Newly Discovered CYP2C9 SNPs Also May Slow Warfarin Metabolism

While genotyping 32 Japanese patients who were slow metabolizers of phenytoin, Imai et al. (20) found a new polymorphism designated as CYP2C9*4: a T1076C transversion that leads to an Ile359Thr substitution. This mutation was not present in 100 unselected Japanese volunteers. The effect on warfarin metabolism is unknown, but because it alters the same amino acid (359) similar to the 2C9*3 mutation, it could decrease the metabolism of S-warfarin. Dickman et al. (21) found a C1080G transversion that leads to an Asp360Glu substitution. They found this mutation, CYP2C9*5, in four out of 120 African American participants and in zero of out 140 European American participants. The intrinsic clearance (Vmax/Km) was estimated as 8% of that of the wild type, suggesting that carriers of CYP2C9*5 will eliminate S-warfarin more slowly than non-carriers. Kidd et al. (22) reported a null polymorphism, 818delA, which they named CYP2C9*6. The patient presented with an overdose of phenytoin (an anticonvulsant that is metabolized by CYP2C9) and was found to have a phenytoin clearance that was only 17% of the normal. Finally, in a cohort of 89 Chinese patients who were prescribed warfarin, Leung et al. (23) found several CYP2C9 SNPs in exon 4. The Leu208Val variant was relatively common in this population and was associated with a decreased warfarin dose.

Table 2 Independent Predictors of Warfarin Dose in Three Studies

Variable

Reference 19

Reference 14

Reference 12

Model R2

35%

26%

38%

Sample size

156

153

297

Age, yr

*

*

*

BSA, m2

*

Not examined

*

2C9*3, per allele

*

*

*

2C9*2, per allele

*

*

*

Target INR

Not examined

Not examined

*

Amiodarone

*

Not examined

*

Dietary vitamin K

NS

Not examined

NS

'Statistically significant, p < 0.05.

Abbreviations: R2, percent of variability explained by the model; BSA, body surface area; NS, not significant; INR, international normalized ratio.

'Statistically significant, p < 0.05.

Abbreviations: R2, percent of variability explained by the model; BSA, body surface area; NS, not significant; INR, international normalized ratio.

Table 3 New Cytochrome P450 2C9 SNPs that May Affect Warfarin Metabolism

Designation Protein change

Effect on warfarin dose

References

CYP2C9*4 CYP2C9*5 CYP2C9*6 Unnamed

Ile359Thr Asp360Glu Null allele Tyr358Cys

T1076C C1080G 818delA G1061A

Not examined Not examined Not examined Not examined

Abbreviation: SNP, single-nucleotide polymorphism.

However, more recent studies suggest that these apparent variants are actually results from PCR amplification of a pseudogene and are not likely to be of functional relevance. In summary, further research is needed to determine if these new CYP2C9 SNPs (Table 3) affect warfarin metabolism significantly.

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