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dc.contributor.authorBuas, Matthew Fen
dc.contributor.authorHe, Qianchuanen
dc.contributor.authorJohnson, Lisa Gen
dc.contributor.authorOnstad, Lynnen
dc.contributor.authorLevine, David Men
dc.contributor.authorThrift, Aaron Pen
dc.contributor.authorGharahkhani, Puyaen
dc.contributor.authorPalles, Claireen
dc.contributor.authorLagergren, Jesperen
dc.contributor.authorFitzgerald, Rebeccaen
dc.contributor.authorYe, Weiminen
dc.contributor.authorCaldas, Carlosen
dc.contributor.authorBird, Nigel Cen
dc.contributor.authorShaheen, Nicholas Jen
dc.contributor.authorBernstein, Leslieen
dc.contributor.authorGammon, Marilie Den
dc.contributor.authorWu, Anna Hen
dc.contributor.authorHardie, Laura Jen
dc.contributor.authorPharoah, Paulen
dc.contributor.authorLiu, Geoffreyen
dc.contributor.authorIyer, Prassaden
dc.contributor.authorCorley, Douglas Aen
dc.contributor.authorRisch, Harvey Aen
dc.contributor.authorChow, Wong-Hoen
dc.contributor.authorPrenen, Hansen
dc.contributor.authorChegwidden, Lauraen
dc.contributor.authorLove, Sharonen
dc.contributor.authorAttwood, Stephenen
dc.contributor.authorMoayyedi, Paulen
dc.contributor.authorMacDonald, Daviden
dc.contributor.authorHarrison, Rebeccaen
dc.contributor.authorWatson, Peteren
dc.contributor.authorBarr, Hughen
dc.contributor.authordeCaestecker, Johnen
dc.contributor.authorTomlinson, Ianen
dc.contributor.authorJankowski, Januszen
dc.contributor.authorWhiteman, David Cen
dc.contributor.authorMacGregor, Stuarten
dc.contributor.authorVaughan, Thomas Len
dc.contributor.authorMadeleine, Margaret Men
dc.date.accessioned2016-08-16T07:33:52Z
dc.date.available2016-08-16T07:33:52Z
dc.date.issued2016-08-02en
dc.identifier.issn0017-5749
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/257282
dc.description.abstract${\bf Objective}$ Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett’s oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. ${\bf Design}$ We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. ${\bf Results}$ We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-Stransferase 1 ($\small \textit{MGST1}$); (p=0.0005, q=0.005). Assessment of 36 $\small \textit{MGST1}$ SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10$^{−5}$) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for $\small \textit{MGST1}$. Three such variants were associated with similar elevations in OA risk. ${\bf Conclusions}$ This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in $\small \textit{MGST1}$ influence disease susceptibility.
dc.description.sponsorshipThis work was principally supported by the National Institutes of Health (R21DK099804 to MMM and R01CA136725 to TLV and DCW). Support for studies related to the Oxford data set was granted by the Esophageal Adenocarcinoma GenE Consortia incorporating the ChOPIN project (grant C548/A5675) and Inherited Predisposition of neoplasia analysis of genomic DNA (IPOD) from AspECT and BOSS clinical trials project (grant MGAG1G7R); Cancer Research UK (AspECT, grants C548/A4584 and D9612L00090, and Histological AssessmeNt Determining EpitheliaL Response (HANDEL), grant C548/A9085); AstraZeneca UK educational grant; University Hospitals of Leicester R and D grant; and AspECT (T91 5211 University of Oxford grant HDRMJQ0).
dc.languageEnglishen
dc.language.isoenen
dc.publisherBMJ Publishing
dc.titleGermline variation in inflammation-related pathways and risk of Barrett’s oesophagus and oesophageal adenocarcinomaen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from BMJ Publishing via http://dx.doi.org/10.1136/gutjnl-2016-311622en
prism.publicationDate2016en
prism.publicationNameGuten
dc.identifier.doi10.17863/CAM.1212
dcterms.dateAccepted2016-07-02en
rioxxterms.versionofrecord10.1136/gutjnl-2016-311622en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2016-08-02en
dc.contributor.orcidFitzgerald, Rebecca [0000-0002-3434-3568]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
dc.contributor.orcidPharoah, Paul [0000-0001-8494-732X]
dc.identifier.eissn1468-3288
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (16561)
pubs.funder-project-idMedical Research Council (MC_UU_12022/2)
pubs.funder-project-idCancer Research UK (10124)


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