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.

接触铍的工人会产生针对铍的 T 细胞依赖性免疫反应 抗原。这些铍敏感 (BeS) 受试者的一部分发展为慢性铍病 (CBD)， 肉芽肿性肺病。我们的工作表明 HLA-DPB1 的多态性含有 第 69 位氨基酸 (Glu69) 的谷氨酸是 CBD 和 BeS 的危险因素。其他遗传易感性 CCR5、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等 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。除上述所列外，其他遗传易感因素的信息有限 迄今为止的研究中，候选基因方法产生的结果不明确或负面。关系 基因与疾病风险暴露之间的关系也尚不清楚。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，并与环境中的暴露相互作用。 BeS 和 CBD 的开发。该项目的中心目标是利用全基因组关联 （GWA）研究，以确定赋予 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性 (SNP)/遗传区域相比 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 所有目标的分层。在目标 2 中，我们将在同一过程中细化与 BeS 和 CBD 相关的 SNP/区域。 使用 lllumina GoldenGate 检测的人群。目标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群体。目标 4a 将利用所有病例和对照对大约 20 个基因进行详细表征，同时 评估基因-环境相互作用。在迄今为止最大的人口研究中，该项目将 通过定义 BeS 和 CBD 中重要的新基因来链接其他项目，重点关注与 与项目 1 相关的抗原呈递以及与项目 3 相关的免疫和 T 细胞调节。 依靠临床实验室核心 B 进行受试者招募和 DNA 样本，并依靠生物统计学 用于分析和暴露评估的Exposure Core C。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/转化目标相结合时，和/或未来 机制研究可能会为这种疾病和其他类似疾病找到未来的治疗靶点。它将 还定义了导致 BeS 和 CBD 的暴露，这可能会对设置新的暴露产生影响 标准，在作为环境引起的致敏模型的疾病中。