Functional impact of CYP2C9*5, CYP2C9*6, CYP2C9*8, and CYP2C9*11 in vivo among black Africans*1

Abstract

The CYP2C9*5 and *6 alleles are associated with decreased enzyme activity in vivo compared with the wild-type variant, whereas the CYP2C9*8 and *11 variants did not appear to have large in vivo effects.

CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism Regulates mRNA Expression in Human Livers

“…The two clinically most important alleles, CYP2C9*2 and CYP2C9*3, occur at a minor allele frequency of ϳ10 and 6%, respectively, in white populations but are less abundant or undetectable in individuals of African and Asian descent (Lee et al, 2002). In contrast, other potentially important variants, e.g., CYP2C9*8, *9, and *11, occur in the African population with frequencies of 3.6, 13, and 5.6%, respectively, whereas these alleles, in turn, are low or undetectable in other racial groups (Allabi et al, 2004;Blaisdell et al, 2004). Convincing evidence suggests that CYP2C9*2 and CYP2C9*3 alleles convey reduced enzyme activity and have been associated with drug dosage requirements and treatment outcomes (Aithal et al, 1999;Higashi et al, 2002;Lee et al, 2002).…”

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Whether an altered conversion of losartan to EXP3174 is associated with an altered blood pressure response to losartan remains unclear, as this was observed in Japanese (Sekino et al, 2003) but not Caucasian healthy volunteers (Lee et al, 2003b); however, the subject groups being tested were small, and ARBs typically cause only minor blood pressure reductions in healthy subjects to begin with. Later studies based on black African subjects found that the *5 and *6 alleles of CYP2C9 are also associated with lower enzyme activity for losartan conversion in vivo, whereas the *8 and *11 alleles had little effect (Allabi et al, 2004). The *13 allele of CYP2C9 was also reported to be associated with a reduced conversion of losartan to EXP3174 in healthy volunteers (Li et al, 2009b).…”

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

“…CYP2C9*6 (818delA, frameshift) contains a premature stop codon, resulting in a null allele that dramatically decreases the metabolism of phenytoin and warfarin. [31,32]Based on studies with recombinant CYP2C9 [25,26] CYP2C9*11 is predicted to have greatly diminished catalytic activity, but has not received extensive clinical study. One study [38] reported significantly lower warfarin dose requirements in patients with the CYP2C9*1/*11 genotypes compared to those with CYP2C9*1/*1 genotype.…”

“…[25,26] Therefore, this variant was also included in this study. The *10 allele (A815G, E272G) is a rare allele reported in European Americans.…”