Functional constraints on the constitutive androstane receptor inferred from human sequence variation and cross-species comparisons

Emma E Thompson; Hala Kuttab-Boulos; Matthew D Krasowski; Anna Di Rienzo

doi:10.1186/1479-7364-2-3-168

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Functional constraints on the constitutive androstane receptor inferred from human sequence variation and cross-species comparisons

Journal article

Open access

Peer reviewed

Functional constraints on the constitutive androstane receptor inferred from human sequence variation and cross-species comparisons

Emma E Thompson, Hala Kuttab-Boulos, Matthew D Krasowski and Anna Di Rienzo

Human genomics, Vol.2(3), pp.168-178

09/2005

DOI: 10.1186/1479-7364-2-3-168

PMCID: PMC3525124

PMID: 16197734

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Abstract

Members of the NR1I subfamily of nuclear receptors play a role in the transcriptional activation of genes involved in drug metabolism and transport. NR1I3, the constitutive androstane receptor (CAR), mediates the induction of several genes involved in drug response, including members of the CYP3A, CYP2B and UGT1A subfamilies. Large inter-individual variation in drug clearance has been reported for many drug metabolising enzyme genes. Sequence variation at the CAR locus could potentially contribute to variation in downstream targets, as well as to the substantial variation in expression level reported. We used a comparative genomics-based approach to select resequencing segments in 70 subjects from three populations. We identified 21 polymorphic sites, one of which results in an amino acid substitution. Our study reveals a common haplotype shared by all three populations which is remarkably similar to the ancestral sequence, confirming that CAR is under strong functional constraints. The level and pattern of sequence variation is approximately similar across populations, suggesting that interethnic differences in drug metabolism are not likely to be due to genetic variation at the CAR locus. We also identify several common non-coding variants that occur at highly conserved sites across four major branches of the mammalian phylogeny, suggesting that they may affect CAR expression and, ultimately, the activity of its downstream targets.

Polymerase Chain Reaction

Genetic Variation

Likelihood Functions

Animals

Receptors, Steroid - genetics

Species Specificity

Humans

Phylogeny

DNA Primers

Genome, Human

Details

Title: Subtitle: Functional constraints on the constitutive androstane receptor inferred from human sequence variation and cross-species comparisons
Creators: Emma E Thompson - Committee on Genetics, University of Chicago, Chicago, IL 60637, USA
Hala Kuttab-Boulos
Matthew D Krasowski
Anna Di Rienzo
Resource Type: Journal article
Publication Details: Human genomics, Vol.2(3), pp.168-178
Publisher: England
DOI: 10.1186/1479-7364-2-3-168
PMID: 16197734
PMCID: PMC3525124
ISSN: 1473-9542
eISSN: 1479-7364
Grant note: GM61393 / NIGMS NIH HHS GM07197 / NIGMS NIH HHS
Language: English
Date published: 09/2005
Academic Unit: Pathology
Record Identifier: 9984047987702771

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