Genetic Variation in PXRs Intron 1 and Its Functional Relevance

The 5-UTR SNP -24381 (called -566 in King et al. [40]) was associated with higher P-gp and CYP3A4 expression in colon tumors. This SNP has also been associated with risk of IBD (inflammatory bowel disease). This SNP was not found to be associated with hepatic PXR regulated traits [17]. It may be that the functional consequence of this SNP is tissue specific, or that it requires further studies in larger populations. 

A number of SNPs in LD in PXR intron 1 were associated with CYP3A4 (Table 9.2). A 6bp deletion in intron la (-24020) has been reported [39, 33]. Intron la also represents the promoter for the PXR variant PAR2 that uses exon lb as the first coding exon. This 6 bp deletion occurred with a frequency of 27-28% in the Japanese population and was associated with complete loss of PXR promoter activity in HepG2 cells [33], 

Although any of the SNPs alone or in combination with the intron 1 LD block could be affecting PXR activity, one LD TAG SNP was randomly chosen to represent the block of associated SNPs. For example, 63396C T was chosen as an intron 1 LD Tag SNP [it was in LD with intron 1 SNPs 63704G A and a polymorphic repeat at 63813 (CAAA)5/6(CA)12/13 and in partial LD with intron 1 SNPs 63877T C 

Position in AF364606 Position from Translation Start Site (+ l)t Position from Transcription Start Site (+l)c rs Number (HAPMAP) Putative or In Vivo Functional Consequences Population Allele Frequency (Caucasians) Reference 

HNI 3(i site gained by (CAAA)CA insertion hepatic CYP3A Hepatic CYP3A Hepatic CYP3A 

---