Shared Genetic Susceptibility in CBD and Sarcoidosis

描述（由申请方提供）：非干酪化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）和已知原因的疾病（如慢性铍病（CBD））。此外，这些疾病具有相似的临床表现和病理生理机制，涉及先天性和适应性免疫。具体而言，这两种疾病可能需要人类白细胞抗原（HLA）II类依赖性抗原呈递细胞与寡克隆CD4+ T淋巴细胞的相互作用。因此，促进肉芽肿性炎症的细胞因子和生长因子的异常产生。遗传易感性是这两种多基因疾病的重要决定因素。迄今为止，大多数关于这些疾病的研究都是单独检查疾病，通常针对单个或小组候选基因，通常产生模糊或阴性结果。这项R21应用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。我们假设在人类基因组中存在共同的多态性位点，这些位点赋予肉芽肿病的风险。在本研究的范围之外，我们的中心假设是，共享的遗传区域反映了这些疾病之间共享的遗传易感性因素。在这项提案中，我们将首先使用基因组扫描确定与CBD相关的遗传区域或SNP，并与铍暴露的非疾病对照组进行比较。反过来，我们将使用同样的方法来定义与结节病相关的遗传区域，使用NIH结节病病例对照病因学研究（ACCESS）病例和匹配的对照。我们将使用的DNA阵列包含116，204个SNP，它们在基因组中的平均物理距离约为8.5 kb。我们将使用基因组控制方法控制CBD和结节病人群的人群分层。将比较患病组和未患病组之间以及两个肉芽肿疾病组之间的数据，以确定与疾病发病机制推定相关的共有遗传区域。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相关性，该研究涉及两个较大的CBD和ACCESS病例和对照人群。随着基因组扫描结果在第二个人群中得到证实作为初步数据，提出未来的研究变得可行，这些研究将涉及对罕见肉芽肿性疾病家族重要的共享基因的详细精细定位和测序，并评估潜在的免疫病理机制与这些共享的遗传因素相关。

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.