Role of Genetics in Idiopathic Pulmonary Fibrosis (IPF)

遗传学在特发性肺纤维化 (IPF) 中的作用

• 批准号: 9041651
• 负责人: Tasha E. Fingerlin
• 金额: $ 211.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-03 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041651
• 关键词: 13q34; 15q14; 15q25; 19p13; 3q23; 3q26; 4q22; 6p21; 6p24; 6q21; Accounting; Age; Age of Onset; Alleles; Asians; Automobile Driving; Biological; Biological Markers; Biology; Clinical; Complex; DNA; Data; Development; Diagnosis; Disease; Dyspnea; Early Diagnosis; Environment; Ethnic group; Family history of; Fibrosis; Future; Gene Expression; Genes; Genetic; Genetic Epistasis; Genetic Risk; Goals; Hamman-Rich syndrome; Health; Hereditary Disease; Hispanics; Individual; Intervention Studies; Knowledge; Lead; Length; MUC5B gene; Odds Ratio; Outcome; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenotype; Play; Prevention; Reporting; Research; Risk; Risk Factors; Role; Scanning; Smoking; Structure of parenchyma of lung; Symptoms; Testing; Variant; base; cigarette smoking; clinical phenotype; deep sequencing; design; disease heterogeneity; disorder risk; gene function; genetic variant; genome wide association study; novel; outcome forecast; patient population; personalized therapeutic; promoter; protein expression; risk variant; study population

 DESCRIPTION (provided by applicant): The overall goals of this proposal are to comprehensively identify the specific sequence variants involved in the development of idiopathic pulmonary fibrosis (IPF), to explore how these key IPF sequence variants contribute to the etiologic, biologic, and clinical phenotypes of this disease, and then examine the generalizability of these genetic risk variants to other ethnic groups. We chose to focus on IPF in the competitive renewal since IPF is the most common and severe fibrosing idiopathic interstitial pneumonia (fIIP), is a well-defined phenotype (1- 3), is more strongly associated with the MUC5B promoter variant than other forms of fIIP (Table 1) (4, 5), composed 81% of the cases in our GWAS (6), and is associated with 16 of the 24 fIIP GWAS loci (Table 1). The overall concept driving the proposed research is that while our GWAS loci can be used to define risk of disease, identification of the specific variant(s) and gene(s) within the 16 high priority PF loci is needed to make progress on understanding disease pathogenesis (7, 8), prognosis (9-25), treatment (26-29), and survival (30), all of which remain major problems in understanding and treating patients with IPF. The findings from the initial cycle of our R01 lead us to conclude that IPF is caused by rare, uncommon, and common variants in a number of risk genes that function alone and/or in concert with or without cigarette smoking to influence the risk of developing both familial and sporadic forms of IPF and that the genetics of IPF may help us identify disease earlier and understand the biological and clinical heterogeneity of this disease. Based on these findings, we hypothesize that specific gene variants and gene variant x gene variant interactions with or without cigarette smoking result in unique etiologic, biologic, and clinical phenotypes of IPF. In Aim 1, we will sequence these targeted regions (16 loci; 6.17 Mb DNA) in 1500 cases of IPF (200 familial and 1300 sporadic) and 1500 controls; thus identifying a broad range of sequence variants potentially associated with IPF. In Aim 2, we will validate these novel sequence variants in independent populations of patients with sporadic IPF (200 familial and 1300 sporadic) and unaffected controls (N=1500). The goal of Aim 3 is to understand how the specific genetic variants identified in Aims 1 and 2 interact with the MUC5B variant, and then explore MUC5B x gene variant, gene x gene, and gene x smoking interactions, and the relationship of genetic variants and interactions to unique biological and clinical manifestations of IPF. In Aim 4, we plan to examine the generalizability of the genetic risk variants to other ethnic groups.

 描述（由申请方提供）：本提案的总体目标是全面鉴定参与特发性肺纤维化（IPF）发展的特定序列变体，探索这些关键IPF序列变体如何促成该疾病的病因学、生物学和临床表型，然后检查这些遗传风险变体对其他种族群体的可推广性。我们选择在竞争性更新中关注IPF，因为IPF是最常见和最严重的纤维化特发性间质性肺炎（fIIP），是一种明确定义的表型（1- 3），与以下疾病更密切相关： MUC 5 B启动子变体比其他形式的fIIP（表1）（4，5），在我们的GWAS中占81%的病例（6），并且与24个fIIP GWAS基因座中的16个相关（表1）。推动拟议研究的总体概念是，虽然我们的GWAS基因座可用于定义疾病风险，但需要鉴定16个高优先级PF基因座内的特定变体和基因，以在理解疾病发病机制（7，8），预后（9-25），治疗（26-29）和生存（30）方面取得进展。所有这些仍然是理解和治疗IPF患者的主要问题。R 01初始周期的结果使我们得出结论，IPF是由罕见的、不常见的，和一些风险基因的常见变异，这些基因单独发挥作用，或与吸烟或不吸烟相关，以影响家族性和散发性IPF的发生风险，IPF的遗传学可能有助于我们更早地识别疾病并了解其生物学和临床异质性。疾病基于这些发现，我们假设特定基因变异和基因变异x基因变异相互作用（伴或不伴吸烟）导致IPF独特的病因学、生物学和临床表型。在目标1中，我们将对1500例IPF病例（200例家族性和1300例散发性）和1500例对照中的这些靶向区域（16个基因座; 6.17 Mb DNA）进行测序;从而鉴定出可能与IPF相关的广泛序列变异。在目标2中，我们将在散发性IPF患者（200例家族性和1300例散发性）和未受影响的对照（N=1500）的独立人群中验证这些新型序列变体。目的3的目的是了解目的1和2中确定的特定遗传变异如何与MUC 5 B变异相互作用，然后探索MUC 5 B x基因变异、基因x基因和基因x吸烟相互作用，以及遗传变异和相互作用与IPF独特生物学和临床表现的关系。在目标4中，我们计划研究遗传风险变异对其他种族群体的普遍性。