Investigating of Candidate Genes in SLE

系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病， 环境风险因素尚未完全确定。免疫调节的改变 通路被认为在疾病发病机制中起重要作用，数百项研究 研究了潜在候选基因在不同种族和规模的人群中的作用， 结果往往相互矛盾。免疫调节途径中的数百个其他候选基因 研究的时机似乎也已经成熟，特别是因为还没有关于它们在 SLE。这个可行性研究项目的目的是筛选出一长串有兴趣的候选人 一些值得在未来的大型提案中专门研究的基因。在具体目标1中，我们将测试 一组由400例SLE病例和400例匹配对照组成的欧美样本， 通过SNP-Gen Core在我们的候选列表中的基因内选择了384个SNP。我们有400 非裔美国人病例和近300名匹配的对照，对于具体目标2，我们将 招募更多的非裔美国人患者和对照，在同一阵列上进行测试。为特定 目的3我们利用这些欧洲裔美国人和非洲裔美国人队列的结果来选择 有希望进行进一步研究的相关基因，并在包含以下两种基因的确认中对其进行测试： 来自欧洲裔美国人、非洲裔美国人和西班牙裔美国人的基于家族的样本和病例对照样本 家庭对于在这一阶段确认的关联，具体目标4将检查基因， 在相关SNP不编码结构多态性的情况下， 变体或已知的调控位点。这些结果将使确定无可争议的遗传 SLE的危险因素发现与SLE相关的功能性多态性将是 更广泛的结构/功能研究的完美跳板， 随后申请资助。

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with both genetic and environmental risk factors that remain incompletely defined. Alterations in the immune regulatory pathways are believed to play an important role in disease pathogenesis, and hundreds of studies have examined the role of potential candidate genes in populations of varying ethnicity and size, often with conflicting results. Hundreds of other candidate genes in immune regulatory pathways appear ripe for study as well, especially since no results have been published regarding their role in SLE. The purpose of this feasibility project is to winnow down our long list of interesting candidates to a few genes worthy of dedicated study in future large proposals. In Specific Aim 1, we will test a cohort of European-American samples consisting of 400 SLE cases and 400 matched controls at 384 SNPs chosen within genes in our candidate lists through the SNP-Gen Core. We have 400 African-American cases and nearly 300 matched controls on hand, and for Specific Aim 2 we will recruit additional African-American patients and controls for testing on the same array. For Specific Aim 3 we utilize on the results of these European-American and African-American cohorts to select genes with promising associations for further study and test them on a confirmation containing both family-based and case-control samples from European-American, African-American, and Hispanic families. For those associations confirmed in this phase, Specific Aim 4 will examine the genes to find functional polymorphisms in cases where the associated SNP does not encode a structural variant or a known regulatory site. These results will enable identification of indisputable genetic risk factors for SLE. The finding of a functional polymorphism associated with SLE would be the perfect springboard for more extensive structure/function studies and the starting point of subsequent applications for funding.