Project 2 - Immunogenetic and Exposure Factors in Berylliosis

接触铍的工人产生针对铍的依赖T细胞的免疫反应 抗原。这些铍敏化(BES)受试者的子集进展为慢性铍病(CBD)， 一种肉芽肿性肺部疾病。我们的工作表明，人类白细胞抗原-DPB1基因的一个多态性包含一个 氨基酸第69位谷氨酸(Glu69)是CBD和BES的危险因素。其他遗传易感性 CCR5、转化生长因子-β和谷胱甘肽生物合成基因等因素似乎影响疾病风险和更多因素。 严重的疾病，表明调节铍特异性免疫反应的因素是重要的 在BES和CBD。除了上面列出的那些，关于其他遗传易感因素的信息有限。 在迄今为止的研究中，候选基因方法产生了模棱两可或否定的结果。两国关系 基因和疾病风险暴露之间的关系也不清楚。这项研究的中心假设是 免疫和其他致病易感因素相互作用，并与暴露在 BES和CBD的发展。这个项目的中心目标是使用全基因组关联 (GWA)研究，以确定导致BES和CBD风险的基因区域。在《目标1》中，我们将筛选 与CBD和BES相关的单核苷酸多态(SNPs)/遗传区域与 对照使用Affymetrix V5.0阵列对超过500,000个SNP进行基因分型。我们将控制人口 所有目标的层次化。在目标2中，我们将细化与BES和CBD相关的SNPs/区域 使用LLumina Gold Gate检测的种群。靶向基因探索的复制阶段将是 在目标3中进行，利用CBD、BES和对照受试者的独立人群。在目标4 a中 利用所有病例和对照，将对大约20个基因进行详细的表征， 评估基因与环境的相互作用。在迄今为止研究的最大人群中，该项目将 通过定义在BES和CBD中重要的新基因，将其他项目联系起来，重点放在与 与项目1相关的抗原呈递，与项目3相关的免疫和T细胞调节。它将 依靠临床实验室核心B进行受试者招募和DNA样本，以及生物统计学 以及用于分析和暴露评估的暴露核心C。这项研究将定义有前景的生物标记物 疾病，当与项目1和3的功能/翻译目标相结合时，和/或未来 机制研究可能会导致这种疾病和其他类似疾病的未来治疗靶点。会的 还要定义导致BES和CBD的暴露，这些暴露可能会对设置新的暴露产生影响 标准，在一种疾病中，作为环境诱导致敏的模型。

Workers exposed to beryllium develop a T cell-dependent immune response directed against a beryllium antigen. A subset of these beryllium sensitized (BeS) subjects progress to chronic beryllium disease (CBD), a granulomatous lung disorder. Our work has shown that a polymorphism in HLA-DPB1 containing a glutamic acid at amino acid position 69 (Glu69), is a risk factor for CBD and BeS. Other genetic susceptibility factors, such as CCR5, TGF-p and glutathione biosynthesis genes appear to affect risk of disease and more severe disease, suggesting that factors which regulate the beryllium specific immune response are important in BeS, and CBD. Besides those listed above, information on other genetic susceptibility factors is limited with a candidate gene approach yielding ambiguous or negative results in studies to date. The relationship between genes and exposure in disease risk is also unclear. The central hypothesis of this study is that immune and other pathogenic susceptibility factors interact with each other and with exposure in the development of BeS and CBD. The central goal of this project is to use a genome wide association (GWA) study to identify genetic regions that confer risk of BeS and CBD. In Aim 1 we will screen for single nucleotide polymorphisms (SNPs)/genetic regions associated with CBD and BeS compared to controls using the Affymetrix v5.0 array to genotype over 500,000 SNPs. We will control for population stratification in all Aims. In Aim 2, we will refine the SNPs/regions associated with BeS and CBD in the same population utilizing the lllumina GoldenGate assay. A replication phase for targeted gene exploration will be conducted in Aim 3, utilizing an independent population of CBD, BeS, and control subjects. In Aim 4 a detailed characterization of approximately 20 genes utilizing all cases and controls will be undertaken, along with assessment of gene-environment interactions. In the largest population studied to date, this Project will link the other projects by defining new genes important in BeS and CBD focusing on those relevant to antigen presentation, relevant to Project 1 and to immune and T cell regulation, relevant to Project 3. It will rely on the Clinical Laboratory Core B for subject recruitment and DNA specimens, and on the Biostatistics and Exposure Core C for analysis and exposure assessment. This study will define promising biomarkers of disease, which when combined with the function/translational aims of Projects 1 and 3, and/or future mechanistic study may result in future therapeutic targets for this disease and other similar diseases. It will also define exposures resulting in BeS and CBD that may have implications for setting new exposure standards, in a disease that serves as a model of environmentally-induced sensitization.