This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inglis, G. C. Articles by Connell, J. M. C. Search for Related Content PubMed PubMed Citation Articles by Inglis, G. C. Articles by Connell, J. M. C.

Familial Pattern of Corticosteroids and Their Metabolism in Adult Human Subjects - the Scottish Adult Twin Study¹

Medical Research Council Blood Pressure Group, Department of Medicine and Therapeutics, Western Infirmary, Glasgow, G11 6NT

Address correspondence and requests for reprints to: Prof. J. M. C. Connell, Medical Research Council Blood Pressure Group, Department of Medicine and Therapeutics, Western Infirmary, Glasgow, G11 6NT, United Kingdom.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Corticosteroids are important in the regulation of normal physiology and are key factors in regulating cardiovascular physiology and disease, the development of which is known to have a genetic component. However, there is little information on the extent to which plasma and urine steroid levels are determined by familial and genetic factors. We have examined basal and ACTH-stimulated plasma steroid levels and 24-h corticosteroid metabolite excretion rates in 146 pairs of adult twins [75 monozygotic (MZ); 71 dizygotic (DZ)]. Intraclass correlation coefficients were measured for all variables; several plasma steroid measurements were strongly related in both (MZ) and (DZ) twins, consistent with a familial pattern. These included basal levels of 11-deoxycortisol and aldosterone. ACTH-stimulated plasma aldosterone levels were also significantly correlated, to a significant degree, in both MZ and DZ twins. The index of 11ß-hydroxysteroid dehydrogenase activity (tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone) and of the more specific index of activity of the type 2 isoform of this enzyme (urine free cortisol/cortisone) also correlated, to a similar degree, in DZ and MZ twins. In contrast, for the basal and ACTH-stimulated plasma concentrations and 24-h urine excretion rates of several corticosteroids, there was evidence of significant heritability (H2), in that correlation in MZ twins was greater than in DZ. For example, basal plasma corticosterone concentrations (B) (H2 = 0.44), basal and stimulated 11-deoxycorticosterone concentrations (DOC) (H2 = 0.44 and 0.41, respectively), stimulated 11-deoxycortisol concentrations (H2 = 0.53), and the index of 11ß-hydroxylase activity DOC/B (H2 = 0.49) were all significantly heritable. For the urinary variables, 24-h tetrahydrodeoxycortisol (H2 = 0.59) and free aldosterone (H2 = 0.56) were significantly heritable. Our data provide the first evidence that plasma and urine levels of important glucocorticoids and mineralocorticoids show a strong familial pattern, and in some instances, there is evidence of a genetic component to this. This suggests that corticosteroids have a plausible role in essential hypertension that has a similar heritable component.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
CORTICOSTEROIDS are important in the regulation of normal physiology and, when secreted in excess (for example in Cushing’s syndrome and primary aldosteronism), lead to hypertension and cardiovascular disease. More common forms of cardiovascular disease are also associated with alteration in steroid secretion, metabolism, and action. For example, in animal models of hypertension (such as the Dahl salt-sensitive rat, the Milan hypertensive rat, the Lyon rat, and the spontaneously hypertensive rat), differences in adrenal steroid secretory and excretory patterns, in comparison with the appropriate control strains, have been described (1). In man, several rare monogenic forms of hypertension, including 11ß- and 17-hydroxylase deficiencies and glucocorticoid-remediable hyperaldosteronism, are characterized by altered steroid synthesis; they reflect abnormalities in the respective hydroxylase genes (2, 3, 4).

Although these syndromes are rare, alterations in steroid levels in plasma and urine are also reported in common forms of cardiovascular disease, including essential hypertension. Thus, de Simone and colleagues (5) described increased basal and ACTH-stimulated 11-deoxycorticosterone (DOC) plasma concentrations in subjects with essential hypertension. Soro et al. (6) reported evidence of altered steroid 11ß-hydroxysteroid dehydrogenase activity in a group of hypertensive patients from Sardinia, and a similar abnormality was described in a study of cortisol metabolism in a small group of hypertensive subjects, by Walker et al. (7). Watt et al. (8) found slightly, but significantly, raised plasma cortisol levels in young adults with a predisposition to hypertension; and, more recently, Litchfield et al. (9) reported that urinary cortisol excretion was higher in hypertensive subjects than in controls and was bimodally distributed, suggesting that this was caused by a major gene effect. This cortisol/blood pressure relationship is not apparent in normotensive subjects (10).

