The missing linkage: what pharmacogenetic associations are left to find in CYP3A?

IMPORTANCE OF THE FIELD: An enormous amount of drugs and endogenous substrates are metabolized by the enzymes encoded in the CYP3A gene cluster, making variation at this locus of utmost importance in the field of pharmacogenetics. However, the identification of genetic variation that contributes to the wide phenotypic variability at this locus has been elusive. While dozens of studies have investigated the effects of coding variants, none have found the definitive answer to what variant or variants explain the distribution of enzyme activity and clinical effects seen with the drug metabolized by these genes. AREAS COVERED IN THIS REVIEW: This review highlights the recent pharmacogenetic work at the CYP3A locus, in particular studies on known functional variants in CYP3A4 and CYP3A5. In addition, common pharmacogenetic strategies as well as considerations specific to the CYP3A locus are discussed. WHAT THE READER WILL GAIN: The reader will gain a greater understanding of the complexities involved in studying the CYP3A locus, population differences that may affect pharmacogenetic studies at this locus and the importance of variation that affect gene regulation. TAKE HOME MESSAGE: More innovative and comprehensive methods to assay this region are needed, with particular attention paid to the role of gene regulation and non-coding sequence.