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遗传变异型，这些变异对于开发间隙肺部疾病（FILD）至关重要。由于遗传变异和环境都增加了fild疾病发展的风险，因此我们试图通过考虑环境暴露在研究这一组复杂疾病的遗传学的同时，全面地识别与FILD相关的遗传变异。该提案中包括的FILD研究人群（家族性间质肺炎（FIP），零星特发性间质性肺炎（IIP）和石棉病）将使我们能够发现与FILD相关的遗传变异，同时跨越了fild，而跨越可能会跨越了幻想和幻想的频谱。遗传基础的证据是大量的。 FILD与多效性遗传疾病有关，至少3％的IIP病例具有类似疾病的一级亲戚。据报道，维持端粒长度（TERT和TERC）的基因的罕见突变与FIP的发展（定义为一个家族中的IIP）和特发性肺纤维化（IPF）有关，这是IIP的最常见形式。已经证明了两个具有疾病相关的FIP家族在表面活性剂蛋白中与疾病相关的突变。我们在82个FIP家族中进行了一项连锁研究，并确定了染色体10、11和12的链接区域。此外，我们发现MUC5AC（CHR11位置候选）在MUC5AC（CHR11候选）中发现了与FIP和IPF相关的共同变化。大约40％的FIP家族在家庭成员中具有不一致的IIP类型，这表明IIP可能是由常见的基因变异引起的，这些变体是由环境暴露在表型上改变的。实际上，FIP和IPF可能会受到环境暴露的影响，在男性中（可能是由于职业暴露）和吸烟者中发生的频率更高。 IPF还与接触金属或木质灰尘有关。职业接触石棉会导致与IPF（通常的间质肺炎，UIP）的组织学没有区别的FILD。我们发现，在有FIP的患者中，CHR11 LOD评分受吸烟的强烈影响。因此，我们假设FILD是由多种遗传变异引起的，独立起作用或与环境暴露结合起来，并且相同的遗传变异可以导致不同形式的FILD。我们计划通过在家族和零星IIP和石棉病中进行全基因组的关联研究来确定FILD的遗传原因，并确定与这些疾病相关的遗传变异。此外，我们将研究这些FILD遗传变异对其他种族和FIP个体家庭的普遍性。这些方法将鉴定肺纤维化常见的遗传变异，以及石棉暴露和/或香烟烟雾更独特的遗传变异。 公共卫生相关性：特发性间质性肺炎（IIP）代表了各种各样的慢性纤维肺部疾病，可能导致无法治疗的呼吸衰竭。尽管在理解这些疾病的临床，放射学和病理表现方面取得了重大进展，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，尤其是从具有相同诊断的个体的个体。该提案的目的是发现基因和基因变异体，这些变体是触觉间质肺疾病（FILD）发展的核心；一旦确定了这些fild的遗传风险，可以在以后的研究中测试以增强早期检测，预测结果并塑造个性化的治疗策略。