GWAS in Fibrosing Interstitial Lung Disease

纤维化间质性肺疾病中的 GWAS

• 批准号: 8119630
• 负责人: David Albert Schwartz
• 金额: $ 164.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119630
• 关键词: Address; Age of Onset; Asbestos; Asbestosis; Biological; Chromosomes, Human, Pair 10; Chronic; Cigarette Smoker; Clinical; Complex; Databases; Development; Diagnosis; Disease; Dust; Early Diagnosis; Environment; Environmental Exposure; Ethnic group; Exposure to; Family; Family history of; Family member; Fibrosis; First Degree Relative; Future; Gender; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genotype; Hamman-Rich syndrome; Haplotypes; Health; Hereditary Disease; Heterogeneity; Histology; Iceland; Individual; Inflammatory; Interferons; Interstitial Lung Diseases; Interstitial Pneumonia; Korea; Lead; Length; Link; Lung; MUC5AC gene; Maps; Metal exposure; Molds; Mutation; Occupational Exposure; Outcome; Patients; Population Study; Predisposition; Pulmonary Surfactant-Associated Protein C; Race; Recording of previous events; Reporting; Research; Respiratory Failure; Structure of parenchyma of lung; Study Subject; Testing; Therapeutic; United Kingdom; Variant; Wood material; base; cigarette smoking; cigarette smoking; cohort; disorder risk; follower of religion Jewish; gene discovery; genetic variant; genome wide association study; genome-wide; male; public health relevance; response; telomere

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.

描述（由申请人提供）：该提案的目的是发现对纤维化间质性肺疾病（fILD）发展至关重要的遗传变异。由于遗传变异和环境都会增加 fILD 疾病发展的风险，因此我们在研究这组复杂疾病的遗传学时考虑环境暴露，力求全面识别与 fILD 相关的遗传变异。本提案中包含的 fILD 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 fILD 相关的遗传变异，同时涵盖一系列赋予 fILD 易感性的基因并且越来越有可能受到环境暴露的影响。 fILD 的遗传基础证据充足。 fILD 与多效遗传性疾病有关，至少 3% 的 IIP 病例的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（定义为一个家庭中有 2 例 IIP 病例）和特发性肺纤维化 (IPF)（最常见的 IIP 形式）的发生有关。两个 FIP 家族已被证明在表面活性剂蛋白 C 中存在与疾病相关的突变。我们对 82 个 FIP 家族进行了连锁研究，并确定了 10、11 和 12 号染色体上的连锁区域。此外，我们发现了共同点MUC5AC（chr11 位置候选）中的变体与 FIP 和 IPF 相关。大约 40% 的 FIP 家庭成员之间的 IIP 类型不一致，这表明 IIP 可能是由常见基因变异引起的，这些基因变异因环境暴露而发生表型改变。事实上，FIP 和 IPF 可能受到环境暴露的影响，更常见于男性（可能是由于职业暴露）和吸烟者。 IPF 还与接触金属或木屑有关。职业接触石棉可导致 fILD，其与 IPF（普通间质性肺炎，UIP）的组织学无法区分。我们发现，在 FIP 患者中，chr11 LOD 评分受吸烟的影响很大。因此，我们假设 fILD 是由多种遗传变异引起的，这些变异独立作用或与环境暴露结合作用，并且相同的遗传变异可以导致不同形式的 fILD。我们计划通过对家族性和散发性 IIP 和石棉肺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 fILD 的遗传原因。此外，我们将检查这些 fILD 遗传变异对其他种族群体和 FIP 个体家庭的普遍性。这些方法将识别肺纤维化常见的遗传变异，以及石棉接触和/或香烟烟雾所特有的遗传变异。 公共卫生相关性：特发性间质性肺炎 (IIP) 是一种广泛的慢性纤维化肺部疾病，可导致无法治疗的呼吸衰竭。虽然在了解这些疾病的临床、放射学和病理学表现方面已经取得了实质性进展，但临床医生仍然很难预测 IIP 亚型的临床过程或对治疗的反应，特别是在患有相同疾病的个体之间。诊断。该提案的目的是发现对纤维化间质性肺疾病（fILD）发展至关重要的基因和基因变异；一旦确定这些 FILD 的遗传风险，就可以在未来的研究中进行测试，以加强早期检测、预测结果并制定个性化治疗策略。