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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.

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Acknowledgements

This work was made possible with the assistance in statistical and computational analysis by David Witonski and Cheryl Roe, LC/MS/MS assistance by Larry House, and genotyping via dHPLC by Pei Xian Chen. Special thanks go to Dr Emma Thompson for her instruction in population genetics and enlightening conversations and theories. This study was supported by NIH grants GM60346, GM61393 and GM07019.

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Correspondence to M A Perera.

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Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj)

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Perera, M., Thirumaran, R., Cox, N. et al. Prediction of CYP3A4 enzyme activity using haplotype tag SNPs in African Americans. Pharmacogenomics J 9, 49–60 (2009). https://doi.org/10.1038/tpj.2008.13

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