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一种T细胞依赖性免疫反应，直接针对铍