Allelic, genotypic and phenotypic distributions of S-mephenytoin 4 '-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world

Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymor phism affecting drug metabolism in humans. The reported population prevalen ce of the CYP2C19 poor metabolizer phenotype in Caucasians of European desc ent has been described as ranging from 0.9% to 7.7%. To address the questio n of whether the difference in the frequency of poor metabolizers represent s an ethnic genetic microheterogeneity in the structure and expression of t he CYP2C19 gene in Caucasian individuals, we performed a pooled analysis of available studies. Combined data from the 22 homogeneous studies showed th at the frequency of poor metabolizers in healthy unrelated Caucasians deter mined by phenotyping was 2.8% (110 of 3990; 95% confidence interval 2.3-3.3 ), Data obtained from eight homogeneous studies that determined the frequen cy of poor metabolizers by genotyping showed that the genotypic frequency o f poor metabolizers was 2.1% (28 of 1356; 95% confidence interval 1.3-2.8), consistent with the poor metabolizer frequency determined by phenotyping. In the extensive metabolizers, 26% (471 of 1786; 95% confidence interval 24 .4-28.4) were heterozygotes. The observed frequencies of the three Mendelia n genotypes were 73% for wt/wt, 26% for wt/m, and 2.1% for m/m. Based on th e overall phenotypic poor metabolizer frequency of 2.8%, the expected genot ypic frequencies were 69% for wt/wt, 28% for wt/m and 2.8% for mim, which a re in good agreement to the observed values. However, in the 84 Caucasian p henotyped and genotyped poor metabolizers, approximately 10% of the putativ e poor metabolizer alleles(17 of 168) were unknown. This study provides a s ystematic overview of the population distribution of the CYP2C19 poor metab olizer phenotype and CYP2C19 alleles and genotypes in healthy Caucasians li ving in different geographical areas, and shows a similar polymorphic patte rn in the structure and expression of the CYP2C19 gene in the worldwide Cau casian populations. Pharmacogenetics 9:539-549 (C) 1999 Lippincott Williams & Wilkins.