Genomics of Lupus

描述(申请人提供)：尽管反向遗传学方法将SLE疾病风险与几个具有已知免疫功能的基因联系在一起，包括补体蛋白、抗体受体和免疫信号分子，但新开发的扫描整个基因组的能力为新发现疾病发病机制中的关键途径提供了前所未有的机会。SLEGEN是一个由狼疮研究人员组成的富有成效的多机构联盟，它将当前最先进的全基因组技术的能力与大量具有表型特征的参与者集合相匹配，这为全基因组研究提供了适当的统计能力。SLEGEN已经成功地进行了全基因组关联研究，在欧洲派生的种群中独立复制，并确认了以前的候选基因，并发现了多种新的遗传效应。由于SLEGEN和其他人的工作，已知的导致狼疮风险的基因变异包括ITGAM(CDI lb，CR3)、STAT4、Bank1、BLK、HLA-DR、IRF5、FCGR3A、FCGR2a、Clq、补体C4和PTPN22等。然而，具有不同祖先的其他人群的表型差异和最初的数据都表明，并不是所有的欧洲变体在这些人群中都具有类似的作用，我们对人类狼疮的遗传结构有很多需要了解的地方。跨种族作图方法提供了一个独特的机会来识别共同的变种和可能特定于人群的变种。SLEGEN处于独特的地位，可以利用这一机会。项目1将利用现有的欧洲衍生受试者的基因组数据，探索6000名非裔美国人、美洲印第安人混血拉美裔或亚洲人的人类白细胞抗原区域变异，这些受试者的基础是人类白细胞抗原DRB2基因。项目2-4将通过评估6000个非欧洲受试者的180万个标记来探索整个基因组，并在9000个额外受试者中进行复制、精细作图和跨种族作图。这将是在狼疮中尝试的最大规模的基因组探索，总的来说，将受益于从27,000例病例和对照中收集的基因数据。这些实验是高度相互依赖的，依赖于一个群体中的推论来透视另一个群体中的解释。由此产生的理解水平有望建立狼疮的遗传病因学，产生新的诊断、预后和治疗方法，为这种疾病和许多相关疾病提供治疗益处。

DESCRIPTION (provided by applicant): Although the 'reverse genetics' approach has associated SLE disease risk with several genes with known immune function including complement proteins, antibody receptors and immune signaling molecules, the newly developed ability to scan the entire genome provides an unprecedented opportunity for novel discovery of critical pathways in disease pathogenesis. SLEGEN, a productive multi-institutional consortium of lupus investigators, matches the capacity for current state-of-the-art genome-wide technology with large phenotypically characterized participant collections which provide appropriate statistical power for genomewide studies. SLEGEN has successfully conducted a genome wide association study (GWAS) with independent replication in European-derived populations and has both confirmed previous candidate genes and discovered multiple new genetic effects. As a result of SLEGEN, and the work of others, the genetic variants known to contribute to the risk of lupus now include ITGAM (CDI lb, CR3), STAT4, BANKl, BLK, HLA-DR, IRF5, FCGR3A, FCGR2A, Clq, Complement C4, and PTPN22, among others. However, both the phenotypic variation in other populations with different ancestries and initial data indicate that not all European variants have similar roles in these populations and that we have much to learn about the genetic architecture of human lupus. A trans-racial mapping approach provides a unique opportunity to identify both variants in common and variants which may be population specific. SLEGEN is uniquely positioned to take advantage of this opportunity. Project 1 will explore the HLA region variation in >6000 subjects who are African-American, Amerindian admixed Hispanics, or Asians and grounded at HLA-DRB2 using existing genome data for European-derived subjects. Projects 2-4 will explore the whole genome by evaluating 1.8 million markers in 6000 non-European subjects with replication, fine mapping, and trans-racial mapping in 9000 additional subjects. This will be the largest genomic exploration attempted in lupus, and in aggregate, will benefit from genetic data assembled from >27,000 cases and controls. These experiments are highly interdependent, relying upon inferences in one population group for perspective and interpretation in the others. The resulting level of understanding promises to establish the genetic etiology of lupus, spawn new diagnostics, prognostics, and therapeutics which provide therapeutic benefit to this and many related illnesses.