DIFFERENCES IN THE INCIDENCE OF THE CYP2C19 POLYMORPHISM AFFECTING THE S-MEPHENYTOIN PHENOTYPE IN CHINESE HAN AND BAI POPULATIONS AND IDENTIFICATION OF A NEW RARE CYP2C19 MUTANT ALLELE

The incidence of the S-mephenytoin polymorphism was compared in two Ch inese ethnic groups, Han (n = 101) and Bai (n = 202) by phenotype and genotype analysis. The frequency of poor metabolizers (PMs) in Han vs. Bai subjects was 19.8% vs. 13.4%. Han subjects had a higher frequency of the mutant CYP2C19(m1) allele (0.366 vs. 0.257, P < .01) and a low er frequency of the wild-type allele (0.559 vs. 0.688, P < .01) than B ai subjects, which is consistent with the difference in the frequencie s of PMs between the two ethnic groups. This results in a lower percen tage of homozygous wild-type extensive metabolizers of mephenytoin (EM s) in Han subjects than in Bai subjects (40% vs. 59%, P = .005). There fore, Han subjects may be more susceptible than Bai subjects to the dr ugs metabolized by the CYP2C19 enzyme. Ratios of urinary S/R-mephenyto in in homozygous EMs were lower than those of heterozygous EMs for bot h Han and Bai subjects, which shows a gene-dosage effect. Genotype ana lysis identified all but one PM as homozygous or heterozygous for the two known mutant CYP2C19(m1) and/or CYP2C19(m2) alleles. A single Bai PM outlier was shown to be heterozygous for CYP2C19(m1) and a new muta nt CYP2C19 allele containing a single amino acid change of Arg(433) -- > Trp(433). A genotyping test demonstrated that only this one individu al carried this rare allele (frequency of 0.0025 in Bai subjects).