Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas.
Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas.
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DOI：
10.1210/jc.2005-0299
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发表时间：
2005-11
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影响因子：
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通讯作者：
Hiromichi Tanahashi;T. Mune;Yoshito Takahashi;M. Isaji;T. Suwa;H. Morita;N. Yamakita;K. Yasuda;T. Deguchi;P. White;Jun Takeda
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作者：
Hiromichi Tanahashi;T. Mune;Yoshito Takahashi;M. Isaji;T. Suwa;H. Morita;N. Yamakita;K. Yasuda;T. Deguchi;P. White;Jun Takeda
研究背景：醛固酮合成酶编码基因CYP11B2具有几种常见的多态性。特别是，Lys173Arg(K173R)多态性与CYP11B2启动子中的-344T/C多态性完全遗传连锁不平衡，该多态性涉及类固醇生成因子-1转录因子的结合位点。这些多态与心血管参数相关，包括高血压，但与基因表达没有直接关系。目的探讨肾上腺组织中CYP11B2基因表达与基因表达的关系。设计：我们测量了与K173R多态相关的CYP11B2[与甘油醛-3-磷酸脱氢酶之比(B2/G)]和CYP11B1的mRNA水平。研究对象：28例醛固酮腺瘤(APA)患者和18例正常肾上腺患者。主要结果指标主要结果指标为细胞色素P11B2的表达水平。结果5例APA患者术前应用螺内酯或β-受体阻滞剂治疗后，B2/G比值升高，其余23例APA患者的B2/G和B2/B1比值均明显高于肾上腺正常者。正常肾上腺和APA的B2/G、B2/B1比值KK型高于RR型。在APA患者中，KK基因型者的尿醛固酮排泄量高于KR基因型者。对KR等位基因的正常和APA样本的DNA条带强度测定显示，R173等位基因的转录水平分别为K173等位基因的46.6+/-12.2%(平均+/-SD；n=7)和49.1+/-20.8%(n=6)。结论包括-344T和K173的CYP11B2单倍型与-344C/R173单倍型相比具有更高的基因表达，支持已报道的-344T与更高的醛固酮产生和血压的关联。
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 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.