Identification and functional characterization of 11 novel CYP2C19 variants in the Chinese Han population

The cytochrome P450 2C19 (CYP2C19) enzyme plays a critical role in the metabolism of several clinically important drugs, but the genetic polymorphisms of CYP2C19 have been partially characterized in the Chinese population.

Genomic DNA from 1210 Chinese Han individuals was subjected to next-generation sequencing to screen for CYP2C19 variants, and newly identified mutations were confirmed by Sanger sequencing. CYP2C19 microsomes were expressed in vitro using an insect cell expression system, and their metabolic activity toward (S)-mephenytoin was quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).

Genetic screening of CYP2C19 gene in 1210 Chinese Han individuals was performed and identified 11 previously unreported variants. Recombinant expression of these novel variants in insect microsomes demonstrated that approximately half of the variants exhibited protein expression levels comparable to the wild type. Using (S)-mephenytoin as a probe substrate, in vitro metabolic activity assays revealed that five variants (G79X, D188fs, A297D, A297V, and T302R) exhibited abolished enzymatic activity, whereas the remaining variants showed significantly reduced activity compared to the wild-type enzyme.

This study reveals a high prevalence of functionally impaired rare CYP2C19 variants in the Chinese Han population, underscoring their potential clinical relevance for personalized medicine.