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

Division of Endocrinology, Diabetes, and Hypertension (B.C., N.S.K., J.S.W., E.W.S., G.H.W.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; Cardiovascular Genetics Division (S.C.H.), University of Utah School of Medicine, Salt Lake City, Utah 84132; Department of Medicine (N.J.B., L.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; and Department de Genetique (X.J.), Hôpital Européen Georges Pompidou, 75908 Paris, France

Address all correspondence and requests for reprints to: Gordon H. Williams, M.D., Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: gwilliams{at}partners.org.

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 µg 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.

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