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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2097-2101
Copyright © 1997 by The Endocrine Society

Clinical Research Center Studies

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

Selma F. Witchel, Peter A. Lee, Makiko Suda-Hartman, Massimo Trucco and Eric P. Hoffman

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.

CORTISOL has a crucial role in maintaining homeostasis, influencing differentiation, suppressing inflammation, and effecting cross-talk among the immune, nervous, and endocrine systems. Diurnal variations in cortisol concentrations and stress-induced cortisol secretion are tightly regulated through feedback inhibition by the hypothalamic-pituitary-adrenal axis to maintain optimal cortisol concentrations (1).

Disorders of cortisol biosynthesis are known as the congenital adrenal hyperplasias. The most common is 21-hydroxylase deficiency, an autosomal recessive disorder due to mutations in the 21-hydroxylase gene (CYP21) located on the short arm of chromosome 6 (Fig. 1Go) where it lies in close proximity to a nonfunctional pseudogene (CYP21P) (2, 3, 4, 5, 6). In affected homozygotes, decreased adrenal 21-hydroxylase activity interferes with cortisol and aldosterone biosynthesis, but leaves the adrenal androgen biosynthetic pathway intact. Loss of negative feedback inhibition by cortisol leads to increased secretion of ACTH by the pituitary, with subsequent excessive adrenal 17-hydroxyprogesterone (17-OHP) and adrenal androgen production. The clinical consequences of these allelic variants range from the classical salt-wasting form with glucocorticoid and mineralocorticoid deficiencies to the simple virilizing form with premature pubic hair and the nonclassical form with hirsutism, menstrual irregularity, and infertility (7). Nonclassical 21-hydroxylase deficiency occurs in both sexes, but the clinical manifestations create an ascertainment bias favoring the detection of affected women. The high prevalence, mild symptoms, negligible effect on life span, and only partial infertility of nonclassical 21-hydroxylase deficiency has led some to suggest that this disorder may instead be a variant of normal (8).



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  		Figure 1. Structure of the CYP21 locus and location of the mutations tested. The upper panel illustrates the C4-CYP21 gene modules in the context of the tenascin-X genes (adapted and redrawn from Ref. 46). The scale is in kilobases. The direction of gene transcription is denoted by arrows. C4A and C4B code for the fourth component of complement, 21B codes for CYP21, and XB codes for tenascin-X (47). Bristow et al. identified only YA transcripts originating from the CYP21P (21A) promoter (48). The lower panel illustrates the intron/exon structure of CYP21 and the locations of the mutations tested..

 
The frequency of heterozygotic carriers for 21-hydroxylase deficiency appears to be high in all populations studied to date. Based on 17-hydroxyprogesterone responses to pharmacological ACTH stimulation, approximately 1 in 16 Caucasians was classified as a probable carrier of 21-hydroxylase deficiency (9). Linkage of nonclassical congenital adrenal hyperplasia with HLA-B14 and, subsequently, to the Val281->Leu CYP21 mutation in conjunction with ACTH-stimulated hormone responses suggested that one of three persons of Ashkenazi Jewish descent was probably a carrier for nonclassical 21-hydroxylase deficiency (10). Based on ACTH-stimulated 17-OHP responses, heterozygote frequencies have been estimated as one in four for Hispanics, one in five for Yugoslavs, one in eight for Yupik Eskimos, and one in 10 for Italians (10, 11, 12, 13). Despite the potential for a high rate of de novo mutations, homozygosity for the intron 2 splicing mutation and a distinct HLA-extended haplotype (DR4;DRw53;DQw3) in the Yupik Eskimos suggest a founder effect in this isolated population (13).

Clearly, cortisol and mineralocorticoid deficiencies leading to lethal salt loss and/or genital ambiguity in affected patients cannot impart selective or reproductive advantages. However, as with other common autosomal recessive gene disorders, the high prevalence of CYP21 heterozygosity suggests a survival advantage for carriers (14). In considering possible heterozygotic advantages, we hypothesized that if there is elevated adrenal androgen (androstenedione with peripheral conversion to testosterone) production, it could potentially advance the onset of puberty and increase assertive behavior; this could be advantageous during times of severe environmental or social stress. Alternatively, partial infertility in carrier females could increase the interval between pregnancies, thereby decreasing the birth rate and improving maternal and infant survival. Perhaps most intriguing is the possible effects of the carrier state on cortisol homeostasis. One would predict decreased cortisol production in carriers. However, decreases in cortisol cause a loss of negative feedback inhibition to the hypothalamus and pituitary. This, in turn, could increase pituitary ACTH secretion, leading to up-regulation of adrenal steroidogenic enzymes (15). This "turned-on" or "primed" adrenal cortex could secrete cortisol more robustly in response to physiological stimulation and offer a selective advantage by preventing excessive or inappropriate immune responses, such as autoimmune disease (16, 17, 18). Thus, we hypothesized that a paradoxical increase in stimulated cortisol concentrations could ensue.

