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Effects of Pregnane X Receptor Genetic Polymorphisms on Stable Warfarin Doses

Title
Effects of Pregnane X Receptor Genetic Polymorphisms on Stable Warfarin Doses
Authors
Moon, Jung YeonChang, Byung ChulLee, Kyung EunBang, Jun SeokGwak, Hye Sun
Ewha Authors
곽혜선
SCOPUS Author ID
곽혜선scopus
Issue Date
2015
Journal Title
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS
ISSN
1074-2484JCR Link1940-4034JCR Link
Citation
vol. 20, no. 6, pp. 532 - 538
Keywords
warfarinsingle-nucleotide polymorphismtranscription factorCYP2C9PXR
Publisher
SAGE PUBLICATIONS INC
Indexed
SCIE; SCOPUS WOS scopus
Abstract
Objective: Pregnane X receptor (PXR) is a transcriptional regulator of many drug-metabolizing enzymes including cytochrome P450 (CYP) 2C9. The objective of this study was to assess the possible association between PXR single-nucleotide polymorphisms (SNPs) and stable warfarin doses. Methods: A total of 201 patients with stable warfarin doses from the EwhA-Severance Treatment (EAST) Group of Warfarin were included in this study. The influence of genetic polymorphisms on stable warfarin doses was investigated by genotyping 11 SNPs, that is, vitamin K epoxide reductase complex 1 (VKORC1) rs9934438, CYP2C9 rs1057910, CYP4F2 rs2108622, constitutive androstane receptor (CAR) rs2501873, hepatocyte nuclear factor 4 (HNF4) rs3212198, and PXR (rs3814055, rs1403526, rs3732357, rs3732360, rs2276707 and rs2472682). Subgroup analysis was conducted on CYP2C9 wild-type homozygote allele (AA) carriers. Results: One PXR SNP of rs2472682 (A>C) exhibited significant association with stable warfarin doses in study population and the subgroup; variant homozygote carriers required significantly lower daily doses of warfarin than those carrying wild allele by about 0.8 mg. Approximate 43.7% of overall interindividual variability in warfarin dose requirement was explained by multivariate regression model. VKORC1, CYP2C9, age, CYP4F2, PXR rs2472682, and CAR/HNF4 rs2501873/rs3212198 accounted for 29.6%, 5.9%, 3.7%, 2.3%, 1.3%, and 0.9% of the variability, respectively. PXR SNP of rs2472682 remained a significant factor in CYP2C9 wild-type homozygote carriers based on univariate and multivariate analyses. The combination of CAR/HNF4/PXR SNPs of rs2501873/rs3212198/rs2472682 showed about 1 mg dose difference between grouped genotypes in study population and subgroup. Conclusion: Our results revealed that PXR could be a determinant of stable warfarin doses.
DOI
10.1177/1074248415578906
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약학대학 > 약학과 > Journal papers
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