These examples suggest that corticosteroid measurements in plasma or urine may provide a useful intermediate phenotype in patients with hypertension and other cardiovascular conditions, disorders which are complex and oligogenic in etiology. If corticosteroids are important in their pathophysiology, their circulating levels should show evidence of genetic determination. However, there is very little information on this topic. The current study has examined heritability (H2) of common corticosteroid phenotypes in an adult monozygotic (MZ) and dizygotic (DZ) twin population, in an attempt to distinguish between genetic and environmental influences on trait variation.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A total of 146 pairs of adult twins were recruited by media advertisement. To prevent self-selection bias, the purpose of the study was not specified in the advertisement. The age range of the twins was 31–83 yr; other demographic details are shown in Table 1. The study was approved by the West Glasgow Hospitals ethics review committee.

Corticosteroid assays:

Plasma aldosterone and cortisol concentrations were measured by direct RIA (Diagnostic Products Corporation, Los Angeles, CA); plasma concentrations of other cortcosteroids were measured by RIA after partial purification by paper chromatography (see Ref. 11). Cross-reactivity for direct RIAs was less than 1% apart for 11-deoxycortisol (S), which showed a cross-reactivity of 11.4% with cortisol. However, because the circulating concentration of cortisol is much higher than that of deoxycortisol, this was not felt to be a significant source of error.

Urinary metabolites and free steroids were measured by gas chromatography-mass spectrometry using the methods of Shackleton (12) and Palermo et al. (13) respectively. Cortisol excretion rate (‘total cortisol’) was estimated by summing the rates of THF, alloTHF and THE. The activity of 11ß-hydroxysteroid dehydrogenase (11ßHSD) was assessed by the ratio THF + alloTHF/THE, and that of the type 2 isoform more specifically by the ratio urinary free cortisol/cortisone. Activity of 5-reductase was assessed by the ratio THF/allo-THF. Activity of 11ß-hydroxylase was assessed by the ratios of 11-deoxysteroid to 11-hydroxysteroid concentrations (both deoxycortisol/cortisol and DOC/ corticosterone).

Confirmation of zygosity

Twin zygosity was assessed by questionnaire and verified by analyzing four short tandem repeat polymorphisms (AFM238xd10, AFM288vb9, AFM273yf1, and AFM199zb6) obtained from the Centre d’Etudes du Polymorphism Humain (Paris, France). The SF-1 binding site and intron 2 gene conversion polymorphisms in CYP11B2 (aldosterone synthase gene) were also genotyped (14). MZ twin pairs were homozygous for each of the markers, whereas DZ pairs were heterozygous for at least one marker. The estimated probability of misassignment of zygosity with this number of markers is < 10^-5.

Statistical analysis

Because the proportion of MZ twins who were female was higher than for DZ twins, the potential effects of confounders on corticosteroid variables were first assessed by univariate analysis. No significant effects of sex or age were identified, and no differences were found when male and female twin pairs were analyzed separately. Analyses are presented without stratification by age or sex.

