AHRR is located on chromosome 5p15.33. The gene is a key regulator of the aryl hydrocarbon receptor (AHR) pathway which is responsible for the detoxification of toxins such as polyaromatic hydrocarbons and dioxins found in burnt products via the P450 cytochrome system [60]. AHRR is a complexly regulated gene, with 5 CpG islands, at least 21 known splice variants and 10 known protein isoforms. The exact relationship between methylation changes at each of these CpG islands to production of these isoforms is not well understood. But increased transcription of AHRR protein serves as a negative feedback loop for the AHR mediated activation of CYP1A1, CYP1A2 and CYP1B1 via competitive inhibition of AHR binding to its cognate nuclear receptor (aryl hydrocarbon nuclear translocator; ARNT) partner or occupation of AHR DNA binding motifs [60]. Interestingly, the most replicated association with this gene is for a probe located within intron 3 of AHRR, not in a promoter region, a region that contains an enhancer motif whose demethylation is associated with the recruitment of DNA Complex C2 and C3, with the subsequent increase in AHRR mRNA production [49,61].
