Shared Genetic Susceptibility in CBD and Sarcoidosis

描述(申请人提供)：非干酪性肉芽肿是许多罕见疾病的重要病理后果，包括原因不明的疾病，如结节病，以及已知原因的疾病，如慢性铍病(CBD)。此外，这些疾病具有相似的临床表现和涉及先天免疫和获得性免疫的病理生理机制。具体地说，这两种疾病都可能需要人类白细胞抗原(人类白细胞抗原)II类依赖抗原提呈细胞与寡克隆性CD4+T淋巴细胞相互作用。因此，促进肉芽肿炎症的细胞因子和生长因子的异常产生随之而来。遗传易感性是这两种多基因疾病的重要决定因素。到目前为止，对这些疾病的大多数研究都是单独检查疾病，通常针对单个或小群候选基因，往往产生模棱两可或否定的结果。这个R21应用程序的中心目标是使用全基因组单核苷酸多态性(SNP)DNA扫描来识别赋予肉芽肿疾病风险的遗传区域。我们假设人类基因组中存在共同的多态位点，这些多态位点具有患肉芽肿性疾病的风险。除了这项研究的范围之外，我们的中心假设是，共同的遗传区反映了这些疾病之间共同的遗传易感因素。在这项建议中，我们将首先使用基因组扫描确定与CBD相关的基因区域或SNPs，并与暴露于铍的非疾病对照进行比较。反过来，我们将使用同样的方法来定义与结节病相关的基因区域，使用NIH A病例对照病例对照研究(ACCESS)病例和匹配对照。我们将使用的DNA阵列包含116,204个SNPs，它们在整个基因组中的平均物理距离约为8.5kb。我们将使用基因组控制方法控制CBD和结节病人群的人口分层。数据将在患病组和未受影响组之间以及两个肉芽肿性疾病组之间进行比较，以确定与疾病发病机制可能相关的共同基因区域。然后，我们将在一项病例对照研究中确认这些区域与这两种疾病的关联，该研究涉及两个更大的CBD和ACCESS病例和对照人群。随着基因组扫描的结果在第二个人群中被确认为初步数据，提出未来的研究变得可行，这些研究将涉及对罕见肉芽肿疾病家族重要的共同基因的详细精细定位和测序，并评估与这些共同遗传因素相关的潜在免疫致病机制。

DESCRIPTION (provided by applicant): The non-caseating granuloma is an important pathologic consequence in many rare diseases, including those of unknown cause, such as sarcoidosis, and of known cause, such as chronic beryllium disease (CBD). Additionally, these disorders share similar clinical presentation and pathophysiologic mechanisms involving both innate and adaptive immunity. Specifically, both disorders likely require interaction of Human Leukocyte Antigen (HLA) Class II dependent antigen presenting cells with oligoclonal CD4+ T lymphocytes. Consequently, an aberrant production of cytokines and growth factors that promote granulomatous inflammation ensues. Genetic susceptibility is an important determinant in both of these multigenic diseases. To date, most studies of these disorders have examined the diseases individually, usually targeting single or small groups of candidate genes, often yielding ambiguous or negative results. The central goal of this R21 application is to use whole genome single nucleotide polymorphism (SNP) DNA scans to identify genetic regions that confer granulomatous disease risk. We hypothesize that there are shared polymorphic sites within the human genome that confer risk for granulomatous disease. Beyond the scope of this study, our central hypothesis is that the shared genetic regions reflect shared genetic susceptibility factors between these diseases. In this proposal we will first determine genetic regions or SNPs associated with CBD compared to beryllium-exposed non-diseased controls using genome scans. In turn, we will use this same approach to define genetic regions associated with sarcoidosis, using the NIH A Case Control Etiologic Study of Sarcoidosis (ACCESS) cases and matched controls. The DNA arrays we will use contain 116,204 SNPs spaced at a median physical distances of approximately 8.5 kb across the genome. We will control for population stratification in both the CBD and sarcoidosis populations using genome control methods. Data will be compared both between diseased and non-affected groups and between the two granulomatous disease groups, in order to define shared genetic regions of putative relevance to disease pathogenesis. We will then confirm the association of these regions with both diseases in a case control study involving two larger populations of CBD and ACCESS cases and controls. With results from genome scans confirmed in a second population as preliminary data, it becomes feasible to propose future studies that would involve detailed fine mapping and sequencing of shared genes of importance to the family of rare granulomatous disorders, and that evaluate the underlying immunopathogenic mechanisms associated with these shared genetic factors.