Systemic complement and age-related macular degeneration.

全身补体和年龄相关性黄斑变性。

• 批准号: 9131741
• 负责人: RICHARD D SEMBA
• 金额: $ 47.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9131741
• 关键词: Address; Age related macular degeneration; Alternative Complement Pathway; Anti-Inflammatory Agents; Anti-inflammatory; Binding Sites; Biological Assay; Blindness; C-reactive protein; Cells; Coagulation Process; Complement; Complement 3b; Complement Activation; Complement Factor H; Detection; Developed Countries; Development; Disease; Elderly; Environment; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Fundus photography; Gene Cluster; Genetic; Genetic study; Health; Heparin Binding; Histidine; Homologous Gene; Human Chromosomes; Immune response; Immunoassay; Incidence; Inflammation; Investigation; Isoleucine; Knowledge; Lead; Malondialdehyde; Mass Spectrum Analysis; Measures; Natural Immunity; Participant; Pathogenesis; Pathology; Pathway interactions; Pilot Projects; Plasma; Play; Positioning Attribute; Post-Translational Protein Processing; Predisposition; Protein Family; Protein Isoforms; Proteins; Public Health; Regulation; Risk; Role; Single Nucleotide Polymorphism; Stratification; Surface; Therapeutic Intervention; Tyrosine; Valine; Variant; Visit; aging gene; base; candidate marker; cell growth regulation; complement pathway; complement system; genome wide association study; insight; multiple reaction monitoring; novel; population based; rare variant; risk variant

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of visual loss among older adults in developed countries. Complement factor H (CFH) and CFH-related proteins (CFHR1 to CFHR5) are implicated in the development of AMD. These related proteins are encoded in the Regulation of Complement Activation (RCA) gene cluster in human chromosome 1q31. Two major protein variants of CFH, Y402H and I62V, are strongly associated with risk of AMD. A homozygous deletion in CFHR3/CFHR1 is protective in AMD. The Y402H and I62V risk variants have structural changes that impair anti-inflammatory and regulatory CFH functions. CFHR proteins compete with CFH at several binding sites. Although complement proteins encoded in the RCA gene cluster are strongly implicated by genetic studies in the pathogenesis of AMD, a major gap in knowledge is how systemic levels of CFH and the five CFHR proteins are related to AMD. This multi-center, collaborative study will use an epidemiological approach to advance knowledge from the genetic level to the expression of circulating proteins and their variants and isoforms. We have developed a novel multiplexed multiple reaction monitoring (MRM) assay based upon mass spectrometry that can measure the plasma levels of all four variants of CFH. MRM overcomes the limitations of immunoassays in detection of highly similar homologues and sequence variants such as that found in CFH and CFHR proteins. Our pilot studies suggest that systemic CFH risk variants are associated with AMD. We propose, under the support of this proposal, to further develop the MRM assay to include all five CFHR proteins and their isoforms. We hypothesize: (1) risk of AMD is associated with plasma concentrations of CFH variants Y402H and I62V and plasma concentrations of complement factor H-related proteins CFHR1 to CFHR5, (2) common single nucleotide polymorphisms (SNPs) and other factors are associated with variations in plasma levels of both CFH variants and CFHR proteins. The specific aims are to: (1) characterize the relationship between plasma CFH Y402H and I62V variant levels and risk of AMD, (2) develop MRM assays for measuring plasma CFHR1 to CFHR5, (3) characterize the relationship between plasma CFHR1 to CFHR5 levels and risk of AMD, and (4) identify SNPs and other factors associated with plasma levels of CFH variants and CFHR1 to CFHR5 through a genome-wide association study (GWAS). To address these aims, we will examine the relationship of plasma CFH Y402, H402, I62, and V62 variants and CFHR1 to CFHR5 at baseline in 4,907 participants in the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) Study with prevalent and incident AMD. A GWAS will identify SNPs associated with respective CFH and CFHR protein levels. The AGES-Reykjavik Study is a population-based epidemiological study aimed at identifying factors that contribute to disease in older adults. This study will evaluate promising candidate biomarkers and help to determine whether systemic CFH and CFHR proteins play a role in AMD and represent a potential pathway for risk stratification and/or therapeutic intervention.

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是发达国家老年人视力丧失的主要原因。补体因子H （CFH）和CFH相关蛋白（CFHR1至CFHR5）与AMD的发生有关。这些相关蛋白编码在人类染色体1q31的补体激活调控（RCA）基因簇中。CFH的两种主要蛋白变体Y402H和I62V与AMD的风险密切相关。CFHR3/CFHR1的纯合缺失对AMD具有保护作用。Y402H和I62V风险变异具有结构变化，损害抗炎和调节CFH功能。CFHR蛋白在几个结合位点与CFH竞争。尽管RCA基因簇编码的补体蛋白与AMD的发病机制密切相关，但对CFH和五种CFHR蛋白的系统性水平与AMD的关系仍是一个主要的知识缺口。这项多中心的合作研究将使用流行病学方法来推进从遗传水平到循环蛋白及其变体和异构体表达的知识。我们开发了一种基于质谱的新型多路多反应监测（MRM）方法，可以测量CFH所有四种变体的血浆水平。MRM克服了免疫分析法在检测高度相似的同源物和序列变异（如CFH和CFHR蛋白）方面的局限性。我们的初步研究表明，系统性CFH风险变异与AMD相关。在此提案的支持下，我们建议进一步发展MRM分析，以包括所有五种CFHR蛋白及其亚型。我们假设：(1)AMD的风险与CFH变体Y402H和I62V的血浆浓度以及补体因子h相关蛋白CFHR1至CFHR5的血浆浓度有关；(2)常见的单核苷酸多态性（snp）和其他因素与CFH变体和CFHR蛋白的血浆水平变化有关。具体目的是：(1)表征血浆CFH Y402H和I62V变异水平与AMD风险之间的关系；(2)建立血浆CFHR1至CFHR5的MRM测定方法；(3)表征血浆CFHR1至CFHR5水平与AMD风险之间的关系；(4)通过全基因组关联研究（GWAS）确定血浆CFH变异水平和CFHR1至CFHR5水平相关的snp和其他因素。为了实现这些目标，我们将在年龄、基因/环境易感性-雷克雅未克（Age - reykjavik）研究中研究4,907名参与者的血浆CFH Y402、H402、I62和V62变异和CFHR1至CFHR5与流行和发生率AMD的关系。GWAS将识别与CFH和CFHR蛋白水平相关的snp。AGES-Reykjavik研究是一项基于人群的流行病学研究，旨在确定导致老年人疾病的因素。本研究将评估有希望的候选生物标志物，并帮助确定系统性CFH和CFHR蛋白是否在AMD中发挥作用，并代表风险分层和/或治疗干预的潜在途径。