Genetic Susceptibility to Chronic Beryllium Disease

描述(由申请人提供)：这项研究提案将检验宿主遗传因素在吸入铍的不良肺部影响中的作用。调查人员已经清楚地证明，只有部分接触者会患上慢性铍病(CBD)。对吸入铍的反应产生差异的原因尚不清楚，但强有力的证据表明，免疫系统蛋白质分子编码的个体间差异起到了主要作用。使用逐个基因的研究方法，研究人员已经证明，人类白细胞抗原(HLA)中的一个或多个核苷酸多态与CBD的发生显著相关。这些分子流行病学研究主要集中在主要组织相容性复合体的遗传差异上，从而忽略了其他基因在解释铍诱导的CBD反应的差异性方面的潜在作用。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的诱导中起着重要作用。因此，了解基因环境的相互作用对于阐明宿主对铍暴露的反应机制(S)至关重要。 CBD个体间变异的预测性遗传动物模型将使CBD的基因和环境因素的剖析成为可能。尽管先前对小鼠和豚鼠的遗传学研究表明，菌株间对铍的反应存在差异，但尚未对CBD的易感基因进行系统和完整的全基因组搜索。我们将通过使用铍诱导的肺肉芽肿小鼠模型来检测暴露于铍的遗传同质性、近交系小鼠的反应，从而直接解决这一研究差距。该项目的主要目标是：1)检验吸入铍气雾剂引起CBD存在遗传基础的假设；2)量化遗传因素与环境因素的作用；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.