Budinsky R, Urban J, Rowlands JC. 2011. An evaluation of single nucleotide polymorphisms in the human aryl hydrocarbon receptor nuclear translocator gene. Presented at the Society of Toxicology’s 50th Annual Meeting, March 6-10, Washington, D.C.
The effects of dioxin-like chemicals (DLCs) are mediated through the aryl hydrocarbon receptor (AHR); a key step in activation of this pathway involves heterodimerization with aryl hydrocarbon receptor nuclear translocator (ARNT) and subsequent activation of xenobiotic metabolizing enzymes. The objective of this study was to identify single nucleotide polymorphisms (SNPs) in the human ARNT gene that could potentially affect the sensitivity of the AHR response pathway. DNA from 101 human samples from six ethnic populations was sequenced using PCR and resulting exonic SNPs were compared with SNPs described previously in the literature or public databases. Results indicated that 69 samples had at least one SNP, and five samples had two SNPs. Five unique SNPs were identified, three of which were non-synonymous (two were novel). Several previously identified SNPs were not identified in the current study, though the most commonly reported SNP (V189V) in other studies was observed at a frequency of 0.49 in this study. The potential functional consequences of the three non-synonymous SNPs identified in the current dataset appear to be limited as the frequency of occurrence was very low (< 0.02), and because two of the SNPs appear in regions of the protein that are not within a defined functional domain. The remaining SNP (V304M) occurred in the PAS domain of a single sample. Studies have suggested that a single point mutation in this domain can negatively impact transcriptional function and potentially lower ARNT levels. With respect to DLC exposures, this would suggest that carriers of this SNP would be less sensitive to effects. However, loss and/or decrease of ARNT function has also been associated with type 2 diabetes and thus additional research is needed to fully understand the functional impact of the V304M variant in the human population. Overall, results indicate a very limited presence of polymorphisms in functional regions of the human ARNT.