Common functional mineralocorticoid receptor polymorphisms modulate the cortisol awakening response: Interaction with SSRIs

Abstract

Cortisol controls the activity of the hypothalamic-pituitary-adrenal (HPA) axis during stress and during the circadian cycle through central mineralocorticoid (MR) and glucocorticoid receptors (GR). Changes in MR and GR functioning, therefore, may affect HPA axis activity. In this study we examined the effect of common functional MR gene variants on the cortisol awakening response (CAR), which is often disturbed in stress-related disorders like depression. Common functional MR single nucleotide polymorphisms (SNPs; MR -2G/C and I180V) and haplotypes were tested for association with variability in the CAR in a large cohort (Netherlands Study of Depression and Anxiety, NESDA) of patients diagnosed with a lifetime major depressive disorder (MDD). Saliva cortisol measurements and genotypes could be obtained from a total of 1026 individuals, including 324 males and 702 females. The MR -2C/C genotype was associated with an attenuated CAR increase in women (p=.03) but not in men (p=.18; p=.01 for SNP-by-sex interaction). The MR I180V SNP had no significant effect on the CAR. Additional analysis revealed that effect of the -2G/C SNP on the CAR was due to an interaction with frequent use of selective serotonin reuptake inhibitors (SSRIs). Only in subjects using SSRIs (men and women) highest total morning cortisol levels were observed in -2G/G carriers, while the CAR was completely flattened in women with the -2C/C genotype (p<.05). The results were independent of multiple potential confounders and had an effect size of r=.14-.27. This study shows that the MR -2G/C SNP modulated the CAR only in the MDD patients using SSRIs, with a clear allele-dose effect in women. This suggests that effect of SSRIs on cortisol regulation depends in part on the MR genotype with possible implications for future treatment selection.