Project 2 - Immunogenetic and Exposure Factors in Berylliosis

接触铍的工人产生针对铍的T细胞依赖性免疫反应 抗原的这些铍致敏（BeS）受试者的一个子集进展为慢性铍病（CBD）， 肉芽肿性肺病我们的工作表明，HLA-DPB 1中含有一个 氨基酸位置69处的谷氨酸（Glu 69）是CBD和BeS的危险因素。其他遗传易感性 CCR 5、TGF-β和谷胱甘肽生物合成基因等因素似乎会影响疾病风险， 严重的疾病，这表明调节铍特异性免疫反应的因素是重要的 在BeS和CBD。除上述因素外，关于其他遗传易感因素的信息有限 在迄今为止的研究中，候选基因方法产生模糊或否定的结果。的关系 基因和疾病风险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 发展生物多样性和生物多样性。该项目的中心目标是利用基因组范围内的关联 (GWA)这项研究旨在确定赋予BeS和CBD风险的遗传区域。在目标1中，我们将筛选 单核苷酸多态性（SNP）/与CBD和BeS相关的遗传区域， 对照使用Affymbv5.0阵列对超过500，000个SNP进行基因分型。我们将控制人口 在所有目标中分层。在目标2中，我们将在相同的条件下细化与BeS和CBD相关的SNP/区域。 使用Illumina GoldenGate测定法对群体进行检测。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4a中， 将利用所有病例和对照对大约20个基因进行详细表征，沿着 评估基因与环境的相互作用。在迄今为止研究的最大人口中，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， 与项目1相关的抗原呈递和与项目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样本采集，并依靠生物统计学 和暴露核心C进行分析和暴露评估。这项研究将确定有前途的生物标志物， 疾病，当与项目1和3的功能/翻译目标相结合时，和/或未来 机制的研究可能会导致这种疾病和其他类似疾病的未来治疗目标。它将 还定义了导致BeS和CBD的暴露，这些暴露可能对设定新的暴露产生影响 标准，在一种疾病，作为一个模型的环境引起的敏化。

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.