Association of Positional Candidate Gene Variants with SLE

描述（由申请人提供）：我们的目标是确定系统性红斑狼疮（SLE）发展的主要遗传危险因素，这些因素在多个种族中很常见。在过去的十年中，超过10个全基因组连锁扫描已经定位了许多SLE易感基因座。我们的研究小组和其他研究人员使用高加索人、非洲裔美国人、墨西哥裔美国人或其他种族的多重家族鉴定并证实了1q23 - 25和1q31 - 32与SLE相关的证据。我们假设1q包含SLE易感基因共享一个以上的种族。为此，我们有证据表明SLE易感性与两个或多个种族中的四个位置候选基因（1q23 - 25中的PBX 1和OX40 L，以及1q31 - 32中的CFH/CFHR 3/CFHR 1和CR 2）相关，包括CFH/CFHR 3/CFHR 1的拷贝数变异（CNV）与SLE相关。最近，在SLE遗传学联盟（SLEGEN）使用317，000个SNP对高加索病例和对照进行的全基因组关联（WGA）和复制研究中，一个匿名的1q25.1位点被确定为与SLE的4个新关联之一。由于WGA在独立的高加索人样本中复制和将WGA扩展到每个非高加索人种族群体的成本很高，我们建议使用覆盖两个1q间隔（1q23 - 25加上1q31 - 32）的高密度SNP和CNV进行靶向基因组关联研究，这些SNP和CNV在多个种族群体中具有很强的连锁和关联证据。此外，我们计划在我们的独立样本中评估在SLE和其他自身免疫性疾病的WGA研究中发现的与SLE相关的新基因。可用于本研究的样品来自> 15，000名受试者，包括高加索人、亚洲人和非洲裔美国人队列。我们预计，这些实验将确定主要的遗传效应位于染色体1q以及新的基因变异与SLE是常见的几个种族群体。这些关联研究的结果将导致致病基因变异（SNP和/或CNV）的定位，并表征其对基因产物的影响。从这些研究中获得的知识可能揭示疾病发病机制的新范式，并可能为疾病管理提供新的治疗靶点。几种但不是所有自身免疫性疾病的常见风险变体将有助于阐明这些复杂疾病的共同和独特途径。7.公共卫生相关性本研究旨在确定位于1号染色体长臂上的主要遗传风险因素，这些因素会增加系统性红斑狼疮（SLE）的风险。如果我们确定一个特定的遗传因素是由一个以上的种族群体共享，它很可能在狼疮的发病机制中发挥重要作用。鉴定多个种族群体共有的新基因将对疾病的潜在机制产生新的见解，这可能导致开发治疗干预的特定靶点。

DESCRIPTION (provided by applicant): Our goal is to identify major genetic risk factors for the development of systemic lupus erythematosus (SLE) that are common to multiple ethnic groups. During the last decade, more than 10 whole genome linkage scans have mapped many SLE susceptibility loci. Evidence for linkage to SLE at 1q23-25 and 1q31-32 have been identified and confirmed by our group and other investigators using multiplex families of Caucasian, African- American, Mexican-American, or other ethnic origins. We hypothesize that 1q contains SLE susceptibility genes shared by more than one ethnic group. To this end, we have evidence for association of SLE susceptibility with four positional candidate genes (PBX1 and OX40L in 1q23-25, and CFH/CFHR3/CFHR1 and CR2 in 1q31-32) in two or more ethnic groups, including association of copy number variants (CNVs) of CFH/CFHR3/CFHR1 with SLE. An anonymous 1q25.1 locus has recently been identified as one of the 4 novel associations with SLE in whole genome association (WGA) and replication studies of Caucasian cases and controls conducted by the SLE Genetic consortium (SLEGEN) using 317,000 SNPs. Because of the high cost of WGA for replicating in independent Caucasian samples and for extending WGA to each of the non- Caucasian ethnic groups, we propose to conduct a targeted genome association study using both high-density SNPs and CNVs covering the two 1q intervals (1q23-25 plus 1q31-32) that have strong linkage and association evidence in multiple ethnic groups. In addition, we plan to assess novel genes identified in WGA studies in SLE and other autoimmune diseases for association with SLE in our independent samples. Samples available for this study are from > 15,000 subjects including Caucasian, Asian, and African-American cohorts. We anticipate that these experiments will identify major genetic effects located in chromosome 1q as well as novel gene variants associated with SLE that are common to several ethnic groups. Results of these association studies will lead to localization of causal gene variants (SNPs and/or CNVs), and characterization of their effects on the gene products. Knowledge gained from these studies may reveal new paradigms for the pathogenesis of the disease, and may provide new therapeutic targets for disease management. Common risk variants to several, but not all, autoimmune diseases will help elucidate both shared and unique pathways underlying these complex disorders. 7. PUBLIC HEALTH RELEVANCE This study aims to identify major genetic risk factors, located on the long arm of chromosome 1, that increase risk for systemic lupus erythematosus (SLE). If we identify a particular genetic factor that is shared by more than one ethnic group, it is likely to play an important role in the pathogenesis of lupus. The identification of novel genes common to multiple ethnic groups will yield new insights into the mechanisms underlying the disease, which may lead to the development of specific targets for therapeutic interventions.