For each variable in the MZ and DZ groups, intraclass correlations (r) were calculated by ANOVA, which were then compared between the two groups by Fisher’s z test. For the variables where r was significantly higher in the MZ group than in the DZ group, H2 was calculated (H2 = VA + VD, where VA is the additive variance and VD is the dominance variance) by the method of Haseman and Elston (15, 16). Other comparisons were by Student’s t test and chi-square test, where appropriate.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
There was no significant difference in body mass index between the groups, but the MZ group was slightly older and contained a greater proportion of women (Table 1). Corticosteroid measurements are summarized in Table 1. Basal concentrations were not significantly different between groups. ACTH caused a marked stimulation in the plasma levels of the corticosteroids measured; the levels achieved were similar in the two groups except for 11-deoxycorticosterone (DOC) and S, which reached higher levels in the MZ group. Moreover, the response of DOC and S to ACTH was significantly bigger in MZ twins, but that of other corticosteroids was not. Urinary corticosteroid excretion rates were not different between groups. As stated above, there were no significant relationships among age, sex, measurements of body habitus, and either plasma or urinary corticosteroids.

Intraclass correlation coefficients for the two groups and their comparison (z) are shown in Table 2. With the exception of stimulated cortisol, all basal and ACTH-stimulated plasma steroids were significantly correlated within MZ twins. Furthermore, only basal DOC and corticosterone failed to correlate in DZ pairs. For urinary metabolites, free aldosterone and tetrahydrodeoxycortisol (THS) correlated in MZ pairs only, whereas there was significant and similar correlation in the index of 11ß-HSD activity within both types of twin pairs. Urinary free cortisol and cortisone were correlated in both MZ and DZ twins, and the ratio of cortisol to cortisone, which is an index of the activity of the type 2 11ß-HSD isoform, was likewise correlated in both types of twins.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Corticosteroid levels in plasma and urine provide a potentially important intermediate phenotype in hypertension and cardiovascular disease. Such phenotypes are of value in identifying basic mechanisms of disease and give important clues to candidate genetic abnormalities (see introduction). For example, in the rare, monogenic cause of hypertension, glucocorticoid-remediable aldosteronism, elevated levels of 18-hydroxycortisol provide a defining intermediate phenotype that draws attention to the genes encoding aldosterone synthase and 11ß-hydroxylase as the responsible locus. In a similar way, studies in commoner forms of cardiovascular disease have reported a range of abnormalities in corticosteroids that identify candidate genes that might be associated with the development of high blood pressure (5, 6, 7, 8). However, the extent to which these phenotypes are genetically determined, and what contribution is made by environmental factors, remains unclear. For example, exposure to raised cortisol levels will be influenced by levels of environmental stress, which will then confound the assessment of the impact of genetic control.

It is possible, by several methods, to distinguish between these two sources of variation. For example, in a recent study of the relationship of steroids with obesity and plasma cholesterol levels, Rosmond et al. (17) corrected measured cortisol levels for intradiem variability that, they argued, was stress-related. There remained a strong relationship between the corticosteroid and LDL (positive), HDL (negative), and weight, suggesting that this environmental influence did not completely account for the potential effect on cardiovascular physiology and pathophysiology. Furthermore, Huizenga et al. (18) reported that basal plasma cortisol variability and sensitivity to suppression by dexamethasone was relatively reproducible within individuals, providing further evidence of familial and/or genetic influence.

A more reliable way to isolate the genetic component of variation is to compare the concordance of phenotype in MZ and DZ twins. This classical approach uses data from MZ and DZ twins to test for the existence of a genetic influence on trait variation, using the argument that MZ and DZ pairs share the same degree of similarity of environments; any excess similarity in the trait between MZ, as opposed to DZ twins, is assumed to reflect the greater sharing of alleles, and is taken as evidence of a genetic influence (expressed as H2). With this approach, it is assumed that the principal difference between MZ and DZ twins is genetic, but it is worth noting that, whereas some factors (e.g. maternal nutrition) are common to twin pairs of either zygosity, in many MZ twins, placentation is shared, so that factors dependent on placental function may lead to a greater similarity between MZ than DZ twins. Thus, apparent H2 might reflect shared early (fetal) life events and placental function rather than genetic factors. However, this interpretation has not been unchallenged. Walker et al. (19) recently demonstrated that blood pressure in young adults did, indeed, reflect size at birth but that both variables significantly correlated with maternal blood pressure; and they proposed that the link between placental function and subsequent phenotype might not be causal but might depend on genetic factors that affect both. We do not have information on placentation, placental size, or birth weight in our cohort; and we believe that differences between middle-aged twin pairs of contrasting zygosity are more likely to reflect genetic influences.

