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Clinical Research Center Studies |
Divisions of Endocrinology (S.F.W., P.A.L., M.S.-H.) and Immunogenetics (M.T.), Department of Pediatrics, Children’s Hospital of Pittsburgh, and the Department of Molecular Genetics and Biochemistry (E.P.H.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Selma F. Witchel, M.D., Division of Endocrinology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, Pennsylvania 15213.
Abstract
21-Hydroxylase deficiency is one of the most common inherited disorders, with carrier frequencies of approximately 10% in all world populations studied to date. The high prevalence of the mutant gene is probably due to a flanking pseudogene serving as a reservoir for mutations. Despite the potential for a high rate of de novo mutations, a founder effect for specific gene conversions is observed in most populations. We hypothesized that there was a survival advantage to 21-hydroxylase heterozygotes, and here we report endocrinological and molecular investigations to test this hypothesis. We defined 28 carriers and 22 mutation-negative controls by molecular genotyping and determined ACTH-stimulated adrenal hormone responses. We found significantly elevated cortisol responses in the carriers compared to controls (30 min cortisol levels: normal, 24.2 ± 4.6 µg/dL; carrier, 28.1 ± 4.2 µg/dL; P < 0.005). Cortisol has a crucial role in maintaining homeostasis, influencing differentiation, suppressing inflammation, and effecting cross-talk among the immune, nervous, and endocrine systems. The brisk cortisol response we have documented in carriers of 21-hydroxylase may enable a rapid return to homeostasis in response to infectious, inflammatory, or other environmental stresses and may protect from inappropriate immune responses, such as autoimmune diseases.
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