Increased Risk of Hemorrhage with CYP2C92 or CYP2C93 SNPs

Recent studies suggest that the CYP2C9*2 and CYP2C9* 3 variants are associated with hemorrhage during warfarin induction but not during maintenance therapy. In their retrospective cohort of 180 patients who were given warfarin, Margaglione et al. (10) found that the odds of bleeding was increased 2.6-fold in patients with the CYP2C9*2 and/or the CYP2C9*3 SNPs than in the carriers of the wild type. They also found a statistical interaction between these variants and the presence of a local bleeding source, but the etiology and significance of that interaction are unclear. In their retrospective cohort of 185 patients who were given warfarin, Higashi et al. (9) found a 2.4-fold increased risk of hemorrhage among patients with either of the two variant alleles. In contrast to these two positive studies, Taube et al. (18) found no association between CYP2C9 genotype and bleeding in 561 patients who were taking warfarin for more than 2 months. The most likely explanation for the association between genotype and bleeding is that patients with the CYP2C9*2 and/or the CYP2C9*3 SNPs metabolize warfarin more slowly than wild-type patients and, therefore are more likely to be overdosed when beginning warfarin with a traditional dose. Indeed, Aithal et al. (11) found that patients who required tiny doses of warfarin (<1.5mg/day) were six times more likely to have the CYP2C9*2 and/or CYP2C9*3 SNPs and four times more likely to bleed during warfarin induction.

Table 1 Cytochrome P450 2C9 SNPs that Are Known to Affect Warfarin Metabolism

Effect on

Designation

Protein change

SNP

warfarin dose

Allele frequencya

References

CYP2C9* 1

None

None

Referent

81.5-93%

CYP2C9*2

Arg144Cys

C430T

-14% to -20%

5.6-12.8%

(8,10,12,18,19)

CYP2C9*3

Ile359Leu

A1061C

-21% to -49%

1.4-5.7%

(10,12,18,19)

aCYP2C9*2 and *3 are most common in white populations.

Abbreviations: SNP, single-nucleotide polymorphism; CYP2C9*!, wild-type allele.

aCYP2C9*2 and *3 are most common in white populations.

Abbreviations: SNP, single-nucleotide polymorphism; CYP2C9*!, wild-type allele.

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