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A Method to Study the C924T Polymorphism of the Thromboxane A2 Receptor Gene
Published on: April 1, 2019
CYP2C9 promoter variable number tandem repeat polymorphism regulates mRNA expression in human livers
Danxin Wang1, Xiaochun Sun, Yan Gong
1Program in Pharmacogenomics, Department of Pharmacology, School of Medicine, The Ohio State University, 333 West 10th Ave., Columbus, OH 43210, USA. wang.808@osu.edu
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|February 1, 2012
Summary
A novel promoter polymorphism (pVNTR) influences CYP2C9 mRNA levels, but its effect on warfarin dose is linked to the CYP2C9*3 variant. Therefore, pVNTR is not recommended as a separate biomarker for warfarin dosing.
Area of Science:
- Pharmacogenomics
- Drug Metabolism
- Genetic Polymorphisms
Background:
- CYP2C9 is a key enzyme metabolizing approximately 25% of clinical drugs.
- Known coding region polymorphisms (CYP2C9*2, *3) cause variability in drug response.
- The impact of regulatory polymorphisms on CYP2C9 activity remains unclear.
Purpose of the Study:
- To investigate the role of a novel regulatory polymorphism in CYP2C9 gene expression.
- To determine the association of this polymorphism with warfarin dosage.
Main Methods:
- Analysis of allelic CYP2C9 mRNA expression in 87 human liver samples.
- Genotyping, sequencing, and reporter gene assays were employed.
- Association studies with warfarin maintenance doses in patients.
Main Results:
- A promoter variable number tandem repeat (pVNTR) polymorphism was identified, explaining allelic expression differences.
- The pVNTR-S allele reduced CYP2C9 mRNA levels compared to the pVNTR-M reference allele.
- While pVNTR-S correlated with warfarin dose, this association was not significant when CYP2C9*3 was included in multivariate models.
Conclusions:
- The pVNTR-S polymorphism affects CYP2C9 mRNA expression but its in vivo impact on warfarin metabolism is confounded by the CYP2C9*3 variant.
- pVNTR-S is not recommended as an independent biomarker for warfarin dosing.
- Further research is needed to elucidate the precise in vivo contribution of pVNTR-S.
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