Identification of a Functional CYP2C8 Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases Drug Exposure.

Novel CYP2C8*19 allele (rs2071426) creating an intronic splice donor site → reduced protein expression and enzyme activity, increased drug exposure

This study investigates the genetic determinants of the pharmacokinetics of CYP2C8 substrates (repaglinide, gemfibrozil) in healthy volunteers. Sequencing data reveal a novel functional allele, CYP2C819 (rs2071426), predicted to create an intronic splice donor site. In human liver samples, this allele is associated with transcript-specific reductions in CYP2C8 mRNA and protein expression and decreased activity. CYP2C8*19/19 carriers have a 45% greater repaglinide AUC than 1/1, and the inhibitory effect of gemfibrozil is attenuated; a GWAS also confirms a role for SLCO1B1 c.521T>C.

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

A solid discovery of a novel functional CYP2C8 allele, with a clear pharmacokinetic impact and mechanistic demonstration (splicing, human liver, kinetics). It is not yet in CPIC guidelines — its regulatory status should not be overstated — but it is precisely the kind of early signal that a watch should capture and bring to the attention of expert societies ahead of any future incorporation.

Analysis by Dr Thibaut Benquey