Project 2 - Immunogenetic and Exposure Factors in Berylliosis

项目 2 - 铍中毒的免疫遗传学和暴露因素

• 批准号: 8382597
• 负责人: LISA A MAIER
• 金额: $ 42.31万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382597
• 关键词: Affect; Alleles; Amino Acids; Anabolism; Antigen Presentation; Antigen-Presenting Cells; Antigens; Berylliosis; Beryllium; Bioinformatics; Biological Assay; Biological Markers; Biometry; CCR5 gene; CD4 Positive T Lymphocytes; Candidate Disease Gene; Chronic berylliosis; Clinical; Collaborations; Colorado; Complex; Conflict (Psychology); DNA; Data; Development; Disease; Future; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Screening; Genome Scan; Genotype; Glutamic Acid; Glutathione; Goals; Granuloma; Granulomatous; HLA-DPB1 gene; Haplotypes; Health; Immune; Immune response; Immunogenetics; Individual; Inflammation; Inflammatory Response; Institutes; Instruction; Interferons; Interleukin-2; Joints; Laboratories; Lead; Link; Lung; Lung diseases; Lymphocyte; Minority; Modeling; Names; National Institute for Occupational Safety and Health; Other Genetics; Pathway interactions; Patients; Pediatric Hospitals; Pennsylvania; Phase; Phenotype; Population; Population Control; Population Study; Positioning Attribute; Predisposition; Prevalence; Prevention; Process; Proliferating; Public Health; Recommendation; Recruitment Activity; Research; Risk; Risk Factors; Sampling; Severity of illness; Single Nucleotide Polymorphism; Specimen; Stratification; T cell regulation; T-Lymphocyte; TNF gene; Testing; Universities; University Hospitals; Work; Workplace; case control; chemokine; cytokine; disorder risk; experience; follower of religion Jewish; forest; gene environment interaction; genetic risk factor; genome wide association study; interstitial; lymphocyte proliferation; novel; reconstruction; response; therapeutic target

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.

暴露于铍的工人会形成针对铍的T细胞依赖性免疫反应 抗原。这些铍敏化（BES）受试者的一个子集发展为慢性铍病（CBD）， 肉芽肿性肺疾病。我们的工作表明，HLA-DPB1中的多态性含有 氨基酸位置69（GLU69）处的谷氨酸是CBD和BES的危险因素。其他遗传易感性 诸如CCR5，TGF-P和谷胱甘肽生物合成基因之类的因素似乎会影响疾病的风险和更多 严重疾病，表明调节铍特异性免疫反应的因素很重要 在BES和CBD中。除了上面列出的其他遗传敏感性因素的信息有限 迄今为止，使用候选基因方法产生模棱两可或负面的结果。关系 基因与疾病风险暴露之间也不清楚。这项研究的中心假设是 免疫和其他致病敏感性因素相互相互作用，并与 BES和CBD的开发。该项目的核心目标是使用基因组广泛的关联 （GWA）研究确定赋予BES和CBD风险的遗传区域。在AIM 1中，我们将筛选 与CBD相关的单核苷酸多态性（SNP）/遗传区域 使用Affymetrix V5.0阵列对超过500,000个SNP的基因型进行控制。我们将控制人口 各个目标的分层。在AIM 2中，我们将在同一中完善与BES和CBD相关的SNP/区域 利用Lllumina Goldengate分析的人口。靶向基因探索的复制阶段将是 在AIM 3中进行了独立的CBD人群，BES和控制对象。在AIM 4 A中 利用所有病例和控制的大约20个基因的详细表征将被沿着 通过评估基因环境相互作用。在迄今为止研究的最大人口中，这个项目将 通过定义重要的BES和CBD的新基因来链接其他项目 抗原呈现与项目1有关以及与项目3相关的免疫和T细胞调节有关。它将 依靠临床实验室核心B进行受试者募集和DNA标本，以及生物统计学 和暴露核心C进行分析和暴露评估。这项研究将定义有希望的生物标志物 疾病，与项目1和3的功能/翻译目的结合在一起，以及/或未来 机械研究可能会导致该疾病和其他类似疾病的未来治疗靶标。会 还定义了导致BES和CBD的暴露，这可能对设置新的接触有影响 标准是一种作为环境引起的敏化模型的疾病。