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dc.contributor.authorKhera, Amit V
dc.contributor.authorWon, Hong-Hee
dc.contributor.authorPeloso, Gina M
dc.contributor.authorO'Dushlaine, Colm
dc.contributor.authorLiu, Dajiang
dc.contributor.authorStitziel, Nathan O
dc.contributor.authorNatarajan, Pradeep
dc.contributor.authorNomura, Akihiro
dc.contributor.authorEmdin, Connor A
dc.contributor.authorGupta, Namrata
dc.contributor.authorBorecki, Ingrid B
dc.contributor.authorAsselta, Rosanna
dc.contributor.authorDuga, Stefano
dc.contributor.authorMerlini, Piera Angelica
dc.contributor.authorCorrea, Adolfo
dc.contributor.authorKessler, Thorsten
dc.contributor.authorWilson, James G
dc.contributor.authorBown, Matthew J
dc.contributor.authorHall, Alistair S
dc.contributor.authorBraund, Peter S
dc.contributor.authorCarey, David J
dc.contributor.authorMurray, Michael F
dc.contributor.authorKirchner, H Lester
dc.contributor.authorLeader, Joseph B
dc.contributor.authorLavage, Daniel R
dc.contributor.authorManus, J Neil
dc.contributor.authorHartzel, Dustin N
dc.contributor.authorSamani, Nilesh J
dc.contributor.authorSchunkert, Heribert
dc.contributor.authorMarrugat, Jaume
dc.contributor.authorElosua, Roberto
dc.contributor.authorMcPherson, Ruth
dc.contributor.authorFarrall, Martin
dc.contributor.authorWatkins, Hugh
dc.contributor.authorLander, Eric S
dc.contributor.authorRader, Daniel J
dc.contributor.authorDanesh, John
dc.contributor.authorArdissino, Diego
dc.contributor.authorGabriel, Stacey
dc.contributor.authorWiller, Cristen
dc.contributor.authorAbecasis, Gonçalo R
dc.contributor.authorSaleheen, Danish
dc.contributor.authorDewey, Frederick E
dc.contributor.authorKathiresan, Sekar
dc.contributor.authorMyocardial Infarction Genetics Consortium, DiscovEHR Study Group, CARDIoGRAM Exome Consortium, and Global Lipids Genetics Consortium
dc.date.accessioned2018-06-25T13:40:23Z
dc.date.available2018-06-25T13:40:23Z
dc.date.issued2017-03-07
dc.identifier.issn0098-7484
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/277478
dc.description.abstractImportance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.
dc.format.mediumPrint
dc.languageeng
dc.publisherAmerican Medical Association (AMA)
dc.subjectMyocardial Infarction Genetics Consortium, DiscovEHR Study Group, CARDIoGRAM Exome Consortium, and Global Lipids Genetics Consortium
dc.subjectHumans
dc.subjectLipoprotein Lipase
dc.subjectTriglycerides
dc.subjectLipoproteins
dc.subjectOdds Ratio
dc.subjectCase-Control Studies
dc.subjectCross-Sectional Studies
dc.subjectAge of Onset
dc.subjectGenotype
dc.subjectHeterozygote
dc.subjectMutation
dc.subjectAdult
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectCoronary Artery Disease
dc.titleAssociation of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.
dc.typeArticle
prism.endingPage946
prism.issueIdentifier9
prism.publicationDate2017
prism.publicationNameJAMA
prism.startingPage937
prism.volume317
dc.identifier.doi10.17863/CAM.15796
dcterms.dateAccepted2017-02-08
rioxxterms.versionofrecord10.1001/jama.2017.0972
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-03
dc.contributor.orcidDanesh, John [0000-0003-1158-6791]
dc.identifier.eissn1538-3598
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/L003120/1)
pubs.funder-project-idEuropean Research Council (268834)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (None)


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