Genetic variation in P450c11AS in Chilean patients with low renin hypertension.
Genetic variation in P450c11AS in Chilean patients with low renin hypertension.
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DOI：
10.1210/jcem.81.12.8954040
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发表时间：
1996-12
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影响因子：
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通讯作者：
C. Fardella;H. Rodriguez;J. Montero;G. Zhang;P. Vignolo;A. Rojas;L. Villarroel;W. Miller
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文献类型：
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作者：
C. Fardella;H. Rodriguez;J. Montero;G. Zhang;P. Vignolo;A. Rojas;L. Villarroel;W. Miller
低肾素高血压（LRH）占原发性高血压患者的10-20%，与盐皮质激素诱导的高血压具有激素相似性，但尚未发现盐皮质激素浓度升高。一些LRH患者的血浆醛固酮浓度正常，而不是受到抑制，因此醛固酮浓度与PRA的比值可能与高血压患者的血浆醛固酮浓度有关。（Aldo/PRA）高，表明醛固酮生物合成不适当地增加。我们在智利圣地亚哥的一家诊所中，对高血压人群和对照人群中编码醛固酮合酶P450 c11 AS的CYP 11 B2基因进行了鉴定。我们直接测序了12例LRH患者、2例高肾素高血压对照和2例血压正常对照的整个CYP 11B 2基因。所有的序列是相同的，除了8的24个LRH等位基因编码精氨酸，而不是赖氨酸的位置173。Arg 173和Lys 173变体在转染的MA-10细胞中表达，并测量它们将脱氧皮质酮转化为醛固酮的能力; Lys 173的表观米氏常数（Km）为2.73 mumol/L; Arg 173的Km为2.53 mumol/L。Lys 173的表观最大流速（Vmax）为6.5 x 10（-3）μ g/mL.24 h; Arg 173的Vmax为7.8 x 10（-3）μ g/mL.24 h。一级反应速率常数Vmax/Km分别为2.38（Lys 173）和3.08（Arg 173）。由于这些值没有显著差异，我们试图确定Arg 173是否是与LRH连锁的多态性。我们通过PCR扩增CYP 11B 2外显子3-5，然后用Bsu 361消化，检测了52例原发性高血压患者和55例正常血压对照的173位，Bsu 361消化的Arg 173序列，但不是Lys 173序列。高血压等位基因携带Arg 173的频率（39/104，37.5%）高于正常血压等位基因（25/110，22.5%）（χ 2 = 5.57; P < 0.02）。大多数Arg 173等位基因（31/72，43.1%）来自Aldo/PRA <30的高血压患者，而Aldo/PRA> 30的患者中仅发现5/24（20.8%）Arg 173等位基因（χ 2 = 3.79; P = 0.05）。因此，CYP 11B 2的ARg 173变异体可能与智利患者的LRH有关。
Low renin hypertension (LRH), which accounts for 10-20% of patients with idiopathic "essential" hypertension, bears hormonal similarities to mineralocorticoid-induced hypertension, but elevated mineralocorticoid concentrations have not been found. Some patients with LRH have normal, rather than suppressed, plasma aldosterone concentrations, so that the ratio of aldosterone concentration to PRA (Aldo/PRA) is high, suggesting inappropriately increased aldosterone biosynthesis. We characterized the CYP11B2 gene that encodes the aldosterone synthase, P450c11AS, in hypertensive and control populations in a single clinic in Santiago, Chile. We directly sequenced the entire CYP11B2 gene in 12 patients with LRH, 2 high renin hypertensive controls, and 2 normotensive controls. All sequences were identical, except that 8 of 24 LRH alleles encoded arginine rather than lysine at position 173. The Arg173 and Lys173 variants were expressed in transfected MA-10 cells, and their ability to convert deoxycorticosterone to aldosterone was measured; the apparent Michaelis constant (Km) for Lys173 was 2.73 mumol/L; the Km for Arg173 was 2.53 mumol/L. The apparent maximal velocity (Vmax) for Lys173 was 6.5 x 10(-3) micrograms/mL.24 h; the Vmax for Arg173 was 7.8 x 10(-3) micrograms/mL.24 h. The first order rate constant, Vmax/Km was 2.38 for Lys173 and 3.08 for Arg173. As these values were not significantly different, we sought to determine whether Arg173 is a polymorphism linked to LRH. We examined position 173 in 52 unselected patients with idiopathic hypertension and 55 normotensive controls by PCR amplification of CYP11B2 exons 3-5 followed by digestion with Bsu361, which digests the Arg173 sequence, but not the Lys173 sequence. More of the hypertensive alleles (39 of 104, 37.5%) than normotensive alleles (25 of 110, 22.5%) carried Arg173 (chi 2 = 5.57; P < 0.02). Most of the Arg173 alleles (31 of 72, 43.1%) were from hypertensive patients with Aldo/PRA below 30, whereas only 5 of 24 (20.8%) Arg173 alleles were found in patients with Aldo/PRA greater than 30 (chi 2 = 3.79; P = 0.05) Thus, the ARg173 variant of CYP11B2 may be linked to LRH in Chilean patients.