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dc.contributor.authorSchmidt, AF
dc.contributor.authorSwerdlow, DI
dc.contributor.authorHolmes, MV
dc.contributor.authorPatel, RS
dc.contributor.authorFairhurst-Hunter, Z
dc.contributor.authorLyall, DM
dc.contributor.authorHartwig, FP
dc.contributor.authorHorta, BL
dc.contributor.authorHyppönen, E
dc.contributor.authorPower, C
dc.contributor.authorMoldovan, M
dc.contributor.authorvan Iperen, E
dc.contributor.authorHovingh, GK
dc.contributor.authorDemuth, I
dc.contributor.authorNorman, K
dc.contributor.authorSteinhagen-Thiessen, E
dc.contributor.authorDemuth, J
dc.contributor.authorBertram, L
dc.contributor.authorLiu, T
dc.contributor.authorCoassin, S
dc.contributor.authorWilleit, J
dc.contributor.authorKiechl, S
dc.contributor.authorWilleit, K
dc.contributor.authorMason, D
dc.contributor.authorWright, J
dc.contributor.authorMorris, R
dc.contributor.authorWanamethee, G
dc.contributor.authorWhincup, P
dc.contributor.authorBen-Shlomo, Y
dc.contributor.authorMcLachlan, S
dc.contributor.authorPrice, JF
dc.contributor.authorKivimaki, M
dc.contributor.authorWelch, C
dc.contributor.authorSanchez-Galvez, A
dc.contributor.authorMarques-Vidal, P
dc.contributor.authorNicolaides, A
dc.contributor.authorPanayiotou, AG
dc.contributor.authorOnland-Moret, NC
dc.contributor.authorvan der Schouw, YT
dc.contributor.authorMatullo, G
dc.contributor.authorFiorito, G
dc.contributor.authorGuarrera, S
dc.contributor.authorSacerdote, C
dc.contributor.authorWareham, NJ
dc.contributor.authorLangenberg, C
dc.contributor.authorScott, R
dc.contributor.authorLuan, J
dc.contributor.authorBobak, M
dc.contributor.authorMalyutina, S
dc.contributor.authorPająk, A
dc.contributor.authorKubinova, R
dc.contributor.authorTamosiunas, A
dc.contributor.authorPikhart, H
dc.contributor.authorHusemoen, LLN
dc.contributor.authorGrarup, N
dc.contributor.authorPedersen, O
dc.contributor.authorHansen, T
dc.contributor.authorLinneberg, A
dc.contributor.authorSimonsen, KS
dc.contributor.authorCooper, J
dc.contributor.authorHumphries, SE
dc.contributor.authorBrilliant, M
dc.contributor.authorKitchner, T
dc.contributor.authorHakonarson, H
dc.contributor.authorCarrell, DS
dc.contributor.authorMcCarty, CA
dc.contributor.authorKirchner, HL
dc.contributor.authorLarson, EB
dc.contributor.authorCrosslin, DR
dc.contributor.authorde Andrade, M
dc.contributor.authorRoden, DM
dc.contributor.authorDenny, JC
dc.contributor.authorCarty, C
dc.contributor.authorHancock, S
dc.contributor.authorAttia, J
dc.contributor.authorHolliday, E
dc.contributor.authorO'Donnell, M
dc.contributor.authorYusuf, S
dc.contributor.authorChong, M
dc.contributor.authorPare, G
dc.contributor.authorvan der Harst, P
dc.contributor.authorSaid, MA
dc.contributor.authorEppinga, RN
dc.contributor.authorVerweij, N
dc.contributor.authorSnieder, H
dc.contributor.authorLifeLines Cohort study group
dc.contributor.authorChristen, T
dc.contributor.authorMook-Kanamori, DO
dc.contributor.authorGustafsson, S
dc.contributor.authorLind, L
dc.contributor.authorIngelsson, E
dc.contributor.authorPazoki, R
dc.contributor.authorFranco, O
dc.contributor.authorHofman, A
dc.contributor.authorUitterlinden, A
dc.contributor.authorDehghan, A
dc.contributor.authorTeumer, A
dc.contributor.authorBaumeister, S
dc.contributor.authorDörr, M
dc.contributor.authorLerch, MM
dc.contributor.authorVölker, U
dc.contributor.authorVölzke, H
dc.contributor.authorWard, J
dc.contributor.authorPell, JP
dc.contributor.authorSmith, DJ
dc.contributor.authorMeade, T
dc.contributor.authorMaitland-van der Zee, AH
dc.contributor.authorBaranova, EV
dc.contributor.authorYoung, R
dc.contributor.authorFord, I
dc.contributor.authorCampbell, A
dc.contributor.authorPadmanabhan, S
dc.contributor.authorBots, ML
dc.contributor.authorGrobbee, DE
dc.contributor.authorFroguel, P
dc.contributor.authorThuillier, D
dc.contributor.authorBalkau, B
dc.contributor.authorBonnefond, A
dc.contributor.authorCariou, B
dc.contributor.authorSmart, M
dc.contributor.authorBao, Y
dc.contributor.authorKumari, M
dc.contributor.authorMahajan, A
dc.contributor.authorRidker, PM
dc.contributor.authorChasman, DI
dc.contributor.authorReiner, AP
dc.contributor.authorLange, LA
dc.contributor.authorRitchie, MD
dc.contributor.authorAsselbergs, FW
dc.contributor.authorCasas, J-P
dc.contributor.authorKeating, BJ
dc.contributor.authorPreiss, D
dc.contributor.authorHingorani, AD
dc.contributor.authorUCLEB consortium
dc.contributor.authorSattar, N
dc.date.accessioned2017-02-16T16:06:15Z
dc.date.available2017-02-16T16:06:15Z
dc.date.issued2017-02
dc.identifier.issn2213-8587
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/262643
dc.description.abstractBACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m(2), -0·09 to 0·30). INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
dc.description.sponsorshipThis work was supported by a British Heart Foundation Programme Grant (RG/10/12/28456). AFS is funded by University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre (BRC10200) and by a UCL springboard population science fellowship. FWA is supported by a Dekker scholarship-Junior Staff Member 2014T001–Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre. ADH is an NIHR Senior Investigator. Funding information and acknowledgments for studies contributing data are reported in the appendix.
dc.languageeng
dc.language.isoen
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titlePCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
dc.typeArticle
prism.endingPage105
prism.issueIdentifier2
prism.publicationDate2017
prism.publicationNameThe Lancet Diabetes and Endocrinology
prism.startingPage97
prism.volume5
dc.identifier.doi10.17863/CAM.7909
dcterms.dateAccepted2016-11-03
rioxxterms.versionofrecord10.1016/S2213-8587(16)30396-5
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2017-02
dc.contributor.orcidWareham, Nicholas [0000-0003-1422-2993]
dc.contributor.orcidLangenberg, Claudia [0000-0002-5017-7344]
dc.contributor.orcidLuan, Jian'an [0000-0003-3137-6337]
dc.identifier.eissn2213-8595
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UU_12015/1)
cam.issuedOnline2016-11-29
rioxxterms.freetoread.startdate2017-05-29


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