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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Perera
Minoli A
MA
University of Chicago, Section of Genetic Medicine and Committee on Clinical Pharmacology and Pharmacogenomics, Division of Biological Sciences, Department of Medicine, Chicago, IL 60637, USA. mperera@bsd.uchicago.edu
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A