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

Hong Guang Xie, C. Michael Stein, Richard B. Kim, Grant R. Wilkinson, David A. Flockhart, Alastair J J Wood

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymorphism affecting drug metabolism in humans. The reported population prevalence of the CYP2C19 poor metabolizer phenotype in Caucasians of European descent has been described as ranging from 0.9% to 7.7%. To address the question of whether the difference in the frequency of poor metabolizers represents an ethnic genetic microheterogeneity in the structure and expression of the CYP2C19 gene in Caucasian individuals, we performed a pooled analysis of available studies. Combined data from the 22 homogeneous studies showed that the frequency of poor metabolizers in healthy unrelated Caucasians determined by phenotyping was 2.8% (110 of 3990; 95% confidence interval 2.3-3.3). Data obtained from eight homogeneous studies that determined the frequency of poor metabolizers by genotyping showed that the genotypic frequency of 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 Mendelian genotypes were 73% for wt/wt, 26% for wt/m, and 2.1% for m/m. Based on the overall phenotypic poor metabolizer frequency of 2.8%, the expected genotypic frequencies were 69% for wt/wt, 28% for wt/m and 2.8% for m/m, which are in good agreement to the observed values. However, in the 84 Caucasian phenotyped and genotyped poor metabolizers, approximately 10% of the putative poor metabolizer alleles (17 of 168) were unknown. This study provides a systematic overview of the population distribution of the CYP2C19 poor metabolizer phenotype and CYP2C19 alleles and genotypes in healthy Caucasians living in different geographical areas, and shows a similar polymorphic pattern in the structure and expression of the CYP2C19 gene in the worldwide Caucasian populations.

Original languageEnglish (US)
Pages (from-to)539-549
Number of pages11
JournalPharmacogenetics
Volume9
Issue number5
StatePublished - 1999
Externally publishedYes

Fingerprint

Population
Confidence Intervals
Alleles
Mephenytoin
Genotype
Phenotype
Gene Expression
Genetic Polymorphisms
Hydroxylation
Heterozygote
Demography
Cytochrome P-450 CYP2C19
Pharmaceutical Preparations

Keywords

  • Allele
  • Caucasians
  • CYP2C19
  • Genetic polymorphism
  • Genotype
  • Meta-analysis
  • Pharmacogenetics
  • Phenotype
  • S-mephenytoin 4'-hydroxylation
  • SNP

ASJC Scopus subject areas

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Allelic, genotypic and phenotypic distributions of S-mephenytoin 4'-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. / Xie, Hong Guang; Stein, C. Michael; Kim, Richard B.; Wilkinson, Grant R.; Flockhart, David A.; Wood, Alastair J J.

In: Pharmacogenetics, Vol. 9, No. 5, 1999, p. 539-549.

Research output: Contribution to journalArticle

Xie, Hong Guang ; Stein, C. Michael ; Kim, Richard B. ; Wilkinson, Grant R. ; Flockhart, David A. ; Wood, Alastair J J. / Allelic, genotypic and phenotypic distributions of S-mephenytoin 4'-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. In: Pharmacogenetics. 1999 ; Vol. 9, No. 5. pp. 539-549.
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abstract = "Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymorphism affecting drug metabolism in humans. The reported population prevalence of the CYP2C19 poor metabolizer phenotype in Caucasians of European descent has been described as ranging from 0.9{\%} to 7.7{\%}. To address the question of whether the difference in the frequency of poor metabolizers represents an ethnic genetic microheterogeneity in the structure and expression of the CYP2C19 gene in Caucasian individuals, we performed a pooled analysis of available studies. Combined data from the 22 homogeneous studies showed that the frequency of poor metabolizers in healthy unrelated Caucasians determined by phenotyping was 2.8{\%} (110 of 3990; 95{\%} confidence interval 2.3-3.3). Data obtained from eight homogeneous studies that determined the frequency of poor metabolizers by genotyping showed that the genotypic frequency of 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 Mendelian genotypes were 73{\%} for wt/wt, 26{\%} for wt/m, and 2.1{\%} for m/m. Based on the overall phenotypic poor metabolizer frequency of 2.8{\%}, the expected genotypic frequencies were 69{\%} for wt/wt, 28{\%} for wt/m and 2.8{\%} for m/m, which are in good agreement to the observed values. However, in the 84 Caucasian phenotyped and genotyped poor metabolizers, approximately 10{\%} of the putative poor metabolizer alleles (17 of 168) were unknown. This study provides a systematic overview of the population distribution of the CYP2C19 poor metabolizer phenotype and CYP2C19 alleles and genotypes in healthy Caucasians living in different geographical areas, and shows a similar polymorphic pattern in the structure and expression of the CYP2C19 gene in the worldwide Caucasian populations.",
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