Genetic Susceptibility to Chronic Beryllium Disease

描述（由申请人提供）：本研究计划将检查宿主遗传因素在吸入铍的不良肺效应中的作用。研究人员已经清楚地证明，只有一部分接触铍的工人会患上慢性铍病（CBD）。对吸入铍反应的变异性的原因尚不清楚，但有力的证据表明，免疫系统蛋白质分子编码的个体间差异起着重要作用。使用逐基因研究方法，研究人员已经表明HLA中的一个或多个核苷酸多态性与CBD的发展显著相关。这些分子流行病学研究集中在主要组织相容性复合体的遗传差异，从而忽略了其他基因的潜在作用，以解释响应铍诱导的CBD的变异性。此外，除了修饰基因外，环境因素如铍的剂量和形态被认为在CBD的诱导中起重要作用。因此，了解基因与环境的相互作用是阐明宿主对铍暴露的反应机制的关键。 CBD个体间变异的预测性遗传动物模型的建立，将为进一步研究CBD的基因和环境因素提供依据。尽管小鼠和豚鼠的遗传研究先前已经表明对铍的反应存在株间变异性，但尚未进行系统和完整的基因组范围内对CBD易感基因的搜索。我们将通过使用铍诱导的肺肉芽肿的小鼠模型来检查暴露于铍的遗传同质的近交系小鼠的反应，直接解决这个研究空白。该项目的主要目标是：1）检验吸入铍气溶胶诱导CBD存在遗传基础的假设; 2）量化遗传因素与环境因素的贡献; 3）确定在导致CBD的分子途径中发挥关键作用的候选基因。

DESCRIPTION (provided by applicant): This research proposal will examine the role of host genetic factors in the adverse pulmonary effects of inhaled beryllium. Investigators have clearly demonstrated that only a portion of exposed workers develop chronic beryllium disease (CBD). The reason for the variability in response to inhaled beryllium is not known, but strong evidence suggests that inter-individual differences in the molecular coding for immune system proteins play a major role. Using a gene-by-gene research approach, investigators have shown that one or more nucleotide polymorphisms in HLA are significantly associated with the development of CBD. These molecular epidemiology studies have focused on genetic differences in the major histocompatiblity complex, thus ignoring the potential role of other genes to explain the variability in response to beryllium-induced CBD. Moreover, in addition to modifying genes, environmental factors such as dose and speciation of beryllium are believed to play significant roles in the induction of CBD. Thus, an understanding of the gene environment interaction is critical in clarifying the mechanism(s) of host response to beryllium exposure. A predictive genetic animal model of inter-individual variation for CBD will permit the dissection of the factors of genes and environment in CBD. Although genetic studies in mice and guinea pigs have previously suggested inter-strain variability in the response to beryllium, a systematic and complete genome wide search for susceptibility genes for CBD has not been conducted. We will directly address this research gap by examining the response of genetically homogeneous, inbred strains of mice exposed to beryllium using a murine model of beryllium-induced lung granulomas. The primary objectives of this project are: 1) to test the hypothesis that there is a genetic basis for the induction of CBD in response to inhalation of beryllium aerosols; 2) to quantify the contribution of genetic versus environmental factors; and 3) to identify candidate genes that play a critical role in the molecular pathways leading to CBD.