There is a common missense polymorphism (rs5522) within exon 2 of the human mineralocorticoid receptor gene (NR3C2) that results in the substitution of isoleucine for valine [iso(A)/val(G)]. In vitro data show that the val allele is characterized by reduced cortisol-related transactivation (20, 21). Animal studies have shown that reductions in mineralocorticoid receptor function (i.e., knockout or antagonism) increase basal and stress-evoked HPA axis activity, while enhanced receptor expression reduces HPA axis activity under these circumstances (19, 22, 23). Because the val allele is associated with reduced cortisol-mediated binding that inhibits HPA axis function (20, 21), it is not surprising that it has been associated with heightened stress reactivity as indexed by endocrine, autonomic, perceptual, and subjective self-report measures (20, 21, 24; but see also 25). Moreover, the val allele has been associated with depressive symptoms as well as stress-induced reward learning deficits, which further suggests the relevance of the mineralocorticoid receptor iso/val polymorphism in the emergence of psychopathology (24, 26).
