A potentially deleterious new CYP2C9 polymorphism identified in an African American patient with major hemorrhage on warfarin therapy

Abstract

Possession of a variant Cytochrome P450 2C9 (CYP2C9) genotype has been associated with a higher risk of hemorrhagic complications among warfarin users. [1; 2] Although the influence of the common variant alleles (CYP2C9*2, CYP2C9*3) on warfarin response is well documented that of other rare defective alleles, CYP2C9*5, the null allele CYP2C9*6 and CYP2C9*11 found in African-Americans [3; 4] has not. The presence of these alleles may represent the higher genomic sequence diversity in populations of African descent. Herein we describe discovery of a new putative deleterious CYP2C9 polymorphism identified in an African American participant from an ongoing prospective study during routine testing.[5] Analysis of the patient’s genotype identified a new CYP2C9 polymorphism G1078A coding for a D360N in the coding region of exon 7 one codon downstream from the I359L coding change seen in CYP2C9*3.

Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8-109A>T and the losartan metabolism phenotype in Swedes

“…(S)-warfarin and phenytoin) [2,4]. CYP2C9 has thus been the focus of attention due to its role in causing adverse drug (ADRs) by these drugs [2,5].…”

Evaluation of the Effects of 20 Nonsynonymous Single Nucleotide Polymorphisms of CYP2C19 onS-Mephenytoin 4′-Hydroxylation and Omeprazole 5′-Hydroxylation

“…Its kinetic behavior was distinct from that of CYP2C19.1A, with significantly higher K m values and lower V max and Cl int values toward both substrates. The same mutation was also identified in CYP2C9 in an African-American patient with major hemorrhage while receiving warfarin therapy (Goldstein et al, 2009). Another mutation at 360, namely D360E (CYP2C9*5), was found to greatly decrease the affinity and catalytic activity of the CYP2C9 enzyme (Dickmann et al, 2001).…”

Clinical Utility of Pharmacogenetic Biomarkers in Cardiovascular Therapeutics: a Challenge for Clinical Implementation

“…Additional identification of variants in CYP2C9*2 (p.Arg144Cys; rs1799853) and *3 (p.Ile359Leu; rs1057910) alleles are associated with 40–70% reduction in ( S )-warfarin clearance and approximately 20–40% lower warfarin dose requirement, respectively [45–48]. As in the case of clopidogrel, there are population and racial differences in minor allele frequencies of important variants as well as sensitivity to warfarin dosage requirement [40,49,50]. The CYP2C9*2 and *3 alleles and VKORC1 −1639G>A genotype explain approximately 50–60% of the variability in dosage in Caucasians but only approximately 20–25% of variability in African–Americans [40,48,51–54].…”