Division of Nephrology and Dialysis, Chair of Nephrology, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele Hospital, Milan 20132, Italy.
Sci Transl Med. 2010 Nov 24;2(59):59ra87. doi: 10.1126/scitranslmed.3001814.
Twenty years of genetic studies have not contributed to improvement in the clinical management of primary arterial hypertension. Genetic heterogeneity, epistatic-environmental-biological interactions, and the pathophysiological complexity of hypertension have hampered the clinical application of genetic findings. In the companion article, we furnished data from rodents and human cells demonstrating two hypertension-triggering mechanisms--variants of adducin and elevated concentrations of endogenous ouabain (within a particular range)--and their selective inhibition by the drug rostafuroxin. Here, we have investigated the relationship between variants of genes encoding enzymes for ouabain synthesis [LSS (lanosterol synthase) and HSD3B1 (hydroxy-δ-5-steroid dehydrogenase, 3β- and steroid δ-isomerase 1)], ouabain transport {MDR1/ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1]}, and adducin activity [ADD1 (adducin 1) and ADD3], and the responses to antihypertensive medications. We determined the presence of these variants in newly recruited, never-treated patients. The genetic profile defined by these variants predicted the antihypertensive effect of rostafuroxin (a mean placebo-corrected systolic blood pressure fall of 14 millimeters of mercury) but not that of losartan or hydrochlorothiazide. The magnitude of the rostafuroxin antihypertensive effect was twice that of antihypertensive drugs recently tested in phase 2 clinical trials. One-quarter of patients with primary hypertension display these variants of adducin or concentrations of endogenous ouabain and would be expected to respond to therapy with rostafuroxin. Because the mechanisms that are inhibited by rostafuroxin also underlie hypertension-related organ damage, this drug may also reduce the cardiovascular risk in these patients beyond that expected by the reduction in systolic blood pressure alone.
二十年来的遗传学研究并未改善原发性高血压的临床管理。遗传异质性、上位-环境-生物学相互作用以及高血压的病理生理复杂性阻碍了遗传发现的临床应用。在相关文章中，我们提供了来自啮齿动物和人类细胞的数据，证明了两种高血压触发机制——结合蛋白和内源性哇巴因的变异（在特定范围内）——以及它们被罗司伐他汀选择性抑制。在这里，我们研究了编码哇巴因合成酶（羊毛甾醇合酶和 HSD3B1）、哇巴因转运蛋白（MDR1/ABCB1 [ATP 结合盒，亚家族 B（MDR/TAP），成员 1]）和结合蛋白活性（ADD1 和 ADD3）的基因变异与对降压药物的反应之间的关系。我们在新招募的、从未接受过治疗的患者中确定了这些变体的存在。这些变体定义的遗传特征预测了罗司伐他汀的降压效果（平均安慰剂校正收缩压下降 14 毫米汞柱），但不预测氯沙坦或氢氯噻嗪的降压效果。罗司伐他汀的降压效果是最近在 2 期临床试验中测试的降压药物的两倍。四分之一的原发性高血压患者显示出这些结合蛋白或内源性哇巴因的变异，预计会对罗司伐他汀治疗有反应。因为罗司伐他汀抑制的机制也是与高血压相关的器官损伤的基础，所以这种药物还可能降低这些患者的心血管风险，超出仅通过降低收缩压所预期的风险。
