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Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism
Barry P King1, Tayyaba I Khan, Guruprasad P Aithal
1School of Clinical and Laboratory Sciences, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne, UK.
Pharmacogenetics
|December 21, 2004
Summary
The primary factor influencing warfarin dose in UK Caucasians is the CYP2C9*2 and CYP2C9*3 genetic variants. Other upstream CYP2C9 polymorphisms do not significantly impact warfarin dose requirements or metabolism.
Area of Science:
- Pharmacogenomics
- Drug Metabolism
Background:
- Warfarin dosing is complex and influenced by genetic factors.
- Cytochrome P450 family 2 subfamily C member 9 (CYP2C9) is crucial for warfarin metabolism.
- CYP2C9*2 and CYP2C9*3 alleles are known to affect warfarin dose requirements.
Purpose of the Study:
- To investigate if CYP2C9 alleles beyond *2 and *3 influence low-warfarin dose requirements.
- To determine the relevance of upstream CYP2C9 polymorphisms on warfarin dose and metabolism.
Main Methods:
- Screening of CYP2C9 exons, intron-exon boundaries, and upstream sequences for novel polymorphisms.
- Utilizing PCR-based genotyping for known and novel upstream polymorphisms in a larger patient cohort.
- Analyzing the association between CYP2C9 genotypes and warfarin dose or S-warfarin total clearance.
Main Results:
- Eight different upstream polymorphism sites were identified, with most in linkage disequilibrium with coding region polymorphisms.
- Two specific upstream polymorphisms (T-1188C and DeltaG-2664DeltaT-2665) were found in both wild-type and variant individuals.
- Neither individual upstream genotypes nor haplotype combinations predicted warfarin dose or S-warfarin clearance in individuals without coding region polymorphisms.
Conclusions:
- Non-synonymous coding region polymorphisms in CYP2C9*2 and CYP2C9*3 are the main determinants of warfarin dose in UK Caucasians.
- Upstream CYP2C9 polymorphisms are not significant independent predictors of warfarin dose requirements.
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