Structure and polymorphisms of human aryl hydrocarbon receptor repressor (AhRR) gene in a French population:: relationship with CYP1A1 inducibility and lung cancer

Objective The aryl hydrocarbon receptor repressor (AhRR) protein may dimerize with the AhR nuclear translocator (ARNT) and may compete with the aryl hydrocarbon receptor (AhR) to bind the xenobiotic responsive elements. The result is a negative feedback mechanism that involves a down regulation of all genes regulated by the AhR transcription factor which positively regulates the expression of the Cytochrome P-4501A1 gene (CYP1A1). Methods The structure of the AhRR gene was reconstituted, then the genetic polymorphisms of this gene including the promoter were investigated and the link between these polymorphisms, CYP1A1 inducibility and lung cancer incidence in a French population was examined. Four polymorphisms were found, two in the coding region (609G>C and 1977G>C) and two in the 5'-untranslated region (-96G>A and -869A>T). Among the four polymorphisms, only one, the 609G>C has been previously described. The 609G>C and 1977G>C are localized respectively in exon 6 and 12 and lead to Pro554Ala and Asp641 His substitutions, respectively. To evaluate the frequency of these allelic variants, a DNA library of a case-control study of lung cancer (164 controls and 171 patients) was screened. These polymorphisms were detected at the same allele frequency (0.40 for 609C, 0.05 for 1977C, 0.24 for -96A and 0.17 for -869T) in both controls and patients. Statistical analysis did not show any relationship between all the mutations found and CYP1A1 inducibility and lung cancer incidence. Conclusion None of the polymorphisms were found to play a key role in CYP1A1 inducibility or in the susceptibility to develop lung cancer. Pharmacogenetics (C) 2003 Lippincott Williams Wilkins.