Culver Daniel A, Newman Lee S, Kavuru Mani S
Department of Pulmonary, Allergy and Critical Care Medicine, Cleveland Clinic, Cleveland, OH 44195 USA.
Clin Dermatol. 2007 May-Jun;25(3):267-75. doi: 10.1016/j.clindermatol.2007.03.005.
Susceptibility to most human diseases is polygenic, with complex interactions between functional polymorphisms of single genes governing disease incidence, phenotype, or both. In this context, the contribution of any discrete gene is generally modest for a single individual, but may confer substantial attributable risk on a population level. Environmental exposure can modify the effects of a polymorphism, either by providing a necessary substrate for development of human disease or because the effects of a given exposure modulate the effects of the gene. In several diseases, genetic polymorphisms have been shown to be context dependent, ie, the effects of a genetic variant are realized only in the setting of a relevant exposure. Because sarcoidosis susceptibility is dependent on both genetic and environmental modifiers, the study of gene-environment interactions may yield important pathogenetic information and will likely be crucial for uncovering the range of genetic susceptibility loci. The complexity of these relationships implies, however, that investigations of gene-environment interactions will require the study of large cohorts with carefully defined exposures and similar clinical phenotypes. A general principle is that the study of gene-environment interactions requires a sample size at least severalfold greater than for either factor alone. To date, the presence of environmental modifiers has been demonstrated for one sarcoidosis susceptibility locus, HLA-DQB1, in African-American families. This article reviews general considerations obtaining for the study of gene-environment interactions in sarcoidosis. It also describes the limited current understanding of the role of environmental influences on sarcoidosis susceptibility genes.
大多数人类疾病的易感性是多基因的，单个基因的功能多态性之间存在复杂的相互作用，这些相互作用决定了疾病的发病率、表型或两者。在这种情况下，任何单个基因对个体的贡献通常较小，但在人群水平上可能会带来相当大的归因风险。环境暴露可以改变多态性的影响，要么是通过为人类疾病的发展提供必要的底物，要么是因为特定暴露的影响调节了基因的作用。在几种疾病中，遗传多态性已被证明是依赖于背景的，即基因变异的影响仅在相关暴露的背景下才会显现。由于结节病的易感性取决于遗传和环境修饰因素，基因-环境相互作用的研究可能会产生重要的发病机制信息，并且对于揭示遗传易感位点的范围可能至关重要。然而，这些关系的复杂性意味着，基因-环境相互作用的研究将需要对具有明确暴露和相似临床表型的大型队列进行研究。一个普遍的原则是，基因-环境相互作用的研究所需的样本量至少比单独研究任何一个因素时大几倍。迄今为止，在非裔美国家庭中，已证明环境修饰因素与一个结节病易感位点HLA-DQB1有关。本文综述了结节病基因-环境相互作用研究的一般注意事项。它还描述了目前对环境影响在结节病易感基因中作用的有限理解。
