Research reportGenetic variants in serotonin and corticosteroid systems modulate neuroendocrine and cardiovascular responses to intense stress

•This study revealed a remarkable synergistic effect of common polymorphisms on acute stress response in healthy men.•5HTTLPR SS carriers revealed higher overall cortisol concentrations than L carriers in response to intense, realistic stress.•5HTTLPR S carriers showed higher overall DBP values than non-carriers (LL), Bcl1 GG were higher than C carriers, and −2C/G G carriers exceeded non-carriers (CC).•A “high” genotype group revealed substantially higher overall cortisol concentrations than a “low” genotype group, as was the case for DBP.

Common variants in serotonin and corticosteroid receptor genes influence human stress in laboratory settings. Little is known of their combined effects, especially in high stress environments. This study evaluated distinct and combined effects of polymorphisms in the serotonin transporter (5HTTLPRL/S), glucocorticoid receptor (Bcl1C/G), and mineralocorticoid (−2C/G) receptor genes on adrenocortical and cardiovascular responses to intense, realistic stress. One hundred and forty four healthy, active-duty military men were studied before, during, and 24 h after a stressful 12-day survival course. Dependent variables were cortisol, heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). 5HTTLPR SS carriers revealed higher overall cortisol concentrations than L carriers (p = .022). 5HTTLPR L carriers demonstrated higher stress-induced HR than non-carriers (SS) yet rebounded to a lower recovery value (p = .026), while Bcl1 G carriers showed higher mean stress-induced HR than non-carriers (CC) (p = .047). For DBP, 5HTTLPR S carriers showed higher overall values than non-carriers (LL) (p = .043), Bcl1 GG were higher than C carriers (p = .039), and −2C/G G carriers exceeded non-carriers (CC) (p = .028). A “high” composite genotype group revealed substantially higher overall cortisol concentrations than a “low” composite genotype group (p < .001), as was the case for DBP (p = .037). This study revealed a synergistic effect of common polymorphisms on the acute stress response in healthy men. Pending additional study, these findings may have implications for drug discovery, gene therapy, and stress inoculation strategies.