The Association Between Promoter Tandem Repeat Polymorphism (pVNTR) and CYP2C9 Gene Expression in Human Liver Samples

Area of Science:

• Pharmacogenomics
• Drug Metabolism
• Genetic Polymorphisms

Background:

• CYP2C9 is crucial for metabolizing 20% of drugs.
• Known CYP2C9 single-nucleotide polymorphisms (SNPs) explain only part of expression variability.
• A promoter variable number tandem repeat (pVNTR) polymorphism was previously identified.

Purpose of the Study:

• To clarify the association between the CYP2C9 promoter pVNTR-S and CYP2C9 mRNA expression.
• To assess the impact of pVNTR-S on CYP2C9 expression independently of known biomarkers.
• To investigate the role of pVNTR-S in explaining unexplained CYP2C9 expression variability.

Main Methods:

• Gene expression measured by real-time quantitative PCR (qPCR).
• Single-nucleotide polymorphisms (SNPs) and pVNTRs genotyped using SNapShot assays and fragment analysis.
• Associations analyzed using multiple linear regression.

Main Results:

• The pVNTR-S was significantly associated with lower CYP2C9 expression (34% reduction, p=0.032) in human liver samples (n=247).
• This association was independent of known CYP2C9 biomarkers (*2, *3, *8, rs12777823).
• pVNTR-S may explain additional variability in CYP2C9 expression.

Conclusions:

• The CYP2C9 promoter pVNTR-S polymorphism directly impacts CYP2C9 mRNA expression.
• pVNTR-S is a novel, independent predictor of reduced CYP2C9 activity.
• This finding contributes to understanding inter-individual variability in drug response.