GWAS in Fibrosing Interstitial Lung Disease

描述（由申请人提供）：本提案的目的是发现对纤维化间质性肺疾病（field）发展至关重要的遗传变异。由于遗传变异和环境都增加了field疾病发展的风险，我们试图在研究这组复杂疾病的遗传学时，通过考虑环境暴露来全面确定与field相关的遗传变异。本提案中包含的field研究人群（家族性间质性肺炎（FIP），散发性特发性间质性肺炎（IIP）和石棉肺）将使我们能够发现与field相关的遗传变异，同时跨越赋予field易感性的基因谱，并且越来越可能受到环境暴露的影响。field的遗传基础的证据是充分的。field与多效性遗传疾病有关，至少3%的IIP病例有一级亲属患有类似疾病。据报道，维持端粒长度的基因（TERT和TERC）的罕见突变与FIP（定义为一个家族中有2例IIP）和特发性肺纤维化（IPF）的发展有关，IPF是IIP最常见的形式。我们对82个FIP家族进行了连锁研究，并在染色体10、11和12上发现了连锁区域。此外，我们还发现MUC5AC （chr11位置候选基因）的常见变异与FIP和IPF相关。大约40%的FIP家庭成员的IIP类型不一致，这表明IIP可能是由环境暴露改变表型的常见基因变异引起的。事实上，FIP和IPF可受到环境暴露的影响，在男性（可能是由于职业暴露）和吸烟者中更常发生。IPF还与接触金属或木材粉尘有关。职业性暴露于石棉可引起与IPF（通常的间质性肺炎，UIP）难以区分的field。我们发现在FIP患者中，chr11 LOD评分受吸烟的强烈影响。因此，我们假设磁场是由多种遗传变异引起的，这些遗传变异可以单独作用，也可以与环境暴露联合作用，并且相同的遗传变异可以导致不同形式的磁场。我们计划通过对家族性和散发性IIP和石棉沉滞进行全基因组关联研究，并确定与这些疾病相关的遗传变异，来确定fields的遗传原因。此外，我们将研究这些field遗传变异在其他种族群体和FIP个体家庭中的普遍性。这些方法将识别肺纤维化常见的遗传变异，以及石棉暴露和/或吸烟所特有的遗传变异。

DESCRIPTION (provided by applicant): The purpose of this proposal is to discover genetic variants that are central to the development of fibrosing interstitial lung diseases (fILD). Since both genetic variants and the environment increase the risk of disease development in fILD, we seek to comprehensively identify genetic variants associated with fILD by considering environmental exposures while studying the genetics of this group of complex diseases. The fILD study populations included in this proposal (familial interstitial pneumonia (FIP), sporadic idiopathic interstitial pneumonia (IIP), and asbestosis) will enable us to discover genetic variants that are associated with fILD while spanning a spectrum of genes that confer susceptibility to fILD and are increasingly likely to be influenced by environmental exposures. Evidence for a genetic basis of fILD is substantial. fILD has been associated with pleiotropic genetic disorders, and at least 3% of cases of IIP have a first degree relative with a similar illness. Rare mutations in genes that maintain telomere length (TERT and TERC) have been reported to be associated with the development of FIP (defined as e 2 cases of IIP in one family) and idiopathic pulmonary fibrosis (IPF), the most common form of IIP. Two families with FIP have been shown to have disease-associated mutations in surfactant protein C. We have performed a linkage study in 82 families with FIP, and have identified linked regions on chromosomes 10, 11, and 12. Furthermore, we have found common variants in MUC5AC (chr11 positional candidate) that are associated with both FIP and IPF. Approximately 40% of families with FIP have discordant types of IIP among family members, suggesting that IIP may be caused by common gene variants that are altered phenotypically by environmental exposures. In fact, FIP and IPF can be influenced by environmental exposures, occurring more frequently in males (probably due to occupational exposures), and among cigarette smokers. IPF is also associated with exposure to metal or wood dust. Occupational exposure to asbestos can cause fILD that is indistinguishable from the histology of IPF (usual interstitial pneumonia, UIP). We have found that among patients with FIP, the chr11 LOD score is strongly influenced by cigarette smoking. Thus, we hypothesize that fILDs are caused by multiple genetic variants, acting independently or in combination with environmental exposures, and that the same genetic variants can lead to different forms of fILD. We plan to identify the genetic causes of fILDs by performing a genome-wide association study in familial and sporadic IIP and asbestosis, and determining the genetic variants associated with these diseases. In addition, we will examine the generalizability of these fILD genetic variants to other ethnic groups and in families of individuals with FIP. These approaches will identify genetic variants that are common to lung fibrosis, and genetic variants that are more unique to asbestos exposure and/or cigarette smoke. PUBLIC HEALTH RELEVANCE: Idiopathic interstitial pneumonia (IIP) represents a broad spectrum of chronic fibrosing lung conditions that can lead to untreatable respiratory failure. While substantial progress has been made in understanding the clinical, radiological, and pathological manifestations of these disorders, it remains difficult for the clinician to predict the clinical course or the response to therapy for the subtypes of IIP, particularly from individual to individual with the same diagnosis. The purpose of this proposal is to discover genes and gene variants that are central to the development of fibrosing interstitial lung diseases (fILD); once established these genetic risks for fILD could be tested in future studies to enhance early detection, to predict outcome, and to mould personalized therapeutic strategies.