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Evidence for a Heterozygote Advantage in Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency1

Evidence for a Heterozygote Advantage in Congenital Adrenal Hyperplasia due to 21-Hydroxylase... 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 ± 4.6μ g/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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Clinical Endocrinology & Metabolism Oxford University Press

Evidence for a Heterozygote Advantage in Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency1

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References (42)

Publisher
Oxford University Press
Copyright
Copyright © 1997 by The Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
DOI
10.1210/jcem.82.7.4086
pmid
9215278
Publisher site
See Article on Publisher Site

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 ± 4.6μ g/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.

Journal

The Journal of Clinical Endocrinology & Metabolism – Oxford University Press

Published: Jul 1, 1997

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