There have been few previous comparisons of adrenocortical activity in twins. An early study of young adult male twins compared plasma 17-hydroxysteroid levels, a relatively nonspecific method of assessing cortisol secretion rate, but zygosity was not reliably established (20). In this type of study, it is crucial that zygosity be established unequivocally; in our study, six loci were compared to attain a high degree of certainty. In the same way, Meikle et al. (16) compared morning plasma cortisol concentrations in male MZ and DZ twin pairs, analyzing their data by the same statistical techniques used in the current study; zygosity was established with a probability of 0.99. They detected significant, albeit marginal, H2 of cortisol (P < 0.05; our current study found P < 0.06) but not of either corticosteroid-binding globulin or another major adrenal product, dehydroepiandrosterone.

We studied a middle-aged population, assuming that any phenotypic similarity that persists many years after twins have escaped common environmental childhood influences must be robust. We also concentrated on those corticosteroids immediately relevant to cardiovascular physiology and pathophysiology. As in other twin studies, there was an excess of female MZ twin pairs in our cohort. However, there was no independent effect of gender on the corticosteroid variables measured, and, for this reason, both males and females were included in our analysis.

There were marked intrapair correlations for a number of plasma and urinary variables that were not influenced by zygosity, consistent with a familial similarity in phenotype that was not necessarily dependent on genotype. This finding applied to both basal S and aldosterone and to the stimulated levels of corticosterone and aldosterone. The index of 11ß-HSD activity seemed to be more affected by nongenetic (intraclass correlation) than genetic (H2) factors (see below). Additionally, free urinary cortisol and cortisone, and the derived index of the 11ß-HSD type 2 isoform, also showed this apparent familial patterning.

There may be several explanations for these apparent familial relationships. For example, twins share common intrauterine and early life environments. and there is strong evidence that programming of the CNS-pituitary-adrenal axis occurs in fetal life and is influenced by exposure to corticosteroids (21). In turn, this may reflect placental size, maternal nutrition, or other maternally-related factors. For example, cortisol levels in middle-aged men in Preston correlate with birth weight (22), suggesting that early life events influence long-term setting of the hypothalamic-pituitary-adrenal (HPA) axis. Although this explanation would certainly be consistent with the familial relationships observed for S, there have been no suggestions that similar programming itself sets the long-term level of secretion of aldosterone. It should be noted that DZ twins do share, on average 50% of alleles; and the within-pair correlation, taken as evidence of a familial effect, might also have some genetic basis (see below). The familial, but not genetic, pattern for the indexes of 11ß-HSD activity may suggest that these isoforms are set by nongenetic factors, and may, again, be subject to early life events. It is possible that influences such as transcriptional regulation of the enzymes are the important determinants of the familial relationships observed.

Basal plasma cortisol (H2 = 0.46) was not significantly heritable, but the calculated level of H2 was not strikingly quantitatively different from that quoted by Meikle et al. (16 H2 = 0.45). We made no allowance for the type of environmental effects identified by Rosmond (17), which may have improved assessment. Alternatively, it is possible that this apparent H2 represents, instead, synchronization of the diurnal rhythm of the HPA axis. We were also unable to identify significant H2 in the 24-h excretion rate of cortisol metabolites (THF+alloTHF+THE) or of urinary free cortisol, although substantial familial resemblance was present for this latter measure. Again, this may be a consequence of multiple exogenous (e.g. stress) and endogenous [e.g. central nervous system (CNS) function] confounding factors. Nevertheless, as mentioned above, there was evidence of a familial relationship in the index of 11ß HSD activity (THF+alloTHF/THE) and of the index of the renal specific isoform. The reason for this is unclear; the possibility of early life programming of the HPA axis might, as discussed above, be extended to the enzymes that dictate glucocorticoid availability at tissue level.

