Novel single nucleotide polymorphism in CYP2C9 is associated with changes in warfarin clearance and CYP2C9 expression levels in African Americans

Abstract

Warfarin is a widely used anticoagulant whose active S-enantiomer is primarily metabolized by the CYP2C9 enzyme. The CYP2C9*2 and CYP2C9*3 alleles are associated with lower warfarin dose requirement and decreased enzyme activity. In contrast, we previously identified a novel SNP (rs7089580 A>T) in CYP2C9 that is associated with higher warfarin dose requirement in African Americans. In this study, we examine the effect of rs7089580 on warfarin pharmacokinetics and CYP2C9 expression in 63 African American patients and 32 African American liver tissues, respectively. We found oral clearance of S-warfarin to be higher among carriers of the minor rs7089580 allele (T) compared to wild type homozygotes (3.73±1.46 ml/min vs. 2.95±1.39 ml/min, p=0.04). CYP2C9 mRNA expression in liver tissue was also higher among A/T and T/T genotypes compared to A/A (p<0.02). Our findings indicate that rs7089580 is associated with higher S-warfarin clearance and CYP2C9 expression and may help explain the higher dose requirement of warfarin in African Americans. Furthermore, rs7089580 is in complete linkage disequilibrium with the promoter SNP rs12251841 in African Americans which may provide a biologically plausible explanation for the observed effect on CYP2C9 expression levels. Given the many clinically relevant substrates of CYP2C9, identifying polymorphisms that affect expression levels and metabolism across ethnicities is essential for individualization of doses with a narrow therapeutic index.

Pharmacogenomic genotypes define genetic ancestry in patients and enable population-specific genomic implementation

“…12,13 In AA-specific warfarin PGx discovery work, the alleles uniquely important to response in AAs have been identified almost exclusively in individuals with at least 70% African (AFR) ancestry. 7,8,14,15 We recently used this threshold to derive and validate a highly predictive AA-specific warfarin dosing algorithm among AAs with ≥70% AFR ancestry. 16 This means that an accurate understanding of individual genetic ancestry (IGA) is important when applying PGx testing.…”

Comparison of CYP2C9 Activity in Ethiopian and Non-Ethiopian Jews Using Phenytoin as a Probe

“…In addition, ethnicity is considered an important determinant explaining substantial difference in the pharmacokinetics of CYP2C9 substrates among subjects with different ethnic origin (Llerena et al, 2014;Hatta et al, 2015). It has been speculated that the observed marked variability in warfarin dose requirement between Caucasians and African Americans may be partly related to racial differences in the activity of CYP2C9, the predominant enzyme mediating the metabolism of (S)-warfarin (Perera et al, 2011;Perera et al, 2013;Hernandez et al, 2015). Findings obtained from extensive research imply that the differences can be categorized into 3 major classes, variability in the frequency of common allelic variants (i.e.…”