Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients

Abstract

CYP2C9 polymorphisms reported in Caucasians (Arg144Cys in exon 3 and Ile359Leu in exon 7) are extremely uncommon in Chinese persons. The genotype of CYP2C9 in this population was characterized to investigate its relation with the interindividual variation in warfarin dosages. Eighty-nine Chinese patients receiving warfarin were recruited. Target sequences in CYP2C9 in exons 1, 4, and 5 were amplified by polymerase chain reaction, followed by direct sequencing. Polymorphisms at 4 positions were demonstrated in exon 4. Heterozygosities for 608TTG>GTG (Leu208Val), 561CAG>CCG (GIn192Pro), 537CAT>CCT (His184Pro), and 527ATT>CTT (11e181Leu) existed at frequencies 0.75, 0.20, 0.10, and 0.09, respectively. Seventeen patients (frequency, 0.19) were homozygous for Va1208. The common genotypic combinations at these loci are Ile181/His184/ GIn192/Leu208Val (n = 50), Ile181/His184/ GIn192/Va1208 (n = 15), Ile181/His184/ GIn192/Leu208 (n = 4), Ile181/His184/ GIn192Pro/Leu208Val (n = 6), Ile181/ His184Pro/GIn192Pro/Leu208Val (n = 4), and Ile181Leu/His184/GIn 192 Pro/ Leu208Val (n = 4). At codon 208, heterozygous Leu208Val and homozygous Va1208 appeared to have a lower warfarin dose requirement than the homozygous Leu208. Patients who are heterozygous for Ile181Leu had a higher warfarin dose requirement than the homozygous llel8l. Amplified sequences in exons, I and 5 did not exhibit polymorphism. In conclusion, Chinese patients showed genetic polymorphisms of CYP2C9 in exon 4 and at codon 208; most were heterozygous Leu208Val and homozygous Va1208. Homozygous Leu208, a common allele in Caucasians, is uncommon in this cohort. The significance of these CYP2C9 polymorphic alleles remains to be determined. © 2001 by The American Society of Hematology.