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）中全基因组关联扫描的荟萃分析和复制工作，验证了几个新型易感基因座，包括TNFRSF1A（RS1800693，p = 1.6x10-11），该基因座为两个主要受体接受者中的一个代码。在用抗TNF1单克隆抗体治疗后，在MS患者中加剧中枢神经系统炎症的报道，这一结果令人着迷。此外，尽管这是TNFRSF1A与炎症性疾病明确相关的第一个常见变体，但许多不同的稀有变体与称为TNFRSF1A相关的周期性综合征（TRAPS）的风湿病疾病有关。我们的初步结果表明，RS1800693的易感性等位基因导致TNFRSF1A外显子6被剪接，从而产生了跨膜受体，该跨膜受体缺乏释放TNFRSF1A的可溶形式所需的切割位点。因此，我们的假设是RS1800693变体通过减少产生的可溶性TNFRSF1A的比例来提高对MS的敏感性，从而有效地提高了TNF1活性的水平，并可能加剧炎症反应。由于在MS中尚不清楚稀有变体的作用，因此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。 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. 公共卫生相关性：该提案的目的是了解TNFRSF1A基因对人免疫系统功能的遗传变异的后果。该基因的变体增加了一个人出现多发性硬化症的风险。因此，了解它如何影响人类的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作，开发新的治疗方法以防止多发性硬化症的发作，并开发临床测试，以预测谁有发展多发性硬化症的风险。