Hunt Steven C
Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84108, USA.
J Nutrigenet Nutrigenomics. 2010;3(4-6):182-91. doi: 10.1159/000324355. Epub 2011 Apr 6.
Multiple factors contribute to the development of hypertension, including genetic factors and environmental exposures. Various pathophysiological mechanisms are at play in the pathogenesis of hypertension and this pathogenesis, by necessity, exhibits substantial variation at the level of the individual, as it depends on the relative contribution of inherited genes and individual lifetime environmental exposures. Over time, long-term compensatory mechanisms, including responses to either chronic hypertension or to therapeutic intervention, can only obscure the initiating mechanisms of disease. Acute compensating mechanisms can also mask initiating gene effects during or after an intervention, so that early phenotype assessments during the intervention may be more likely to detect the genetic initiators. Compensatory mechanisms, working over days, weeks or even years, will likely be variably effective in minimizing the expected blood pressure rise, making it difficult to detect genetic initiating mechanisms in cross-sectional, 'steady state', or 'in balance' studies. If the lifetime risk of hypertension indeed approaches 90%, the power to identify genetic factors can only decrease with duration of disease and treatment, and prediction of hypertension becomes of vanishing significance. With multiple factors at play, we cannot expect that all causes are mutually exclusive, but it is reasonable to assume that one of these mechanisms is predominant in the initiation of the disease in any one individual. Given the heterogeneity of essential hypertension argued above, it becomes evident that the chance of identifying genetic factors that contribute to disease development will be greatest if study subjects at highest genetic predisposition are observed during age ranges when heritability is at a maximum, using the correct phenotypes, measured in the correct tissues, during the correct time window. Genes found to be significant in such studies should be densely typed in clinical trials and large population studies to assess public health and clinical applications of the findings.
多种因素导致高血压的发生，包括遗传因素和环境暴露。多种病理生理机制在高血压的发病过程中起作用，而且这种发病机制在个体层面必然存在很大差异，因为它取决于遗传基因和个体一生的环境暴露的相对贡献。随着时间的推移，长期的代偿机制，包括对慢性高血压或治疗干预的反应，只会掩盖疾病的起始机制。急性代偿机制也可能在干预期间或之后掩盖起始基因效应，因此在干预期间进行早期表型评估可能更有可能检测到遗传起始因素。在数天、数周甚至数年起作用的代偿机制，在最大程度减少预期血压升高方面可能效果各异，这使得在横断面、“稳态”或“平衡”研究中难以检测到遗传起始机制。如果高血压的终生风险确实接近90%，那么识别遗传因素的能力只会随着疾病持续时间和治疗而降低，高血压的预测变得毫无意义。由于多种因素起作用，我们不能期望所有病因都是相互排斥的，但合理的假设是，在任何一个个体中，这些机制之一在疾病起始中占主导地位。鉴于上述原发性高血压的异质性，显而易见的是，如果在遗传易感性最高的研究对象处于遗传度最高的年龄范围时，在正确的组织中、在正确的时间窗口内使用正确的表型进行观察，那么识别导致疾病发展的遗传因素的机会将最大。在这类研究中发现具有显著意义的基因，应在临床试验和大型人群研究中进行密集分型，以评估研究结果的公共卫生和临床应用。
