Urinary Free Cortisol: An Intermediate Phenotype and a Potential Genetic Marker for a Salt-Resistant Subset of Essential Hypertension

CONTEXT: Emerging evidence suggests a role for cortisol in essential hypertension, and preliminary reports indicate that urinary free cortisol (UFC) may be an intermediate phenotype. OBJECTIVES: The objectives of this study were: 1) confirm bimodality of UFC, 2) assess whether UFC variations aggregate in hypertensive families, and 3) compare low-mode and high-mode UFC groups for distinguishing features. SUBJECTS/SETTING: Subjects included 390 hypertensives and 166 normotensives from the general community. DESIGN/INTERVENTIONS: Subjects had blood pressure and laboratory measurements on high- and low-salt diets. Familial aggregation was evaluated in 250 hypertensive siblings from 117 families. RESULTS: Hypertensives had higher UFC than normotensives (P<0.001) and bimodal distribution of UFC (P<0.0001). Analyses were controlled for gender and dietary sodium, which are confounding determinants of UFC. Mean low-mode UFC (33.8+/-10.6 microg per 24 h) was similar to that of normotensives. The high mode, comprising 31.3% of hypertensives, had less change in mean arterial pressure between diets than the low mode (P=0.01) without any other significant differences. Observed proportions of concordance and discordance for UFC mode differed significantly from that expected (P<0.001). Observed concordance for the high mode was twice that expected, whereas for the low mode, it was similar to that expected by chance. Family membership explained a significant proportion of variance in UFC classification (P=0.027). UFC mode of one sibling was a significant predictor of the UFC mode of the other sibling [odds ratio 6.6, 95% confidence interval (2.4-18.0), P<0.001]. CONCLUSION: High-mode UFC is an intermediate phenotype of hypertension associated with salt resistance and a strong familial component supporting heritability.