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)发展的主要遗传风险因素，这些因素在多个种族群体中是常见的。在过去的十年中，10多次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利用高加索人、非裔美国人、墨西哥裔美国人或其他种族血统的多个家庭，已经确定并确认了1q23-25和1q31-32与系统性红斑狼疮有关的证据。我们假设1Q包含一个以上种族共有的SLE易感基因。为此，我们有证据表明，在两个或多个民族中，SLE的易感性与四个位置候选基因(1q23-25中的Pbx1和Ox40L，以及1q31-32中的CFH/CFHR3/CFHR1和CR2)有关，包括CFH/CFHR3/CFHR1的拷贝数变异(CNV)与SLE的关联。最近，在全基因组关联(WGA)和由SLE遗传联盟(SLEGEN)使用317,000个SNP对高加索人病例和对照进行的复制研究中，一个匿名的1q25.1基因座被确定为与SLE有关的4个新的关联之一。由于WGA在独立的高加索人样本中复制和将WGA推广到每个非高加索民族的成本很高，我们建议使用高密度SNPs和覆盖两个1q间隔(1q23-25+1q31-32)的CNV进行有针对性的基因组关联研究，这两个间隔在多个种族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WGA研究中在SLE和其他自身免疫性疾病中发现的与SLE相关的新基因。这项研究的样本来自15,000名受试者，包括高加索人、亚洲人和非裔美国人。我们预计，这些实验将确定位于染色体1Q的主要遗传效应，以及与SLE相关的新基因变异，这些基因变异在几个种族群体中很常见。这些关联研究的结果将导致因果基因变体(SNPs和/或CNV)的定位，并表征它们对基因产物的影响。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(但不是全部)自身免疫性疾病的常见风险变异将有助于阐明这些复杂疾病背后的共同和独特的途径。7.与公众健康的相关性这项研究旨在确定位于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共享的，它很可能在狼疮的发病机制中发挥重要作用。识别多个民族共有的新基因将对疾病的潜在机制产生新的见解，这可能导致针对治疗干预的特定靶点的开发。

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.