Identification and in vitro functional assessment of 16 CYP2A6 variants detected in the Chinese Han population

CYP2A6

CYP2A6 missense variants altering the intrinsic clearance of the recombinant enzyme, measured in vitro with coumarin as probe substrate

CYP2A6 contributes to the metabolism of about 3% of clinically used drugs and to susceptibility to smoking-related disease, yet its allelic landscape remains incompletely characterized in the Chinese Han population. The authors developed a high-throughput genotyping method combining multiplex PCR with next-generation sequencing, applied to 1,163 Han individuals, which identified 12 previously reported allelic variants and 16 novel missense variants. The latter were expressed in a yeast microsomal system and their metabolic activity assessed in vitro by UPLC-MS/MS with coumarin as probe substrate. Five variants (I71F, Q239K, V334E, V334A and P402S) showed significantly increased intrinsic clearance and five others (G100R, E103K, T212M, R372H and Q409R) significantly decreased activity, while the remaining six retained wild-type-comparable function.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is a clean functional characterization study, feeding the annotation of a gene whose rare variants remain largely of uncertain significance — a real need now that exome sequencing already captures these positions without being able to interpret them. The limitation lies in the substrate: coumarin is a laboratory probe, not a drug of clinical interest, so these intrinsic clearances do not translate directly into prescribing guidance. No dose adjustment follows from this work as it stands.

Analysis by Dr Thibaut Benquey