Basal corticosterone levels were genetically influenced to a greater extent than cortisol, with an H2 value of 0.44 (P < 0.02). This evidence of genetic determination of corticosterone is of interest because corticosterone is the final product of the 17-deoxycorticosteroid pathway in the zona fasciculata, and increased concentrations have been reported in hypertensive subjects when compared with matched controls (23).

No evidence of a distinct genetic influence was noted for basal or ACTH-stimulated plasma aldosterone concentrations, although there was evidence of familial similarity for both of these variables, which is discussed above. This discrepancy may be real, or H2 may have been obscured by factors such as posture or sodium and potassium intakes, which were not controlled in this study. That this may be the case is suggested by the highly significant H2 found for urinary aldosterone excretion. The 24-h excretion of aldosterone may be a more robust phenotype that is less influenced by short-term environmental influences, such as posture. To our knowledge, this is the first demonstration that aldosterone levels in the normal population may be genetically influenced in this way; the finding is of relevance to cardiovascular disease, given that we and others (24, 25, 26) have described an association between aldosterone excretion and aldosterone synthase gene (CYP11B2) polymorphisms in patients with essential hypertension.

Finally, our data allow us to assess the H2 of the efficiency of 11ß-hydroxylation, which is the key late step in cortisol and corticosterone biosynthesis. During maximum stimulation by ACTH, the production of cortisol and corticosterone may be limited by the efficiency of this enzyme complex (congenital adrenal hyperplasia caused by deficiency of this enzyme is an extreme example of this), so that concentrations of their respective precursors will rise disproportionately to an extent related to this efficiency. The results show that this rise was greater in MZ than DZ twins and also that concentrations of the precursors (DOC and S) show more H2, whereas their respective products (corticosterone and cortisol) show less. Furthermore, the ratio of DOC to corticosterone was also significantly heritable, although the ratio of S to cortisol was not. The reason for this discrepancy is unclear, and this emphasizes the need to use caution when interpreting data based on ratios. Nevertheless, in this cohort of normal subjects, there is evidence that the phenotype of efficiency of 11ß-hydroxylation, as measured simply by the rise in precursor steroid after ACTH stimulation of the adrenal, is under genetic regulation. The finding of significant H2 for urinary excretion of THS also supports this argument. During a 24-h period, there will be multiple ACTH-entrained increases in plasma S. If, as argued above, 11ß-hydroxylation of S is a rate-limiting step, an integrated profile of its production might reveal a genetic influence on 11ß-hydroxylation efficiency in the adrenal cortex. Taken together, therefore, our data suggest that 11ß-hydroxylase efficiency in normal subjects is genetically influenced. Under stimulated conditions, the rate-limiting nature of the step leads to this influence becoming more obvious. ACTH-stimulated concentrations of DOC are elevated in essential hypertension (5), a finding which has been interpreted as evidence of altered 11ß-hydroxylase activity. Our data suggest that the genes that determine its activity also influence normal physiological variation and may contribute to the corticosteroid phenotype in essential hypertension, a disease which has a substantial genetic component (27).

In summary, we have shown that levels of corticosteroids, their precursors, and their metabolites have a marked familial distribution that may be a consequence of programming of the CNS-pituitary-adrenal axis. The analyses also suggest that 11ß-hydroxylase activity and aldosterone secretion have a significant degree of genetic determination. It is therefore possible, because they have been implicated in essential hypertension, that they may, at least partially, explain the genetic component of this disease.

	Acknowledgments

 
We are grateful to Dr. J. McColl for his advice on statistical analysis. The authors also gratefully acknowledge the efforts of Sister Maria Rowan, who carried out much of the recruiting and phenotyping of the subjects, and to the twins who gave freely of their time to make this investigation possible.

	Footnotes

 
¹ This study was supported by Medical Research Council Programme Grant G9317119 (to J.M. and R.F.) and BHF Project Grant PG 95150 (to D.B., W.S.H., and J.M.C.C).

Received January 5, 1999.

Revised July 27, 1999.

