TY - JOUR
T1 - Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas
AU - Tanahashi, Hiromichi
AU - Mune, Tomoatsu
AU - Takahashi, Yoshito
AU - Isaji, Mako
AU - Suwa, Tetsuya
AU - Morita, Hiroyuki
AU - Yamakita, Noriyoshi
AU - Yasuda, Keigo
AU - Deguchi, Takashi
AU - White, Perrin C.
AU - Takeda, Jun
PY - 2005/11
Y1 - 2005/11
N2 - Context: 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. Design: 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. Subjects: We studied 28 subjects with aldosterone-producing adenomas (APA) and 18 subjects with normal adrenals. Main Outcome Measure: The main outcome measure was CYP11B2 expression levels. Results: Preoperative treatment with spironolactone or β-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.
AB - Context: 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. Design: 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. Subjects: We studied 28 subjects with aldosterone-producing adenomas (APA) and 18 subjects with normal adrenals. Main Outcome Measure: The main outcome measure was CYP11B2 expression levels. Results: Preoperative treatment with spironolactone or β-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.
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U2 - 10.1210/jc.2005-0299
DO - 10.1210/jc.2005-0299
M3 - Article
C2 - 16118341
AN - SCOPUS:27744531466
SN - 0021-972X
VL - 90
SP - 6226
EP - 6231
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 11
ER -