One way to distinguish among these possibilities is to measure basal and stimulated cortisol responses in heterozygous carriers. We have previously shown that cortisol concentrations in both carriers and control subjects increase within minutes following acute ACTH stimulation (19). In this previous study, the carriers and control subjects showed similar cortisol responses, but none of the subjects was genotyped, leading to the potential inclusion of carriers in the control population. Here, we carefully compare steroid hormone responses between genotyped healthy controls and heterozygotic carriers. We document a remarkably vigorous cortisol response in carriers and discuss the implications of this finding as a possible heterozygote advantage.

Materials and Methods

Subjects

First degree and second degree adult relatives of children with 21-hydroxylase deficiency (n = 31; 15 men and 16 women) and normal volunteers (n = 19; 9 men and 10 women) participated in this study. The protocol was approved by the Human Rights Committee of Children’s Hospital of Pittsburgh. Informed consent was obtained from all participants.

Molecular genotype analysis

Blood samples were obtained for HLA haplotype analysis and for DNA extraction from peripheral blood lymphocytes. Standard serologic and molecular methods were used to determine the extended HLA haplotypes for the A, B, C, DR, and DQ loci (20, 21). DNA was extracted from peripheral blood lymphocytes (22).

PCR amplification and allele-specific oligonucleotide hybridization were performed as previously described; at least one primer of each primer pair was specific for the functional 21-hydroxylase gene (23). Additional oligonucleotide probes used were: Arg339-WT, 5'-TACAAGGACCGTGCACGGCT-3'; His339-MUT, 5'-TACAAGGACCATGCACGGCT-3'; exon 6-WT, 5'-CTCAGCTGCATCTCCACGA-3'; exon 6-MUT, 5'-CTCAGCTGCTTCTCCTCGT-3'; GT1769-WT, 5'-ACCCTGAGGTGCGTCCTG-3'; CT1769-MUT, 5'-ACCCTGAGCTGCGTCCTG-3'; Pro453-WT, 5'-CGCTGCTGCCCTCCGGGG-3'; Ser453, 5'-CGCTGCTGTCCTCCGGGG-3'; Arg484-WT, 5'-ATCCCCCGGGGCTGCAG-3'; Pro484-MUT, 5'-ATCCCCGGGGGCTGCAG-3'; STOP484-MUT, 5'-ATCCCGGGGGCTGCAG-3'; 1761-WT, 5'-CGTGAAGCAAAAAAACCACGG-3'; and i1761-MUT, 5'-CGTGAAGCAAAAAAAACCACGG-3'.

Single strand conformational polymorphism analysis was used to detect the splicing mutation in intron 2, V281L in exon 7, Q318X in exon 8, and R356W in exon 8 as previously described (24, 25). Primers 694F (5'-ACCTGTCCTTGGGAGACTAC-3') and 1122R (5'-TCGTCCTGCCAGAAAAGGAG-3') were used to detect the I172N mutation on a 5% acrylamide gel prepared with 10% glycerol, which was electrophoresed at 40 watts at 4 C for 11 h. After electrophoresis, the gels were dried and autoradiographed at -80 C.

Hormonal analysis

ACTH stimulation tests were performed on relatives (16 women and 15 men) and 19 healthy adults (10 women and 9 men). All women had regular menstrual cycles and were tested during the follicular phase of the menstrual cycle (basal plasma progesterone, <45 ng/dL). None was hirsute or taking oral contraceptives. Samples for progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione ({Delta}4), and cortisol were obtained before the administration of Cortrosyn (0.25-mg iv infusion over 1 min). Subsequent blood samples were obtained 10 (n = 46) and 30 (n = 50) min postinfusion. Plasma steroid hormones were measured as previously described (26). For all subjects, the basal cortisol level was less than 20 µg/dL. All hormone determinations for each individual were performed in duplicate within single assays.

