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dc.contributor.authorNeuvonen M
dc.contributor.authorTarkiainen EK
dc.contributor.authorTornio A
dc.contributor.authorHirvensalo P
dc.contributor.authorTapaninen T
dc.contributor.authorPaile-Hyvärinen M
dc.contributor.authorItkonen MK
dc.contributor.authorHolmberg MT
dc.contributor.authorKärjä V
dc.contributor.authorMännistö VT
dc.contributor.authorNeuvonen PJ
dc.contributor.authorPihlajamäki J
dc.contributor.authorBackman JT
dc.contributor.authorNiemi M
dc.date.accessioned2018-01-09T13:52:21Z
dc.date.available2018-01-09T13:52:21Z
dc.date.issued2017
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/5144
dc.description.abstractSeveral single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES1 SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (p = 4.0 × 10−13) and 31% (p = 2.5 × 10−8) reduction in CES1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did not affect CES1 liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the CES1 c.428G>A missense SNV (rs71647871) impaired the hydrolysis of clopidogrel, increased exposure to clopidogrel active metabolite and enhanced its antiplatelet effects. In conclusion, the rs12443580 and rs8192935 variants reduce CES1 expression in whole blood but not in the liver. These tissue-specific effects may result in substrate-dependent effects of the two SNVs on CES1-mediated drug metabolism.en
dc.language.isoENen
dc.publisherWiley-Blackwellen
dc.relation.ispartofseriesBASIC & CLINICAL PHARMACOLOGY & TOXICOLOGYen
dc.relation.urihttp://dx.doi.org/10.1111/bcpt.12916en
dc.rightsAll rights reserveden
dc.titleEffects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effectsen
dc.description.versionfinal draften
dc.contributor.departmentSchool of Medicine / Clinical Medicineen
dc.contributor.departmentSchool of Medicine / Clinical Nutritionen
uef.solecris.id50344465en
dc.type.publicationinfo:eu-repo/semantics/articleen
dc.rights.accessrights© Nordic Association for the Publication of BCPTen
dc.relation.projectidinfo:eu-repo/grantAgreement/EC/FP7-IDEAS-ERC/282106/EU/Transporter pharmacogenomics – the contribution of transporters to variability in drug response/TransporterPGxen
dc.relation.doi10.1111/bcpt.12916en
dc.description.reviewstatuspeerRevieweden
dc.relation.issn1742-7835en
dc.relation.volume[Epub ahead of print 17 Nov 2017]en
dc.rights.accesslevelopenAccessen
dc.type.okmA1en
dc.type.versioninfo:eu-repo/semantics/acceptedVersionen
uef.solecris.openaccessEi


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