Guerra Stefano, Martinez Fernando D
Arizona Respiratory Center, University of Arizona, Tucson, Arizona 85724, USA.
Annu Rev Med. 2008;59:327-41. doi: 10.1146/annurev.med.59.060406.213232.
Asthma risk has a clear hereditary component but, unexpectedly, the majority of reported associations between genetic variants and asthma have not been consistently replicated across studies. Methodological flaws have been indicated as a possible explanation for these inconsistencies. However, an alternative explanation is that the effects of genetic variants depend on other factors whose frequency and distribution vary, both across individuals and across populations. Within this framework, we review recent advances in asthma genetics and conclude that a paradigm shift is needed, because a static model in which the DNA sequence is associated with disease risk in a linear fashion fails to consider the interdependence of the diverse components of asthma risk. We propose an integrated approach, linking sequence variation to specific phenotypic manifestations of the disease by taking into account concurrent influences from biological systems and environmental factors that interact within specific developmental windows of opportunity.
哮喘风险具有明显的遗传因素，但出乎意料的是，大多数已报道的基因变异与哮喘之间的关联在各项研究中并未得到一致的重复验证。方法学缺陷被认为是这些不一致性的一种可能解释。然而，另一种解释是，基因变异的影响取决于其他因素，这些因素的频率和分布在个体间和群体间均有所不同。在此框架内，我们回顾了哮喘遗传学的最新进展，并得出结论认为需要进行范式转变，因为DNA序列以线性方式与疾病风险相关联的静态模型未能考虑哮喘风险的各种不同组成部分之间的相互依存关系。我们提出一种综合方法，通过考虑生物系统和环境因素在特定发育机会窗口内相互作用的同时影响，将序列变异与疾病的特定表型表现联系起来。
