Genetic polymorphism in exon 4 of cytochrome P450CYP2C9 may be associated with warfarin sensitivity in Chinese patients

CYP2C9 polymorphisms reported in Caucasians (Arg144Cys in exon 3 and IIe359 Leu in exon 7) are extremely uncommon in Chinese persons. The genotype of C YP2C9 in this population was characterized to investigate its relation with the interindividual variation in warfarin dosages. Eighty-nine Chinese pat ients receiving warfarin were recruited. Target sequences in CYP2C9 in exon s 1, 4, and 5 were amplified by polymerase chain reaction, followed by dire ct sequencing. Polymorphisms at 4 positions were demonstrated in exon 4. He terozygosities for 608TTG > GTG (Leu208Val), 561 CAG > CCG (Gln192Pro), 537 CAT>CCT (His184Pro), and 527ATT>CTT (IIe181Leu) existed at frequencies 0.75 , 0.20, 0.10, and 0.09, respectively. Seventeen patients (frequency, 0.19) were homozygous for Val208. The common genotypic combinations at these loci are IIe181/His184/ Gln192/Leu208Val(n=50), IIe181/His184/ Gln192Val208 (n= 15), IIe181/His184/Gln192/Leu208 (n=4), IIe181/His184/ Gln192Pro/Leu208Val (n=6), IIe181/ His184Pro/Gln192Pro/Leu208Val(n=4), and IIe181Leu/His184/Gln 192Pro/Leu208Val (n=4). At codon 208, heterozygous Leu208Val and homozygous Val208 appeared to have a lower warfarin dose requirement than the homozyg ous Leu208. Patients who are heterozygous for IIe181Leu had a higher warfar in dose requirement than the homozygous IIe181. Amplified sequences in exon s 1 and 5 did not exhibit polymorphism. In conclusion, Chinese patients sho wed genetic polymorphisms of CYP2C9 in exon 4 and at codon 208; most were h eterozygous Leu208Val and homozygous Val208. Homozygous Leu208, a common al lele in Caucasians, is uncommon in this cohort. The significance of these C YP2C9 polymorphic alleles remains to be determined. (Blood. 2001;98:2584-25 87) (C) 2001 by The American Society of Hematology.