Genetic Risk for Granulomatous Interstitial Lung Disease

描述（由申请人提供）： 该项目的目的是确定肺结节病（一种肉芽肿性间质性肺病（gILD））的遗传危险因素。肺结节病是由对未知抗原刺激的异常适应性免疫反应引起的。在美国，结节病的患病率估计为每10万人中有10至35人，影响所有种族、性别和所有年龄的人。在一些个体中，免疫反应消退而没有长期影响，而在另一些个体中，存在严重的肺损伤。我们不了解肉芽肿性疾病的发病机制，也不了解为什么有些人的疾病消退，但在其他人中发展为严重疾病，往往导致死亡。结节病的死亡率正在上升，原因我们也不清楚。遗传和环境因素对于确定结节病风险都很重要，环境暴露对疾病风险和严重程度的影响可能因遗传因素而异。有很好的证据表明免疫相关的遗传变异在结节病中的重要性，尽管特定的免疫相关变异和其他风险的遗传决定因素在很大程度上仍未确定。吸烟对结节病有保护作用，但在有相似吸烟史的人群中保护作用差异很大。该建议的中心假设是主要组织相容性复合体（MHC）中的遗传变异通过调节抗原刺激在结节病的起始中起主要作用，并且这些变异， 除此之外，还驱动肉芽肿性炎症的发生和持续，并最终导致疾病的严重程度。该项目将通过比较结节病病例与对照，使用靶向MHC检查和通过HumanOmni2.5 BeadChip进行的基因组不可知筛选，来鉴定与肺受累结节病相关的遗传变异。为此，该项目将检查迄今为止研究的最强大的发现样本，根据其他项目的表达结果对变体进行优先排序，并在独立样本中复制我们的发现。该项目还将通过检查重要的吸烟暴露和疾病严重程度亚组来确定疾病风险是否取决于吸烟史和/或这些变异是否与肺部受累的严重程度相关，从而表征可重复相关的结节病风险变异的潜在病因学作用。这项研究的结果应该为后续的精细定位和功能研究提供重要的基因或区域，最终应该为发展提供更好的预防和治疗目标。

DESCRIPTION (provided by applicant): The goal of this project is to identify genetic risk factors for lung-involved sarcoidosis, a granulomatous interstitial lung disease (gILD). Lung-involved sarcoidosis results from an aberrant adaptive immune response to unknown antigenic stimuli. The prevalence of sarcoidosis is estimated to be between 10 and 35 per 100,000 in the United States, affecting people of all races, both genders and all ages. In some individuals, the immune response resolves with no long-term effects while in others there is severe lung impairment. We do not understand the mechanisms of granulomatous disease initiation nor why disease resolves in some individuals but progresses to severe disease, often resulting in death, in others. The mortality rate of sarcoidosis is increasing for reasons we also don't understand. Both genetic and environmental factors are important for determining sarcoidosis risk and the impact of environmental exposures on disease risk and severity likely differs depending on genetic factors. There is good evidence for the importance of immune-related genetic variants in sarcoidosis, although the specific immune-related variants and other genetic determinants of risk remain largely unidentified. Cigarette smoking is protective for sarcoidosis, but protection differs greatly among those with similar smoking histories. The central hypothesis of this proposal is that genetic variants in the major histocompatibility complex (MHC) play a primary role in the initiation of sarcoidosis by modulating antigen stimulation and that these variants, in addition to others, drive the initiation and perpetuation of granulomatous inflammation and ultimately disease severity. This project will identify genetic variants associated with lung- involved sarcoidosis by comparing cases with sarcoidosis to controls using both targeted examination of the MHC and agnostic screening of the genome via the HumanOmni2.5 BeadChip. To do so, this project will examine the most powerful discovery sample studied to date, prioritize variants based on expression findings from other projects and replicate our findings in independent samples. This project will also characterize the potential etiologic roles of reproducibly associated sarcoidosis risk variants by examining important smoking exposure and disease severity subgroups to determine whether disease risk depends on smoking history and/or whether these variants are associated with severity of lung involvement. The results of this study should provide important genes or regions for follow-up fine-mapping and functional studies that should ultimately provide better prevention and treatment targets for development.