Genomics of Lupus

描述（由申请人提供）：尽管“反向遗传学”方法将SLE疾病风险与几种已知免疫功能的基因（包括补体蛋白、抗体受体和免疫信号分子）联系起来，但新开发的扫描整个基因组的能力为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多产的多机构联盟，与当前最先进的全基因组技术相匹配，具有大型表型特征的参与者集合，为全基因组研究提供适当的统计能力。SLEGEN成功开展了一项基因组全关联研究（GWAS），并在欧洲衍生种群中进行了独立复制，证实了之前的候选基因，并发现了多种新的遗传效应。由于SLEGEN和其他人的工作，已知导致狼疮风险的遗传变异现在包括ITGAM (CDI lb, CR3), STAT4, BANKl， BLK, HLA-DR, IRF5, FCGR3A, FCGR2A, Clq， Complement C4和PTPN22等。然而，具有不同祖先的其他人群的表型变异和初始数据表明，并非所有的欧洲变异在这些人群中都具有相似的作用，我们对人类狼疮的遗传结构还有很多需要了解的。跨种族绘图方法提供了一个独特的机会来确定共同的变异和可能特定于人群的变异。斯莱根在利用这一机会方面处于独特的地位。项目1将利用现有的欧洲血统受试者的基因组数据，探索6000名非裔美国人、美洲印第安人、西班牙裔或亚洲人的HLA区域差异。项目2-4将通过评估6000名非欧洲受试者的180万个标记来探索整个基因组，并对另外9000名受试者进行复制、精细定位和跨种族定位。这将是对狼疮进行的最大的基因组探索，总的来说，将受益于从27,000例病例和对照中收集的遗传数据。这些实验是高度相互依赖的，依赖于一个群体的推断来获得观点，并在其他群体中进行解释。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，为狼疮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.