title: Prediction of CYP3A4 enzyme activity using haplotype tag SNPs in African Americans.
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.
authors.affiliation: Committee on Clinical Pharmacology and Pharmacogenomics, Division of Biological Sciences, University of Chicago, Chicago, IL, USA. mperera@bsd.uchicago.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Perera
authors.forename: R K
authors.initials: RK
authors.lastname: Thirumaran
authors.forename: N J
authors.initials: NJ
authors.lastname: Cox
authors.forename: S
authors.initials: S
authors.lastname: Hanauer
authors.forename: S
authors.initials: S
authors.lastname: Das
authors.forename: C
authors.initials: C
authors.lastname: Brimer-Cline
authors.forename: V
authors.initials: V
authors.lastname: Lamba
authors.forename: E G
authors.initials: EG
authors.lastname: Schuetz
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: A
authors.initials: A
authors.lastname: Di Rienzo
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D014162:Transfection; D055815:Young Adult
chemical_list: D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam