CYP2C9*8 is Prevalent Among African–Americans: Implications for Pharmacogenetic Dosing

Abstract

Aims Although the frequencies of pharmacogenetic variants differ among racial groups, most pharmacogenetic algorithms for genotype-guided warfarin dosing only include two CYP2C9 alleles (*2 and *3) and a single VKORC1 allele (g.-1639G>A or g.1173C>T) commonly found among Caucasians. Therefore, this study sought to identify other CYP2C9 and VKORC1 alleles important in warfarin dose variability and to determine their frequencies in different racial and ethnic groups. Materials & methods The CYP2C9 and VKORC1 genes were sequenced in selected sensitive (<21 mg/week) and resistant (>49 mg/week) individuals with discrepant therapeutic and algorithm-predicted warfarin doses based on prior CYP2C9 and VKORC1 genotyping. The CYP2C9 and VKORC1 allele frequencies were determined in healthy, racially self-identified blood donors. Results Sequencing identified an African–American male with a lower than predicted therapeutic warfarin dose (14.4 mg/week), previously genotyped as CYP2C9*1/*1, who was homozygous for CYP2C9*8 (c.449G>A; p.R150H). Genotyping 600 African–American alleles identified CYP2C9*8 as their most frequent variant CYP2C9 allele (0.047), and the combined allele frequency of CYP2C9*2, *3, *5, *6, *8 and *11 was 0.133. Given most warfarin pharmacogenetic dosing algorithms only include CYP2C9*2 and *3, the inclusion of CYP2C9*8 alone could reclassify the predicted metabolic phenotypes of almost 10% of African–Americans, or when combined with CYP2C9*5, *6 and *11, more than 15%. In addition, the African–American VKORC1 g.-1639A allele frequency was 0.108 and three g.1331G>A (p.V66M) carriers were identified. Conclusions CYP2C9*8 is prevalent among African–Americans (~1 in 11 individuals). Thus, in this racial group, the incorporation of CYP2C9*8 into genotyping panels may improve dose prediction of CYP2C9-metabolized drugs, including warfarin.

Priority pharmacogenetics for the African continent: focus on CYP450

“…Since CYP2C9 plays a role in the metabolism of arachidonic acid, a modulator of vascular tone and cardiovascular homeostasis, the increased frequency of defective alleles may be postulated to contribute to the high levels of cardiovascular disease in northern Africa, a concept supported previously by other groups [44,45]. Based on a handful of studies reported to date, CYP2C9*8 may also be regarded as a contributor to decreased drug clearance in populations of African origin, where it is present at allelic frequencies ranging from 1-12% [8,46,47]. When investigating the variants that contribute to variability in warfarin metabolism, it has been reported that this allele, together with CYP2C9*5, *6 and *11, may contribute to up to 30% of the variability in Africa-Americans [48].…”

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

“…18,30 Unfortunately, the VKORC1, CYP2C9 and CYP4F2 genes remain poorly characterized in many population groups, and there may be other variants within these genes affecting warfarin dose that would be relevant to include in the pharmacogenetic-based dosing algorithms. For example, Scott et al 43 recently described a variant (CYP2C9*8) present in an African-American male with a lower than predicted warfarin dose (based on prior genotyping of CYP2C9 and VKORC1 alleles). On further characterization of this variant in an African-American sample, the authors reported that CYP2C9*8 is the most frequent variant in this sample, and predicted that incorporation of this polymorphism in pharmacogenetic-based dosing algorithms could potentially reclassify the predicted metabolic phenotypes of almost 10% of African Americans.…”

Genetic Polymorphisms and <i>in Vitro</i> Functional Characterization of CYP2C8, CYP2C9, and CYP2C19 Allelic Variants

“…41,42) Furthermore, it is recognized that CYP2C9*5, CYP2C9*8, CYP2C9*11, and CYP2C9*13 reduce the clearance of warfarin in humans. [42][43][44][45][46] However, there are still many unknown aspects in terms of the effects of CYP2C9 gene polymorphism on the pharmacokinetics of warfarin.…”