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Upstream and coding region CYP2C9 polymorphisms: Correlation with warfarin dose and metabolism

Lookup NU author(s): Dr Barry King, Dr Tayyaba Khan, Professor Farhad Kamali, Professor Ann Daly

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Abstract

Objectives: To assess whether CYP2C9 alleles other than CYP2C9*2 and *3 are associated with a low-warfarin dose requirement and the relevance of upstream CYP2C9 polymorphisms to dose requirement and metabolism. Methods: CYP2C9 exons, intron-exon boundaries and 3 kb of upstream sequence in 20 patients requiring ≤ 1.5 mg warfarin per day and with apparently homozygous wild-type or heterozygous CYP2C9*2 genotypes were screened for novel polymorphisms by single-strand conformational polymorphism analysis. PCR-based genotyping assays for novel upstream and other known polymorphisms were used to screen a larger patient population of known CYP2C9*2 and *3 genotype requiring a range of warfarin doses. Results: Polymorphisms at eight different upstream sites were found, five of which were already described. We found that the majority of the upstream polymorphisms were in complete linkage disequilibrium with previously described coding region polymorphisms. However, two polymorphisms, T-1188C and the novel ΔG-2664ΔT-2665, occurred both in individuals who were otherwise wild-type and in individuals positive for coding region polymorphisms. Evidence for 11 haplotypes, including 8 with frequencies ≥ 0.01, was obtained. In individuals negative for coding region polymorphisms, neither individual genotypes for T-1188C or ΔG- 2664ΔT-2665 or particular combinations of haplotype pairs were predictive of dose requirement or S-warfarin total clearance, suggesting neither upstream polymorphism was functionally significant. Dose requirements in CYP2C9*11 heterozygotes were not statistically significantly different from homozygous wild-type individuals. Conclusions: The coding region non-synonymous polymorphisms associated with the CYP2C9*2 and CYP2C9*3 alleles are the major CYP2C9-related factor affecting warfarin dose in UK Caucasians. Upstream CYP2C9 polymorphisms do not appear to be important independent determinants of dose requirement. © 2004 Lippincott Williams & Wilkins.


Publication metadata

Author(s): King BP, Khan TI, Aithal GP, Kamali F, Daly AK

Publication type: Article

Publication status: Published

Journal: Pharmacogenetics

Year: 2004

Volume: 14

Issue: 12

Pages: 813-822

ISSN (print): 0960-314X

ISSN (electronic): 1744-6880

Publisher: Lippincott Williams & Wilkins

URL: http://dx.doi.org/10.1097/00008571-200412000-00004

DOI: 10.1097/00008571-200412000-00004

PubMed id: 15608560


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