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- Title
Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects.
- Authors
Neuvonen, Mikko; Tarkiainen, E. Katriina; Tornio, Aleksi; Hirvensalo, Päivi; Tapaninen, Tuija; Paile‐Hyvärinen, Maria; Itkonen, Matti K.; Holmberg, Mikko T.; Neuvonen, Pertti J.; Backman, Janne T.; Niemi, Mikko; Kärjä, Vesa; Männistö, Ville T.; Pihlajamäki, Jussi
- Abstract
Abstract: Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on <italic>CES1</italic> gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on <italic>CES1</italic> 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<italic> </italic>=<italic> </italic>106) and pharmacodynamics (n<italic> </italic>=<italic> </italic>46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two <italic>CES1 </italic>SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (<italic>p </italic>=<italic> </italic>4.0 × 10−13) and 31% (<italic>p </italic>=<italic> </italic>2.5 × 10−8) reduction in <italic>CES1</italic> whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did not affect <italic>CES1</italic> liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the <italic>CES1</italic> 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 <italic>CES1</italic> 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.
- Subjects
CARBOXYLESTERASES; CLOPIDOGREL; PHARMACOKINETICS; GENE expression; PLATELET aggregation inhibitors; XENOBIOTICS
- Publication
Basic & Clinical Pharmacology & Toxicology, 2018, Vol 122, Issue 3, p341
- ISSN
1742-7835
- Publication type
Article
- DOI
10.1111/bcpt.12916