Genes, hypertension, and intermediate phenotypes
Genes, hypertension, and intermediate phenotypes
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DOI：
10.1097/00001573-199609000-00002
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发表时间：
1996-09-01
影响因子：
2.3
通讯作者：
Hollenberg, NK
中科院分区：
文献类型：
--
作者：
Hollenberg, NK
尽管人们认识到高血压的发病机制有很大的遗传成分已有近70年的历史，但直到最近才进行了系统的努力来确定负责任的遗传决定机制。在几种罕见综合征的情况下，在确定负责临床表达的潜在分子机制方面取得了惊人的进展，糖皮质激素抑制性醛固酮增多症和Liddle综合征，每一种都是作为常染色体显性遗传的疾病，完成了列表。在随机选择的原发性高血压患者和家庭中，遗传涉及许多基因，进展要温和得多。可能最有希望的线索涉及控制血管紧张素原结构的基因，血管紧张素原是肾素反应的底物。连锁已经建立并证实。然而，目前既没有确定遗传异常与潜在机制的关系，也没有确定这种异常对个体患者高血压的贡献。我们对其他候选基因知之甚少，除了那些严格排除了贡献的研究。“中间表型”概念的发展，一种使识别同质亚群成为可能的生理特征，应该有助于解决许多这些问题。不幸的是，目前鉴定和表征中间表型比遗传学研究困难得多，因此进展可能很缓慢。这一领域因报告根据少量患者样本提出的索赔而变得复杂。例如，在血管紧张素转换酶基因多态性作为组织损伤的危险因素的情况下，大量的后续研究系统地未能证实原始报告，该报告是基于一个小的患者样本。事实上，同一个DNA集合可能会被多次检查，以寻找多个候选基因，这就创造了一个可能出现I型错误的环境，因此我们可能会看到更多的例子。读者注意同样，相关中间表型的发展将使虚假关联的可能性降低。
Although it has been recognized for almost 70 years that there is a substantial genetic component to the pathogenesis of hypertension, only recently have systematic efforts been made to identify the responsible genetically determined mechanisms. In the case of several rare syndromes, spectacular progress has been made in identifying the underlying molecular mechanisms responsible for the clinical expression, Glucocorticoid-suppressible aldosteronism and Liddle's syndrome, each inherited as an autosomal-dominant condition, complete the list. In the case of randomly selected patients and families with essential hypertension, inheritance involves many genes and progress has been far more modest. Probably the most promising lead has involved the genes governing the structure of angiotensinogen, the substrate in the renin reaction, Linkage has been established and confirmed, At the moment, however, neither the relation of the genetic abnormality to the underlying mechanisms, nor the contribution of this abnormality to hypertension in the individual patient, has been defined. We know less about other candidate genes, with the exception of studies that rigorously ruled out a contribution. The development of the concept of the ''intermediate phenotype,'' a physiological feature that makes it possible to identify a homogeneous subpopulation, should help to sort out many of these issues. Unfortunately, the identification and characterization of intermediate phenotypes is substantially more difficult at the moment than are the genetic studies, and so progress is likely to be slow. The field is complicated by the reporting of claims made on the basis of small patient samples. In the case of polymorphisms in the angiotensin-converting enzyme gene as a risk factor for tissue injury, for example, substantial follow-up studies have systematically failed to confirm the original report, which was based on a small patient sample. The fact that the same DNA collection is likely to be examined many times for multiple gene candidates creates a setting in which type I errors are likely, and so we are likely to see many more examples. Caveat lector. Again, the development of relevant intermediate phenotypes will make the spurious association less likely.