc.titleNeutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthmaen
dc.typeArticle
prism.endingPage1596
prism.issueIdentifier8en
prism.publicationDate2017en
prism.publicationNameHuman Molecular Geneticsen
prism.startingPage1584
prism.volume26en
dc.identifier.doi10.17863/CAM.9277
dcterms.dateAccepted2017-02-08en
rioxxterms.versionofrecord10.1093/hmg/ddx053en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-02-17en
dc.contributor.orcidDanesh, John [0000-0003-1158-6791]
dc.contributor.orcidPaul, Dirk [0000-0002-8230-0116]
dc.contributor.orcidChilvers, Edwin [0000-0002-4230-9677]
dc.identifier.eissn1460-2083
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/P02811X/1)
pubs.funder-project-idEuropean Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (116074)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
pubs.funder-project-idBritish Heart Foundation (CH/12/2/29428)
pubs.funder-project-idMRC (MR/P013880/1)
pubs.funder-project-idUme� University (unknown)
pubs.funder-project-idNHS Blood and Transplant (NHSBT) (WP12-01)
pubs.funder-project-idEC FP7 CP (279143)
pubs.funder-project-idNHS Blood and Transplant (NHSBT) (11-01-GEN)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
pubs.funder-project-idBritish Heart Foundation (RG/13/13/30194)
pubs.funder-project-idMRC (MR/L003120/1)
pubs.funder-project-idEuropean Commission (279233)
pubs.funder-project-idEuropean Research Council (268834)
pubs.funder-project-idMRC (MR/J015709/1)
pubs.funder-project-idMRC (MR/J006602/1)
pubs.funder-project-idMRC (MR/J006599/1)
pubs.funder-project-idMRC (via University of Leicester) (MR/M012816/1)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idBritish Heart Foundation (RG/16/4/32218)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (3819-1617-25)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NIHR BTRU-2014-10024)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (3819-1516-29)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idMRC (MR/J00345X/1)
pubs.funder-project-idMRC (G0800270)
pubs.funder-project-idBritish Heart Foundation (RG/08/014/24067)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International