Using an in vitro reporter assay, we also demonstrated there to be attenuated sensitivity of the rhCRH promoter to corticosteroids in cells expressing the G allele construct. Even with the introduction of the G allele, some degree of corticosteroid sensitivity was maintained. This is not surprising, given that other glucocorticoid receptor binding sites are present in the rhCRH promoter. However, it is possible that the GRE half site in which we identified variation could be functionally important through another mechanism. Binding of a hormone-receptor complex to a consensus GRE half-site can aid in recruitment of glucocorticoid receptors to a particular genomic region and facilitate binding of other receptor monomers to surrounding non-consensus sites 45. This site may aid in GR binding to the non-consensus sites in the rhCRH promoter that have been demonstrated to be important to regulation of CRH transcriptional activity, an effect that would be unlikely to be appreciated in a reporter system, which is enriched for the genomic region of interest. Regardless of the exact mechanism, we do indeed find effects of the -2232 G allele on