Accepted August 3, 1999.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Brownie AC, Alfano J, Gallant S. 1990 Rat models of experimental hypertension. In: Biglieri EG, Melby JC, eds. Endocrine hypertension. New York: Raven Press; 29–69.
2. Geley S, Kappelari K, Johrer K, et al. 1996 CYP11B1 mutations causing congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency. J Clin Endocrinol Metab. 81:2896–2901.[Abstract/Free Full Text]
3. Yanase T, Simpson ER, Waterman MR. 1991 17ß-Hydroxylase/17,20-lyase deficiency: from clinical investigation to molecular definition. Endocr Rev. 12:91–108.[Abstract/Free Full Text]
4. Lifton RP, Dluhy RG, Powers M, et al. 1992 A chimeric 11ß-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 355:262–265.[CrossRef][Medline]
5. de Simone G, Tommaselli AP, Rossi R, Valentino R, Lauria R, Scopocasa F. 1985 Partial deficiency of adrenal 11ß-hydroxylase. A possible cause of primary hypertension. Hypertension. 7:204–210.[Abstract/Free Full Text]
6. Soro A, Ingram MC, Tonolo G, Glorioso N, Fraser R. 1995 Evidence of coexisting changes in 11ß-hydroxysteroid dehydrogenase and 5ß-reductase activity in subjects with untreated essential hypertension. Hypertension. 25:67–70.[Abstract/Free Full Text]
7. Walker BR, Stewart PM, Padfield PL, Edwards CRW. 1991 Increased vascular sensitivity to glucocorticoids in essential hypertension. J Hypertens. 9:1082–1083.
8. Watt GCM, Harrap SB, Foy CJW, et al. 1992 Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure. J Hypertens. 10:473–482.[Medline]
9. Litchfield WR, Hunt SC, Jeunemaitre X, et al. 1998 Increased urinary cortisol. A potential intermediate phenotype of essential hypertension. Hypertension. 31:569–557.[Abstract/Free Full Text]
10. Fraser R, Ingram MC, Anderson NH, et al. 1999 Cortisol effects on body mass, blood pressure and cholesterol, in the general population. Hypertension. 33:1364–1368.[Abstract/Free Full Text]
11. Fraser R, Guest S, Young J. 1975 A comparison of double-isotope derivative and radioimmunological estimation of plasma aldosterone in man. Clin Sci Mol Med. 45:411–415.
12. Shackleton CHL. 1986 Profiling steroid hormones and urinary steroids. J Chromatogr. 379:91–156.[Medline]
13. Palermo M, Gomez-Sanchez C, Roitman E, Shackleton CHL. 1996 Quantitation of cortisol and related 3-oxo-4-ene steroids in urine using gas chromatography/mass spectrometry with stable isotope-labelled internal standards. Steroids. 61:583–589.[CrossRef][Medline]
14. White PC, Slutsker L. 1995 Haplotype analysis of CYP11B2. Endocr Res. 21:437–442.[Medline]
15. Haseman JK, Elston RC. 1970 The estimate of genetic variance from twin data. Behav Genet. 1:11–19.[CrossRef][Medline]
16. Meikle AW, Stringham JD, Woodward MG, Bishop DT. 1988 H2 of variation of plasma cortisol levels. Metabolism. 37:514–517.[CrossRef][Medline]
17. Rosmond R, Dallman MF, Bjorntorp P. 1998 Stress-related cortisol in men: relationships with abdominal obesity and endcrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab. 83:1853–1859.[Abstract/Free Full Text]
18. Huizenga NATM, Koper JW, de Lange P, et al. 1998 Interperson variability but intraperson stability of baseline cortisol concentrations and its relation to feedback sensitivity of the HPA axis to a low dose od dexamethasone in elderly individuals. J Clin Endocrinol Metab. 83:47–54.[Abstract/Free Full Text]
19. Walker BR, McConnachie A, Noon JP, Webb DJ, Watt GCM. 1998 Contribution of parental blood pressures to association between low birthweight and adult blood pressure. Br Med J. 316:834–837.[Abstract/Free Full Text]
20. Maxwell JD, Boyle JA, Greig WR, Buchanan WW. 1969 Plasma corticosteroids in healthy twin pairs. J Med Genet. 6:294–297.[Free Full Text]
21. Seckl JR. 1994 Glucocorticoids and small babies. Q J Med. 87:259–262.
22. Phillips DI, Barker DJP, Fall CHD, et al. 1998 Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome. J Clin Endocrinol Metab. 83:757–760.[Abstract/Free Full Text]
23. Soro A, Ingram MC, Tonolo G, Glorioso N, Fraser R. 1995 Mildly raised corticosterone excretion rates in patients with essential hypertension. J Hum Hypertens. 9:391–393.[Medline]
24. Davies E, Holloway CD, Ingram MC, et al. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene. Hypertension. 33:703–707.
25. Benetos A, Poirier O, Guyenne TT, Gautier S, Pojoga L, Cambien F. 1997 Genetic determination of plasma aldosterone levels. Hypertension. 30:A493 (Abstract).
26. Brand E, Chatelain N, Mulatero P, et al. 1998 Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension. 32:198–204.[Abstract/Free Full Text]
27. Williams RR, Hunt SC, Hasstedt SJ, et al. 1990 Genetics of hypertension: what we know and what we don’t know. Clin Exp Hypertens [A]. 12A:865–876.

