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。这些相关蛋白由人类染色体 1q31 的补体激活调节 (RCA) 基因簇编码。 CFH 的两种主要蛋白质变体 Y402H 和 I62V 与 AMD 风险密切相关。 CFHR3/CFHR1 的纯合缺失对 AMD 具有保护作用。 Y402H 和 I62V 风险变异体具有结构变化，会损害抗炎和调节 CFH 功能。 CFHR 蛋白在多个结合位点与 CFH 竞争。尽管 RCA 基因簇中编码的补体蛋白与 AMD 发病机制的遗传学研究密切相关，但主要的知识空白是 CFH 和五种 CFHR 蛋白的系统水平如何与 AMD 相关。这项多中心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亚型表达的知识。我们开发了一种基于质谱的新型多重多反应监测 (MRM) 测定法，可以测量 CFH 所有四种变体的血浆水平。 MRM 克服了免疫分析在检测高度相似的同源物和序列变异（例如 CFH 和 CFHR 蛋白中发现的序列变异）方面的局限性。我们的试点研究表明，系统性 CFH 风险变异与 AMD 相关。我们建议，在该提案的支持下，进一步开发 MRM 检测，以包括所有五种 CFHR 蛋白及其亚型。我们假设：(1) AMD 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 的血浆浓度相关，(2) 常见的单核苷酸多态性 (SNP) 和其他因素与 AMD 相关。 CFH 变体和 CFHR 蛋白血浆水平的变化。具体目标是：(1) 表征血浆 CFH Y402H 和 I62V 变异水平与 AMD 风险之间的关系，(2) 开发用于测量血浆 CFHR1 至 CFHR5 的 MRM 检测，(3) 表征血浆 CFHR1 至 CFHR5 水平之间的关系(4) 通过全基因组关联研究 (GWAS) 确定与 CFH 变异和 CFHR1 至 CFHR5 血浆水平相关的 SNP 和其他因素。为了实现这些目标，我们将检查年龄、基因/环境易感性-雷克雅未克 (AGES-雷克雅未克) 研究的 4,907 名参与者基线时血浆 CFH Y402、H402、I62 和 V62 变异以及 CFHR1 与 CFHR5 的关系。 AMD 事件。 GWAS 将识别与各自 CFH 和 CFHR 蛋白水平相关的 SNP。 AGES-雷克雅未克研究是一项以人群为基础的流行病学研究，旨在确定导致老年人患病的因素。这项研究将评估有前途的候选生物标志物，并帮助确定全身 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。