A1 Refereed original research article in a scientific journal
Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects
Authors: Neuvonen M, Tarkiainen EK, Tornio A, Hirvensalo P, Tapaninen T, Paile-Hyvarinen M, Itkonen MK, Holmberg MT, Karja V, Mannisto VT, Neuvonen PJ, Pihlajamaki J, Backman JT, Niemi M
Publisher: WILEY
Publication year: 2018
Journal: Basic and Clinical Pharmacology and Toxicology
Journal name in source: BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
Journal acronym: BASIC CLIN PHARMACOL
Volume: 122
Issue: 3
First page : 341
Last page: 345
Number of pages: 5
ISSN: 1742-7835
DOI: https://doi.org/10.1111/bcpt.12916
Abstract
Several 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 300mg or 600mg 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=4.0x10(-13)) and 31% (p=2.5x10(-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.
Several 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 300mg or 600mg 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=4.0x10(-13)) and 31% (p=2.5x10(-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.
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