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dc.contributor.authorSong, Cen
dc.contributor.authorBurgess, Stephenen
dc.contributor.authorEicher, JDen
dc.contributor.authorCHARGE Consortium Hemostatic Factor Working Group,en
dc.contributor.authorICBP Consortium,en
dc.contributor.authorCHARGE Consortium Subclinical Working Group,en
dc.contributor.authorO’Donnell, CJen
dc.contributor.authorJohnson, ADen
dc.date.accessioned2017-05-11T12:34:40Z
dc.date.available2017-05-11T12:34:40Z
dc.date.issued2017-06en
dc.identifier.issn2047-9980
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/264186
dc.description.abstract$\textit{Background—}$Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. $\textit{Methods and Results—}$To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. $\textit{Conclusions—}$Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.
dc.description.sponsorshipThis work was supported by NHLBI Intramural funds to Christopher O’Donnell and Andrew Johnson. Stephen Burgess is supported by a fellowship from the Wellcome Trust (100114).
dc.language.isoenen
dc.publisherWiley
dc.rightsAttribution 4.0 Internationalen
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.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectcoronary heart diseaseen
dc.subjectplasminogen activator inhibitor type 1en
dc.subjectMendelian randomizationen
dc.subjectgenome-wide association studyen
dc.subjectsingle nucleotide polymorphismen
dc.titleCausal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Diseaseen
dc.typeArticle
prism.issueIdentifier6en
prism.numbere004918en
prism.publicationDate2017en
prism.publicationNameJournal of the American Heart Associationen
prism.volume6en
dc.identifier.doi10.17863/CAM.9545
dcterms.dateAccepted2017-02-23en
rioxxterms.versionofrecord10.1161/JAHA.116.004918en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-06en
dc.contributor.orcidBurgess, Stephen [0000-0001-5365-8760]
dc.identifier.eissn2047-9980
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (204623/Z/16/Z)
pubs.funder-project-idMRC (MR/L003120/1)
pubs.funder-project-idWellcome Trust (100114/Z/12/Z)
pubs.funder-project-idBritish Heart Foundation (RG/08/014/24067)
pubs.funder-project-idMedical Research Council (MC_UU_00002/7)
cam.issuedOnline2017-05-26en
cam.orpheus.successThu Jan 30 12:53:57 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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