A multifamily study on the relationship between CYP2C19 genotype and s-mephenytoin oxidation phenotype

Area of Science:

• Pharmacogenetics
• Human Genetics
• Drug Metabolism

Background:

• The CYP2C19 gene is crucial for S-mephenytoin metabolism, with common mutations (m1 and m2) identified in poor metabolizers (PM).
• Understanding the inheritance patterns of these CYP2C19 alleles is essential for accurate pharmacogenetic profiling.

Purpose of the Study:

• To investigate the inheritance of CYP2C19 wild-type (wt) and mutant alleles (m1, m2) in families of Danish PM probands.
• To confirm the autosomal recessive inheritance of defective CYP2C19 alleles.
• To evaluate the specificity and sensitivity of CYP2C19 genotyping for identifying PM individuals.

Main Methods:

• Phenotyping of individuals using the S/R mephenytoin urinary excretion ratio after drug administration.
• Genotyping via a Polymerase Chain Reaction (PCR)-based DNA amplification procedure to identify CYP2C19 alleles (wt, m1, m2).
• Family-based study design involving probands and relatives.

Main Results:

• Genotypes of 9 out of 11 PM probands were consistent with their phenotypes, with 8 being homozygous m1/m1 and one heterozygous m1/m2.
• Genotyping specificity for PM was 100%, and sensitivity was 94% (15/16), with discrepancies attributed to potential unknown mutant alleles or improved phenotyping.
• Seven relatives were phenotyped as PMs, and their genotypes (m1/m1) were consistent with phenotypes, further supporting autosomal recessive inheritance.

Conclusions:

• The study provides unequivocal evidence for autosomal recessive inheritance of the S-mephenytoin poor metabolizer trait.
• CYP2C19 genotyping is a highly specific and sensitive method for identifying individuals with this metabolic phenotype.
• Findings reinforce the importance of genetic testing in understanding drug metabolism variations.