Statistical analysis

Statistical analysis was performed using AbSTAT statistical software (Anderson-Bell, Arvada, CO). The 99% confidence intervals (mean \ 2.57 SD) of hormone concentrations measured in the healthy individuals were used to define the upper limit of the normal hormone concentrations. Student’s independent t test was used to compare hormone concentrations between the two groups.

Results

Molecular diagnostic studies

Genotypes were ascertained by allele-specific oligonucleotide hybridization and single strand conformational polymorphism analyses. Twenty-seven of the 31 family members studied were found to be heterozygotic carriers of 21-hydroxylase deficiency. Deleterious mutations detected were gene conversion/gene deletion (n = 8), intron 2 splicing mutation (n = 7), I172N (n = 2), exon 6 triple codon mutation (n = 1), V281L (n = 1), i1761 (n = 2), Q318X (n = 4), and R356W (n = 2). Four family members carried no deleterious mutations by both mutation studies and HLA linkage data and are included with the healthy controls for statistical analysis of their ACTH-stimulated hormone responses.

Genotype analysis and ACTH stimulation tests were performed in 19 healthy volunteers. The intron 2 splicing mutation was detected in 1 of these 19 volunteers. The ACTH-stimulated hormone responses obtained in this volunteer are included with the heterozygotic carrier group for statistical analysis. Thus, based on molecular genotype analysis, 28 heterozygotic carriers and 22 genotyped normal subjects were identified. We screened for 13 previously identified mutations, but cannot exclude the possibility that control subjects carry unidentified mutations.

Comparison of ACTH stimulation tests

Comparison of ACTH-stimulated hormone responses between the 28 heterozygotic carriers of 21-hydroxylase deficiency and 22 genotyped normal controls showed similar mean basal 17-hydroxyprogesterone levels (106.1 \ 63.4 vs. 105.3 \ 65.5 ng/dL, respectively). As anticipated (27), the heterozygotic carriers had greater mean 17-hydroxyprogesterone responses at 10 and 30 min than the genotyped normal controls (Table 1Go and Fig. 2Go; P < 0.0001).


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  		Table 1. Basal and ACTH stimulated 17-OHP (ng/dL) and cortisol (µg/dL) concentrations in normal and heterozygotic carriers

 


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  		Figure 2. ACTH-stimulated cortisol responses. The graph depicts the cortisol responses (mean ± SEM) in healthy controls ({blacktriangledown}) and heterozygotic carriers ({square}) before and after ACTH stimulation. Blood samples were obtained 10 and 30 min after the iv Cortrosyn bolus. Mean basal cortisol responses are not significantly different. At both 10 and 30 min, mean cortisol concentrations were greater in heterozygotic carriers than controls (P < 0.05 and P < 0.005, respectively).

 
Mean basal cortisol concentrations (Table 1Go) were not different between the heterozygotic carriers and the healthy controls (11.1 \ 3.8 vs. 11.3 \ 3.2 µg/dL, respectively). Ten minutes after iv ACTH stimulation (Fig. 2Go), the heterozygotic carriers had a greater cortisol response (22.0 \ 4.7 vs. 19.1 \ 3.8 µg/dL; P < 0.05). The 30-min cortisol concentrations (Fig. 2Go) were also greater among the heterozygotic carriers (28.1 \ 4.2 vs. 24.2 \ 4.6 µg/dL; P < 0.005).

Among the 50 individuals (22 genotype normal and 28 genotype heterozygotes), there was a positive correlation between stimulated 17-OHP and cortisol concentrations. At 10 min, the correlation coefficient was 0.61 (P < 0.0001). At 30 min, the correlation coefficient was 0.45 (P = 0.001). There was no correlation between specific CYP21 mutation and peak cortisol response.

Discussion

Common recessive disorders, such as sickle cell anemia and cystic fibrosis, are frequently thought to impart a selective survival advantage to heterozygotic carriers (28, 29). Although the concept of heterozygote advantage has been entertained for 21-hydroxylase deficiency, direct evidence delineating the specific mechanism of the survival benefit has proven difficult to obtain. The CYP21 gene is a frequent target of mutations, with carrier frequency between 1 in 3 and 1 in 16 in all populations studied despite the crucial role of the 21-hydroxylase enzyme in adrenal steroidogenesis. This high carrier frequency suggests that heterozygotes could have a survival advantage.

