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dc.contributor.authorWhitworth, Laura
dc.contributor.authorCoxon, Jacob
dc.contributor.authorvan Laarhoven, Arjan
dc.contributor.authorThuong, Nguyen Thuy Thuong
dc.contributor.authorDian, Sofiati
dc.contributor.authorAlisjahbana, Bachti
dc.contributor.authorGaniem, Ahmad Rizal
dc.contributor.authorvan Crevel, Reinout
dc.contributor.authorThwaites, Guy E
dc.contributor.authorTroll, Mark
dc.contributor.authorEdelstein, Paul H
dc.contributor.authorSewell, Roger
dc.contributor.authorRamakrishnan, Lalita
dc.date.accessioned2021-01-09T03:04:09Z
dc.date.available2021-01-09T03:04:09Z
dc.date.issued2021-01-08
dc.date.submitted2020-08-03
dc.identifier.other61722
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/315962
dc.description.abstractTuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory eicosanoids. LTA4H TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an LTA4H TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that LTA4H TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. LTA4H genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it.
dc.languageen
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectResearch Article
dc.subjectGenetics and Genomics
dc.subjectMicrobiology and Infectious Disease
dc.subjectTB meningitis
dc.subjectleukotriene A4 hydrolase
dc.subjectpharmacogenomics
dc.subjectdexamethasone
dc.subjectBayesian inference
dc.subjectHuman
dc.titleA Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis
dc.typeArticle
dc.date.updated2021-01-09T03:04:08Z
prism.publicationNameeLife
prism.volume10
dc.identifier.doi10.17863/CAM.63072
dcterms.dateAccepted2020-11-22
rioxxterms.versionofrecord10.7554/elife.61722
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Kana, Bavesh D
datacite.contributor.supervisorsenior_editor: Kana, Bavesh D
dc.contributor.orcidWhitworth, Laura [0000-0002-8232-4601]
dc.contributor.orcidvan Laarhoven, Arjan [0000-0002-6607-4075]
dc.contributor.orcidThwaites, Guy E [0000-0002-2858-2087]
dc.contributor.orcidEdelstein, Paul H [0000-0002-4069-5279]
dc.contributor.orcidSewell, Roger [0000-0003-4267-7055]
dc.contributor.orcidRamakrishnan, Lalita [0000-0003-0692-5533]
dc.identifier.eissn2050-084X
pubs.funder-project-idNational Institutes of Health (NIAID ULTIMATE project 1R01AI145781-01)
pubs.funder-project-idWellcome Trust (Wellcome International Intermediate Fellowship 206724/Z/17/Z)
pubs.funder-project-idWellcome Trust (110179/Z/15/Z)
pubs.funder-project-idWellcome Trust (Principal Research Fellowship 103950/Z/14)
pubs.funder-project-idNational Institutes of Health (R37 AI054503)


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