Genetic Susceptibility to Chronic Beryllium Disease

描述（由申请人提供）：本研究计划将探讨宿主遗传因素在吸入铍的不良肺效应中的作用。调查人员清楚地表明，只有一部分暴露的工人会患上慢性铍病（CBD）。对吸入铍的反应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着主要作用。利用基因对基因的研究方法，研究人员已经证明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上，从而忽略了其他基因在解释对铍诱导的CBD反应变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物种形成被认为在CBD的诱导中起重要作用。因此，了解基因与环境的相互作用对于阐明宿主对铍暴露的反应机制至关重要。

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.