Cortisol secretion is regulated through the hypothalamic-pituitary-adrenal axis by negative feedback inhibition of ACTH secretion. ACTH acutely increases cortisol secretion and chronically maintains transcription rates of the steroidogenic enzymes and optimal steroidogenic capacity (17). Our interpretation of the more vigorous cortisol response that we observed in heterozygotic carriers was that the adrenal gland of heterozygotic carriers was up-regulated or primed to secrete cortisol, because the clinically imperceptible decrease in cortisol secretion had led to increased ACTH secretion (30).

Comparison of the inbred histocompatible Lewis and Fischer rat strains provides an example of the physiological consequences of subtle alterations in cortisol concentrations. Lewis rats are extraordinarily susceptible to both experimentally induced autoimmune and inflammatory disorders, whereas Fischer rats are resistant to the same challenges (31). Investigation into the basis for the difference in susceptibility has shown that the Lewis rat shows hypothalamic-pituitary-adrenal axis hyporesponsiveness in contrast to the hyperresponsiveness of the Fischer rat (32, 33). Both strains show comparable target tissue sensitivity to glucocorticoids (34, 35). Clinical studies of cortisol concentrations during human cardiac arrest or severe illness suggest that too low or too high cortisol concentrations are associated with increased mortality (36). These data, obtained from animal and clinical studies, indicate that small differences in glucocorticoid concentrations may be physiologically significant.

Three previous studies have looked at ACTH-stimulated cortisol responses in 21-hydroxylase carriers. All were performed without mutation detection, and thus, it is likely that the control populations included carriers. Two studies using less specific assays to measure cortisol (37, 38) found no significant differences in cortisol responses. A third study, using HLA haplotypes to infer carrier status, showed carriers to have slightly greater cortisol responses, although these differences were deemed not significant (36). None of these studies showed the hypersensitization of the adrenal cortex that we have documented here or speculated on a possible heterozygote advantage.

Through secretion of peptide and steroid hormones, i.e. ACTH and cortisol, the hypothalamic-pituitary-adrenal axis restores homeostasis after stress (39). Glucocorticoids function as potent antiinflammatory and immunosuppressive agents. Indeed, the widespread therapeutic use of glucocorticoids in the treatment of immune disorders often overshadows their physiological functions. Specific glucocorticoid actions include trafficking of circulating leukocytes, suppression of accessory immune cells, inhibition of cytokine production, and induction of resistance to cytokines (40, 41, 42). The production of nitric oxide, prostanoids, and platelet-activating factor, three major mediators of the inflammatory response, is decreased by glucocorticoids (42). Glucocorticoids enhance the synthesis of acute phase proteins, which scavenge the toxic superoxide radicals generated to kill invading microorganisms and tumor cells (43). The net result is the prevention of DNA and tissue damage that thwart self-destruction by cytokines and other effectors of immune reactions (18). These restraining actions are thought to hinder the development of autoimmune disorders.

Glucocorticoids also play a role in energy metabolism by maintaining the liver enzymes involved in gluconeogenesis, increasing substrate availability, and inducing phenylethanolamine N-methyl transferase in the adrenal medulla (44). The venous efflux of the adrenal cortex exposes the adrenal medulla to high glucocorticoid levels, which may be important in epinephrine biosynthesis. Thus, cortisol acts by maintaining a state of readiness. Maintenance of epinephrine biosynthesis impacts on the fight or flight response and probably promotes survival (45).

We postulate that the brisk cortisol secretion observed among heterozygotic carriers could be a genetically favorable trait, providing greater survival fitness. If so, these data support speculation that heterozygotic advantage has led to the high gene frequency of CYP21 mutations.

Acknowledgments

We gratefully acknowledge the assistance of Tamara Johnston, R.N.; Amy Jones, R.N.; Janet Bell, R.N.; and Debbie Cleary.

Footnotes

1 This work was supported by NIH Grants HD-00965 (to S.F.W.) and 5M01-RR-00084 (to the General Clinical Research Center). The data were presented in part at the ICE/Endocrine Society Meeting, San Francisco, CA, June 1996. Back

Received February 10, 1997.

Revised March 21, 1997.

Accepted March 25, 1997.

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals