SLE Susceptibility and Clinical Significance at 2q22-24 across Multiple Ethniciti

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种严重的、复杂的、临床异质性的自身免疫性疾病，对某些人群的影响比其他人群更严重。非裔美国人（AA）的患病率比欧洲血统的人高3-5倍，表现更严重，死亡率更高。狼疮的遗传研究表明，许多遗传关联的强度也可能在不同的种族人群中有所不同。也有证据表明，群体混合可能在影响AA患者狼疮风险中起重要作用。我们对1032例AA病例进行全基因组混合扫描的初步数据发现，SLE风险与欧洲血统升高在2q22-24之间存在显著关联（LOD=6.3, p<3.3x10-8）。为了在这个混杂信号中确定SLE易感基因，我们在一项随访研究中对1425例AA病例和1771例无关对照进行了候选基因分析（来自28个基因的284个snp）。我们有6个新基因的关联证据（0.05>p>10-6）。我们在欧洲（0.05>p >0 -5）和亚洲（0.05>p >0 -3）祖先的个体中复制了一些这些关联。此外，其中一些相关基因已被报道与其他自身免疫性疾病（即1型糖尿病）密切相关，这暗示了一般自身免疫基因的作用。综上所述，我们假设2q22-24是一个重要且强大的SLE易感区域，其中包含多个独立的SLE易感变异，这些变异将通过利用不同种族人群中局部LD结构的差异来检测。在目前的建议中，我们将对该区域进行密集的精细定位和候选基因分析，以确定SLE易感基因。我们将使用来自5个不同种族人群的大量个体（来自非洲、欧洲、亚洲和美洲印第安人的7000例病例和8000例对照），这些个体具有良好的临床亚表型特征（通过ACR标准和自身抗体谱）。我们建议的队列有足够的能力检测常见变异，OR=1.2。使用多种族人群不仅可以让我们检测种族特异性或种族多样性人群之间的强大关联，还可以通过跨种族映射来精确定位真正的易感变异及其对SLE易感性的相对贡献。在检测SLE易感基因后，我们将执行与临床（ACR）标准和自身抗体谱的基因型-表型相关性。对临床表型变量及其与相关变异的关系的详细分析可以直接解决SLE临床异质性的某些方面。结合我们的研究策略、专业知识、经验、研究团队的业绩记录，以及可用的生物材料、资源和基础设施，我们有很大的潜力成功检测通过混合图谱确定的2q22-24位点的SLE易感变异。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a severe, complex, and clinically heterogeneous autoimmune disease which affects certain populations more severely than others. African-Americans (AA) exhibit a 3-5 fold increased prevalence with more severe manifestations, and greater mortality than individuals of European ancestry. Genetic research in lupus demonstrates that the strength of many genetic associations may also vary between different ethnic populations. There is also evidence that population admixture may play a significant role in influencing the risk of lupus in AA. Our preliminary data on whole-genome admixture scan using 1032 AA cases detected a significant association of SLE risk with elevated European ancestry at 2q22-24 (LOD=6.3, p<3.3x10-8). To identify SLE susceptibility genes within this admixture signal, we performed a candidate gene analysis (284 SNPs from 28 genes) in a follow-up study using 1425 AA cases and 1771 unrelated controls. We have evidence of association (0.05>p>10-6) for 6 novel genes. We have replicated some of these associations in individuals with European (0.05>p>10-5) and Asian (0.05>p>10-3) ancestry. Additionally, some of these associated genes are already reported to be strongly associated with other autoimmune diseases (i.e., Type 1 diabetes) implicating a role of general autoimmunity genes. Taken together, we hypothesize that 2q22-24 is an important and robust SLE susceptibility region which contains multiple, independent SLE predisposing variants, and these will be detected by leveraging differences in local LD structure among ethnically diverse populations. In the current proposal we will follow-up this region with dense fine-mapping and candidate gene analyses to identify SLE susceptibility genes. We will use a large set of individuals (7000 cases and 8000 controls from African, European, Asian, and Amerindian origin) with well-characterized clinical sub-phenotypes (by ACR criteria and autoantibody profiles) from 5 ethnically diverse populations. Our proposed cohort has adequate power to detect common variants with an OR=1.2. Using multiple ethnic populations will not only allow us to detect ethnic-specific or robust association across ethnically-diverse populations, but will also allow for trans-racial mapping to pin-point true predisposing variants and its relative contribution to SLE susceptibility. Upon detecting SLE susceptibility genes we will perform a genotype-phenotype correlation with clinical (ACR) criteria and autoantibody profiles. A detailed analysis of clinical phenotypic variables and their relationship to associated variants may directly address some aspects of clinical heterogeneity of SLE. Together with our research strategies, expertise, experience, track record of our research team, and available biomaterials, resources and infrastructure, we have great potential to successfully detect SLE predisposing variants at 2q22-24 identified through admixture mapping. PUBLIC HEALTH RELEVANCE: Lupus is a severe, debilitating autoimmune disease that represents a significant healthcare burden in the USA and worldwide. We have identified a genomic region in chromosome 2 that may harbor multiple independent SLE susceptibility genes. None of the previously identified lupus genes are from this genomic interval. We will identify the SLE predisposing variants by comparing the genetic variants among multiple populations from diverse ethnicities. This study will not only identify the susceptibility genes but will also shed light on the relative contribution of genes and predisposing variants to the SLE susceptibility in individuals associated with African, European, Asian, and Native-American ancestries.