Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas

Hiromichi Tanahashi, Tomoatsu Mune, Yoshito Takahashi, Mako Isaji, Tetsuya Suwa, Hiroyuki Morita, Noriyoshi Yamakita, Keigo Yasuda, Takashi Deguchi, Perrin C. White, Jun Takeda

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)6226-6231
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number11
DOIs
StatePublished - Nov 2005

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Cytochrome P-450 CYP11B2
Adrenal Glands
Aldosterone
Polymorphism
Adenoma
Genotype
Gene expression
Gene Expression
Haplotypes
Steroid 11-beta-Hydroxylase
Alleles
Steroidogenic Factor 1
Outcome Assessment (Health Care)
Spironolactone
Glyceraldehyde-3-Phosphate Dehydrogenases
Genetic Linkage
Gene encoding
Blood pressure
Linkage Disequilibrium
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. / Tanahashi, Hiromichi; Mune, Tomoatsu; Takahashi, Yoshito; Isaji, Mako; Suwa, Tetsuya; Morita, Hiroyuki; Yamakita, Noriyoshi; Yasuda, Keigo; Deguchi, Takashi; White, Perrin C.; Takeda, Jun.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 11, 11.2005, p. 6226-6231.

Research output: Contribution to journalArticle

Tanahashi, H, Mune, T, Takahashi, Y, Isaji, M, Suwa, T, Morita, H, Yamakita, N, Yasuda, K, Deguchi, T, White, PC & Takeda, J 2005, 'Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas', Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 11, pp. 6226-6231. https://doi.org/10.1210/jc.2005-0299
Tanahashi, Hiromichi ; Mune, Tomoatsu ; Takahashi, Yoshito ; Isaji, Mako ; Suwa, Tetsuya ; Morita, Hiroyuki ; Yamakita, Noriyoshi ; Yasuda, Keigo ; Deguchi, Takashi ; White, Perrin C. ; Takeda, Jun. / Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. In: Journal of Clinical Endocrinology and Metabolism. 2005 ; Vol. 90, No. 11. pp. 6226-6231.
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abstract = "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.",
author = "Hiromichi Tanahashi and Tomoatsu Mune and Yoshito Takahashi and Mako Isaji and Tetsuya Suwa and Hiroyuki Morita and Noriyoshi Yamakita and Keigo Yasuda and Takashi Deguchi and White, {Perrin C.} and Jun Takeda",
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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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