Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas.
BACKGROUND
CYP11B2, the gene encoding aldosterone synthase, has several frequent polymorphisms. In particular, the Lys173Arg (K173R) polymorphism is in complete genetic linkage disequilibrium with the -344T/C polymorphism in the promoter of CYP11B2 that involves a binding site for the steroidogenic factor-1 transcription factor. These polymorphisms have been associated with cardiovascular parameters, including hypertension, but not directly with gene expression.


OBJECTIVE
The objective of this study was to correlate CYP11B2 genotype with gene expression in adrenal tissue.


METHODS
We measured mRNA levels of CYP11B2 [presented as a ratio against glyceraldehyde-3-phosphate dehydrogenase (B2/G)] and CYP11B1 in relation to the K173R polymorphism.


METHODS
We studied 28 subjects with aldosterone-producing adenomas (APA) and 18 subjects with normal adrenals.


METHODS
The main outcome measure was CYP11B2 expression levels.


RESULTS
Preoperative treatment with spironolactone or beta-blocker in five APA patients was associated with higher B2/G. The B2/G and B2/B1 ratios were much higher even in the remaining 23 APA patients than in subjects with normal adrenals. The B2/G and B2/B1 ratios in normal adrenals and APA were higher in the KK genotype than in the RR genotype. In patients with APA, urinary aldosterone excretion was higher in those with the KK genotype than in those with the KR genotype. Measurement of cDNA band intensities from normal and APA samples of the KR genotype revealed that the R173 allele was transcribed at levels 46.6 +/- 12.2% (mean +/- sd; n = 7) and 49.1 +/- 20.8% (n = 6), respectively, those of the K173 allele.


CONCLUSIONS
A CYP11B2 haplotype including -344T and K173 is associated with higher gene expression than the -344C/R173 haplotype, supporting reported associations of -344T with higher aldosterone production and blood pressure.
Tanahashi
Hiromichi
H
Department of Diabetes and Endocrinology, Room 2S15, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
Mune
Tomoatsu
T
Takahashi
Yoshito
Y
Isaji
Mako
M
Suwa
Tetsuya
T
Morita
Hiroyuki
H
Yamakita
Noriyoshi
N
Yasuda
Keigo
K
Deguchi
Takashi
T
White
Perrin C
PC
Takeda
Jun
J
D000236:Adenoma / Q000201:enzymology* / Q000235:genetics; D000310:Adrenal Gland Neoplasms / Q000201:enzymology* / Q000235:genetics; D000311:Adrenal Glands / Q000201:enzymology*; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis*; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics
D012333:RNA, Messenger; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase