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Functional constraints on the constitutive androstane receptor inferred from human sequence variation and

Emma E Thompson1, Hala Kuttab-Boulos, Matthew D Krasowski

  • 1Committee on Genetics, University of Chicago, Chicago, IL 60637, USA.

Human Genomics
|October 4, 2005
PubMed

Insights

Genetic variations in the constitutive androstane receptor (CAR) gene show limited interethnic differences, suggesting other factors influence drug metabolism. Conserved non-coding variants may impact CAR gene expression and drug response.

Area of Science:

  • Pharmacogenomics
  • Molecular biology
  • Genetics

Background:

  • Nuclear receptors, including NR1I3 (constitutive androstane receptor or CAR), regulate genes vital for drug metabolism and transport.
  • Significant inter-individual variability exists in drug clearance, partly due to genetic factors influencing drug-metabolizing enzymes like CYP3A, CYP2B, and UGT1A.
  • Genetic variations within the CAR locus could explain differences in gene expression and drug response.

Purpose of the Study:

  • To investigate sequence variation in the CAR gene across different populations.
  • To determine if genetic variations in CAR contribute to interethnic differences in drug metabolism.
  • To identify potential regulatory variants affecting CAR expression.

Main Methods:

  • Comparative genomics was used to select resequencing regions in 70 individuals from three distinct populations.
  • DNA sequencing was performed to identify polymorphic sites within the CAR gene.
  • Phylogenetic analysis was employed to assess the conservation of identified variants.

Main Results:

  • Twenty-one polymorphic sites were identified in the CAR gene, with one leading to an amino acid substitution.
  • A common haplotype, highly similar to the ancestral sequence, was found across all populations, indicating strong functional constraints on CAR.
  • Sequence variation patterns were similar across populations, suggesting CAR genetic variation is not a primary driver of interethnic drug metabolism differences.
  • Several conserved non-coding variants were identified, potentially influencing CAR expression.

Conclusions:

  • Genetic variation at the CAR locus does not appear to be a major cause of interethnic differences in drug metabolism.
  • Conserved non-coding variants in the CAR gene may play a role in regulating its expression and downstream drug-metabolizing enzyme activity.
  • Further research into these non-coding variants could provide insights into personalized medicine and drug response variability.

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