This article has been cited by other articles:

				J. M. C. Connell, S. M. MacKenzie, E. M. Freel, R. Fraser, and E. Davies A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function Endocr. Rev., April 1, 2008; 29(2): 133 - 154. [Abstract] [Full Text] [PDF]

				D. Hazard, M. Couty, and D. Guemene Characterization of CRF, AVT, and ACTH cDNA and pituitary-adrenal axis function in Japanese quail divergently selected for tonic immobility Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1421 - R1429. [Abstract] [Full Text] [PDF]

				H. Imrie, M. Freel, B. M. Mayosi, E. Davies, R. Fraser, M. Ingram, H. J. Cordell, M. Farrall, P. J. Avery, H. Watkins, et al. Association between Aldosterone Production and Variation in the 11{beta}-Hydroxylase (CYP11B1) Gene J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 5051 - 5056. [Abstract] [Full Text] [PDF]

				S. Ganapathipillai, G. Laval, I. S. Hoffmann, A. M. Castejon, J. Nicod, B. Dick, F. J. Frey, B. M. Frey, L. X. Cubeddu, and P. Ferrari CYP11B2-CYP11B1 Haplotypes Associated with Decreased 11{beta}-Hydroxylase Activity J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1220 - 1225. [Abstract] [Full Text] [PDF]

				B. Keavney, B. Mayosi, N. Gaukrodger, H. Imrie, M. Baker, R. Fraser, M. Ingram, H. Watkins, M. Farrall, E. Davies, et al. Genetic Variation at the Locus Encompassing 11-{beta} Hydroxylase and Aldosterone Synthase Accounts for Heritability in Cortisol Precursor (11-Deoxycortisol) Urinary Metabolite Excretion J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1072 - 1077. [Abstract] [Full Text] [PDF]

				I. S. Federenko, M. Nagamine, D. H. Hellhammer, P. D. Wadhwa, and S. Wust The Heritability of Hypothalamus Pituitary Adrenal Axis Responses to Psychosocial Stress Is Context Dependent J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6244 - 6250. [Abstract] [Full Text] [PDF]

				F. C. Luft Twins in Cardiovascular Genetic Research Hypertension, February 1, 2001; 37(2): 350 - 356. [Abstract] [Full Text] [PDF]

				M. Quinkler, W. Oelkers, and S. Diederich In Vivo Measurement of Renal 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Activity J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4921a - 4922. [Full Text]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inglis, G. C. Articles by Connell, J. M. C. Search for Related Content PubMed PubMed Citation Articles by Inglis, G. C. Articles by Connell, J. M. C.