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Sequence diversity and haplotype structure at the human CYP3A cluster

The Pharmacogenomics Journal volume 6, pages 105–114 (2006)Cite this article

Abstract

The four members of the human CYP3A subfamily play important roles in the clearance of xenobiotics, hormones, and environmental compounds. Many SNPs at the CYP3A locus have been characterized, with several showing large allele frequency differences across populations. In addition to the effects of CYP3A SNPs on drug metabolism, recent studies have highlighted the potential for CYP3A variation in susceptibility to several common phenotypes, including hypertension and cancer. We previously showed that the CYP3A4 and CYP3A5 genes have a strong haplotype structure at varying frequencies across ethnic groups. Here, we extend our re-sequencing survey to the remaining CYP3A genes in the same cluster, CYP3A7 and CYP3A43. Our study identified a large number of SNPs in coding and conserved noncoding sequences, several of which are common. The combined data set allows us to investigate patterns of sequence variation and linkage disequilibrium at the entire CYP3A locus for use in future association studies.

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Acknowledgements

We thank members of the Pharmacogenetics of Anticancer Agents Research (PAAR) group for helpful discussions throughout the project, particularly E Schuetz. We thank D Nickerson and J Akey for providing polymorphism and divergence data for the Seattle SNPs genes. EET was partially supported by training grant GM07197. Portions of this work were supported by NIH Grant 5 U54 HG02152 to BAR. This Pharmacogenetics of Anticancer Agents Research (PAAR) Group study was supported by the NIH/NIGMS Grant U01GM61393, www.pharmacogenetics.org. Data will be deposited into PharmGKB (supported by NIH/NIGMS Pharmacogenetics Research Network and Database Grant U01GM61374, http://pharmgkb.org/).

Author information

Authors and Affiliations

  1. Committee on Genetics, University of Chicago, Chicago, IL, USA

    E E Thompson & A Di Rienzo

  2. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    E E Thompson, H Kuttab-Boulos & A Di Rienzo

  3. Department of Chemistry and Biochemistry, Advanced Center for Genome Technology, University of Oklahoma, Norman, OK, USA

    L Yang & B A Roe

Authors
  1. E E Thompson
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  2. H Kuttab-Boulos
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  3. L Yang
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  4. B A Roe
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Corresponding author

Correspondence to A Di Rienzo.

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None declared.

Electronic Database Information

Cluster-Buster, http://zlab.bu.edu/cluster-buster/

Coriell Cell Repositories, http://locus.umdnj.edu/ccr/

Di Rienzo Lab Web site, http://genapps.uchicago.edu/labweb/pubs.html (for primer sequences, population sample informa tion, and data)

GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for CYP3A locus (accession number NG_000004) and individual gene accession numbers for CYP3A43 (AC011904), CYP3A4 and CYP3A7 (AC069294), and CYP3A5 (AC005020))

MultiPipMaker, http://bio.cse.psu.edu/pipmaker

PharmGKB, http://www.pharmgkb.org/ (for primer sequences and population samples used in re-sequencing study (individual gene accession numbers for CYP3A43 (PS205160), CYP3A4 (PS203894), CYP3A7 (PS205159), and CYP3A5 (PS203895))

Roe lab web site, http://www.genome.ou.edu/proto.html (for the most recent versions of the protocols used for BAC isolation, random shotgun cloning and sequencing, and sequence finishing)

SLIDER, http://genapps.uchicago.edu/slider/index.html (for computing summary statistics of population genetic data)

University of Washington-Fred Hutchinson Cancer Research Center, http://pga.gs.washington.edu/education.html (for Seattle SNPs, the National Heart Lung and Blood Institute's Program for Genomic Applications)

SIFT (Sorting Intolerant From Tolerant), http://blocks.fhcrc.org/sift/SIFT.html

Multi-Lagan, http://lagan.stanford.edu/cgi-bin/MLaganInput.cgi (for performing sequence alignments)

MATCH 1.0, www.gene-regulation.com/cgi-bin/pub/programs/match/bin/match.cgi (for prediction of transcription factor binding sites)

MAXDIP, http://genapps.uchicago.edu/maxdip/index.html (to generate composite likelihood estimates of recombination rate based on LD data)

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

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Thompson, E., Kuttab-Boulos, H., Yang, L. et al. Sequence diversity and haplotype structure at the human CYP3A cluster. Pharmacogenomics J 6, 105–114 (2006). https://doi.org/10.1038/sj.tpj.6500347

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