title: Evidence for a heterozygote advantage in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
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 micrograms/dL; carrier, 28.1 +/- 4.2 micrograms/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.
authors.affiliation: Division of Endocrinology, University of Pittsburgh, Pennsylvania 15213, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Witchel
authors.forename: P A
authors.initials: PA
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Suda-Hartman
authors.forename: M
authors.initials: M
authors.lastname: Trucco
authors.forename: E P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
chemical_list: D019326:17-alpha-Hydroxyprogesterone; D000324:Adrenocorticotropic Hormone; D013255:Steroid 21-Hydroxylase; D006854:Hydrocortisone