Exploring the consequences of the TNFRSF1A susceptibility allele for MS

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meta分析和验证了几个新的易感位点的复制工作，包括TNFRSF1A (rs1800693， P=1.6x10-11)，它编码TNF1的两个主要受体之一。在使用抗tnf1单克隆抗体治疗后多发性硬化症患者中枢神经系统炎症加重的报道背景下，这一结果是有趣的。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）的风湿病相关。我们的初步结果表明，rs1800693易感等位基因导致TNFRSF1A外显子6剪接，产生一个跨膜受体，缺乏释放可溶性TNFRSF1A所需的切割位点。因此，我们的假设是rs1800693变异通过降低可溶性TNFRSF1A的产生比例来增加对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。由于罕见变异在多发性硬化症中的作用尚不清楚，我们将首先探索是否有其他罕见的TNFRSF1A等位基因影响多发性硬化症的易感性。在对该位点进行全面的遗传评估之后，我们将探索rs1800693和其他变异对TNFRSF1A剪接和可溶性TNFRSF1A形成的功能后果，以验证我们的假设，即可溶性TNFRSF1A水平介导rs1800693对MS易感性的遗传效应。

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.