1. ¹Committee on Clinical Pharmacology and Pharmacogenomics, Division of Biological Sciences, University of Chicago, Chicago, IL, USA
2. ²Department of Human Genetics, University of Chicago, Chicago, IL, USA
3. ³Department of Pharmaceutical Sciences, St. Jude's Research Hospital, Memphis, TN, USA
4. ⁴Department of Medicine, University of Chicago, Chicago, IL, USA

Correspondence: Dr MA Perera, 5841 South Maryland Avenue, MC 6091, Chicago, IL 60637, USA. E-mail: mperera@bsd.uchicago.edu

Received 10 April 2008; Revised 21 July 2008; Accepted 8 August 2008; Published online 30 September 2008.

Abstract

The CYP3A locus encodes hepatic enzymes that metabolize many clinically used drugs. However, there is marked interindividual variability in enzyme expression and clearance of drugs metabolized by these enzymes. We utilized comparative genomics and computational prediction of transcriptional factor binding sites to evaluate regions within CYP3A that were most likely to contribute to this variation. We then used a haplotype tagging single-nucleotide polymorphisms (htSNPs) approach to evaluate the entire locus with the fewest number of maximally informative SNPs. We investigated the association between these htSNPs and in vivo CYP3A enzyme activity using a single-point IV midazolam clearance assay. We found associations between the midazolam phenotype and age, diagnosis of hypertension and one htSNP (141689) located upstream of CYP3A4. 141689 lies near the xenobiotic responsive enhancer module (XREM) regulatory region of CYP3A4. Cell-based studies show increased transcriptional activation with the minor allele at 141689, in agreement with the in vivo association study findings. This study marks the first systematic evaluation of coding and noncoding variation that may contribute to CYP3A phenotypic variability.