Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks.
Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks.
复制标题
侧翼微卫星 11 β-羟基类固醇脱氢酶 2 型 (HSD11B2) 与黑人原发性高血压的遗传关联。
DOI：
10.1161/01.hyp.28.3.478
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Warnock,DG
中科院分区：
文献类型：
--
作者：
WatsonJr,B;Bergman,SM;Myracle,A;Callen,DF;Acton,RT;Warnock,DG
在皮质醇摩尔过量的生理环境中，2 型 11β-羟基类固醇脱氢酶 (11β-HSD2) 特异性调节盐皮质激素醛固酮进入肾脏 1 型盐皮质激素受体。皮质醇和醛固酮对盐皮质激素受体具有相似的亲和力。从机制上讲，11β-HSD2 将皮质醇转化为可的松。另一种已知的异构体 11β-HSD1 不仅能催化皮质醇生成可的松反应，还能催化逆反应，因此它不太可能在调节醛固酮与盐皮质激素受体的接触中发挥重要作用。 HSD11B2 基因突变（外显子和内含子）已被证明会导致该酶在明显盐皮质激素过多综合征（一种罕见的常染色体隐性遗传疾病）中活性降低。我们假设该基因座也与原发性高血压的病因有关。为了测试该基因座和侧翼染色体区域与原发性高血压的等位基因关联和遗传连锁，有必要拥有信息丰富的遗传标记。为此，我们将 11β-HSD2 的定位细化至 16q22.1。我们使用最近的侧翼微卫星（D16S301 和 D16S496）对受试者进行基因分型。我们对患有高血压终末期肾病的黑人受试者、血压正常的黑人对照受试者以及一般人群中的黑人和白人个体进行了一项关联研究。我们使用 χ2 分析和 Fisher 精确检验来测试与这些候选基因标记的关联。 D16S301 与高血压之间没有发现显着关联。然而，在D16S496微卫星位点发现与高血压呈正相关（χ2=6.98，df=1，P≤.008）。我们的数据表明，HSD11B2 与患有高血压终末期肾病的黑人受试者中的高血压相关。 16q22.1 染色体区域可能含有原发性高血压的候选基因。我们在另一组独立确定的高血压受试者中的发现得到证实，将为进行同胞对连锁分析提供基础。
11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) specifically modulates access of the mineralocorticoid aldosterone to the kidney mineralocorticoid type 1 receptors in a physiological environment in which there is a molar excess of cortisol. Cortisol and aldosterone have similar affinities for mineralocorticoid receptors. Mechanistically, 11β-HSD2 converts cortisol to cortisone. The other known isoform, 11β-HSD1, not only catalyzes the cortisol to cortisone reaction but also the reverse reaction, making it unlikely to play an important role in modulating the access of aldosterone to mineralocorticoid receptors. Mutations in the HSD11B2 gene (both exonic and intronic) have been demonstrated to cause reduced activity of this enzyme in the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disorder. We hypothesized that this locus is also involved in the etiology of essential hypertension. To test this locus and flanking chromosomal regions for allelic association and genetic linkage to essential hypertension, it is necessary to have informative genetic markers. To this end, we have refined the localization of 11β-HSD2 to 16q22.1. We genotyped subjects using the nearest flanking microsatellites (D16S301 and D16S496). We conducted an association study using black subjects with hypertensive end-stage renal disease, black normotensive control subjects, and black and white individuals from the general population. We used χ2analysis and Fisher's exact test to test for association with these candidate gene markers. No significant association was found between D16S301 and hypertension. However, a positive association with hypertension was found at the D16S496 microsatellite locus (χ2=6.98,df=1,P≤.008). Our data suggest that HSD11B2 is associated with hypertension in our black subjects with hypertensive end-stage renal disease. The 16q22.1 chromosome region potentially harbors a candidate gene for essential hypertension. Confirmation of our findings in another independently ascertained group of hypertensive subjects will provide a basis for proceeding with sib-pair linkage analyses.