HSD11B2 CA-repeat and sodium balance.

Type 2 11ß-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone and thus protects the mineralocorticoid receptor from cortisol exposure. Impaired activity of this enzyme leads to mineralocorticoid excess, suggesting HSD11B2 as a candidate locus for patients at risk of developing low renin or salt-sensitive essential hypertension. In the present study, we searched for frequent polymorphisms in 155 Japanese subjects but detected none in the proximal promoter or coding regions of HSD11B2. Following this result, we genotyped a highly polymorphic CA-repeat polymorphism within the first intron in 848 normotensive and 430 hypertensive Japanese patients, and we then analyzed its association with disease and clinical parameters. We confirmed 12 alleles (12, 15-25 CA repeats) in the population and found no significant difference in the distribution of the allele length between normotensive and hypertensive patients. In 174 normal subjects without medication, urinary cortisol excretion was higher in subjects with more CA repeats in the shorter allele, but the ratio of urinary cortisone to cortisol, a reliable marker of renal HSD11B2 activity, did not differ. However, longer CA-repeat length was positively correlated with 24-h urinary sodium excretion, fractional sodium excretion and potassium clearance, and this observation was confirmed when the longer CA-repeat length was dichotomized. Thus, HSD11B2 CA-repeat genotype is not associated with hypertension itself, but with renal sodium excretion, probably through salt intake/appetite.

Longer HSD11B2 CA-repeat in impaired glucose tolerance and type 2 diabetes.

Type 2 11ß-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone, and alteration in this enzymatic activity might affect glucose homeostasis by affecting circulating levels or tissue availability of glucocorticoids. We investigated the association of HSD11B2 variant with glucose homeostasis. Subjects with normal glucose tolerance (n=585), impaired glucose tolerance (n=202) and type 2 diabetes (n=355) were genotyped for a highly polymorphic CA-repeat polymorphism in the first intron of HSD11B2. Allele and genotype frequencies differed between normal and impaired glucose tolerance (P = 0.0014 and 0.0407, respectively; 4 degree of freedom) or type 2 diabetes (P = 0.0053 and 0.0078), with significant linear trends between the repeat length and the phenotype fraction. In normal subjects, total CA-repeat length was negatively correlated with fasting insulin and HOMA-ß. Thus, subjects having more CA repeats are susceptible to developing abnormal glucose tolerance, whereas normal subjects carrying more CA repeats appeared to have frugal characteristics in insulin secretion.

Physiologic roles of 11beta-hydroxysteroid dehydrogenase type 2 in kidney.

We developed enzyme-linked immunosorbent assays to measure urinary free cortisone (E) and cortisol (F) and analyzed correlations between clinical measures reflecting mineralocorticoid action and 24-hour urinary excretion of E and F or their ratio, uE/F, which has been considered as the most sensitive index of renal 11beta-hydroxysteroid dehydrogenase type 2 activity. Two hundred nineteen healthy men were enrolled in this study. The uE/F ratio was 1.10 +/- 0.41 (mean +/- SD), and a strong linear correlation between uE and uF was observed in a double reciprocal plot. Urinary acid-labile aldosterone excretion had a negative correlation with 24-hour urinary Na excretion and Na/K ratio, but uE/F ratio had a weak positive correlation with the Na/K ratio and no significant correlation with 24-hour urinary Na excretion. In contrast, uE and uF had positive correlations with 24-hour urinary excretions of Na and K, raising the possibility of separate renal effects mediated by the glucocorticoid receptor. Furthermore, uE and uE/F ratio had strong negative correlations with urinary concentrations of Na and K. These results suggest that renal 11beta-hydroxysteroid dehydrogenase type 2 is an important regulatory factor of renal Na and K handlings independently of and/or complementary to the mineralocorticoid action of aldosterone.

Correlation between left ventricular mass and urinary sodium excretion in specific genotypes of CYP11B2.

BACKGROUND: Aldosterone has essential roles in regulating intravascular volume and blood pressure, and is suggested to influence cardiac structure. However, the association of polymorphisms in the aldosterone synthase gene (CYP11B2) with hypertension or cardiac hypertrophy remains controversial. OBJECTIVE: To evaluate the distribution of polymorphisms in the CYP11B2 gene and the possible associations between genotypes and blood pressure, urinary excretion of aldosterone or electrolytes and echocardiographic measurements, in a Japanese population. METHODS AND RESULTS: We examined the association of two common diallelic polymorphisms within CYP11B2, one in the promoter -344T/C and the other an intron 2 gene conversion, with blood pressure, 24-h urinary excretion of aldosterone and electrolytes, and echocardiographic measurements, in a Japanese population. We confirmed significant linkage disequilibrium between these polymorphic loci and ethnic differences in frequency of the alleles. The -344C and -344T haplotypes apparently diverged before the intron conversion polymorphism was generated on the latter haplotype. Allele frequencies did not differ between 535 normotensive and 360 hypertensive individuals or between hypertensive individuals with higher and lower concentrations of renin. The only significant correlation was a positive correlation of left ventricular mass with 24-h urinary excretion of sodium, which occurred only in individuals with the -344CC genotype or the intron 2 conversion (-/-) genotype. CONCLUSIONS: The -344CC or intron 2 conversion (-/-) genotype in CYP11B2 may be a risk factor for developing sodium-sensitive cardiac hypertrophy. Ethnic differences in the distribution of CYP11B2 genotypes combined with differences in salt intake might account for inconsistencies between previous reports.