Exploring the consequences of the TNFRSF1A susceptibility allele for MS

探索 TNFRSF1A 易感等位基因对 MS 的影响

• 批准号: 7770696
• 负责人: PHILIP L DE JAGER
• 金额: $ 38.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770696
• 关键词: Acetates; Affect; Alleles; Architecture; Biological Assay; Blood Donations; Cataloging; Catalogs; Categories; Clinical; Cloning; Code; Collection; Complementary DNA; Data; Disease; Disease susceptibility; Doctor of Medicine; Doctor of Philosophy; Exons; Extracellular Domain; Frequencies; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Hand; Homozygote; Human; Human Genome; Immune; Immune system; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Investigation; Linkage Disequilibrium; Location; Measures; Mediating; Meta-Analysis; Monoclonal Antibodies; Multiple Sclerosis; Nature; Neuraxis; Nucleotides; Pathway interactions; Patients; Predisposition; Production; Protein Isoforms; Public Health; RNA; RNA Splicing; Relative (related person); Reporting; Research Personnel; Resources; Rheumatoid Arthritis; Risk; Role; Sampling; Serum; Site; Staging; Syndrome; TNFRSF1A gene; Testing; Tissue Banking; Tissue Banks; Validation; Variant; base; cell type; disorder risk; genome wide association study; immune function; interest; monocyte; novel; phorbol-12-myristate; prevent; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): We have recently completed both a meta-analysis of genome-wide association scans in multiple sclerosis (MS) and a replication effort that validated several novel susceptibility loci, including TNFRSF1A (rs1800693, P=1.6x10-11) which codes for one of the two principal receptors for TNF1. This result is intriguing in the context of reports of exacerbation of central nervous system inflammation in MS patients following treatment with an anti-TNF1 monoclonal antibody. In addition, while this is the first common variant of TNFRSF1A to be definitively associated with an inflammatory disease, many different rare variants are associated with the rheumatologic disease called TNFRSF1A associated periodic syndrome (TRAPS). Our preliminary results suggest that the rs1800693 susceptibility allele causes TNFRSF1A exon 6 to be spliced, producing a transmembrane receptor that lacks the cleavage site necessary to release the soluble form of TNFRSF1A. Our hypothesis is thus that the rs1800693 variant increases susceptibility to MS by decreasing the proportion of soluble TNFRSF1A that is produced, which effectively increases the level of TNF1 activity and could exacerbate inflammatory responses. Since the role of rare variants is not known in MS, we will first explore whether additional, rare TNFRSF1A alleles influence MS susceptibility. With this comprehensive genetic assessment of the locus in hand, we will then explore the functional consequences of rs1800693 and other variants on TNFRSF1A splicing and the formation of soluble TNFRSF1A to test our hypothesis that the level of soluble TNFRSF1A mediates the genetic effect of rs1800693 on MS susceptibility. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to understand the consequences of genetic variation in the TNFRSF1A gene on the function of the human immune system. A variant in this gene increases an individual's risk for developing multiple sclerosis. Thus, understanding how it affects human immune function will allow investigators to better understand the onset of multiple sclerosis, to develop new treatments to prevent onset of multiple sclerosis, and to develop clinical tests that may be able to predict who is at risk of developing multiple sclerosis.

描述（由申请人提供）：我们最近完成了多发性硬化症（MS）全基因组关联扫描的荟萃分析，以及验证了几个新的易感性位点的复制工作，包括 TNFRSF1A（rs1800693，P=1.6x10-11） ）编码 TNF1 的两个主要受体之一。这一结果很有趣，因为有报道称，多发性硬化症患者在接受抗 TNF1 单克隆抗体治疗后，中枢神经系统炎症会加剧。此外，虽然这是第一个与炎症性疾病明确相关的 TNFRSF1A 常见变异，但许多不同的罕见变异与称为 TNFRSF1A 相关周期性综合征 (TRAPS) 的风湿病有关。我们的初步结果表明，rs1800693 易感等位基因导致 TNFRSF1A 外显子 6 被剪接，产生跨膜受体，该受体缺乏释放可溶形式 TNFRSF1A 所需的切割位点。因此，我们的假设是，rs1800693 变异体通过减少产生的可溶性 TNFRSF1A 的比例来增加对 MS 的易感性，这有效地增加了 TNF1 活性水平并可能加剧炎症反应。由于罕见变异在 MS 中的作用尚不清楚，我们将首先探讨其他罕见的 TNFRSF1A 等位基因是否影响 MS 易感性。通过对位点的全面遗传评估，我们将探索 rs1800693 和其他变体对 TNFRSF1A 剪接和可溶性 TNFRSF1A 形成的功能影响，以检验我们的假设，即可溶性 TNFRSF1A 水平介导 rs1800693 对 MS 的遗传效应易感性。 公共健康相关性：该提案的目的是了解 TNFRSF1A 基因的遗传变异对人类免疫系统功能的影响。该基因的变异会增加个体患多发性硬化症的风险。因此，了解它如何影响人类免疫功能将使研究人员能够更好地了解多发性硬化症的发病，开发新的治疗方法来预防多发性硬化症的发病，并开发能够预测谁有患多发性硬化症风险的临床测试。硬化。