Role of Genetics in Idiopathic Pulmonary Fibrosis (IPF)

 描述(由申请人提供)：这项建议的总体目标是全面识别参与特发性肺纤维化(IPF)发展的特定序列变异，探索这些关键的IPF序列变异如何对这种疾病的病因学、生物学和临床表型做出贡献，然后检查这些遗传风险变异对其他种族群体的普适性。我们选择关注IPF在竞争中的更新，因为IPF是最常见和最严重的纤维化性特发性间质性肺炎(FIIP)，是一种明确的表型(1-3)，与 MUC5B启动子变异不同于其他形式的fIIP(表1)(4，5)，占本组病例的81%(6)，并与24个fIIP基因座中的16个相关(表1)。推动这项研究的总体概念是，虽然我们的GWA基因座可以用来定义疾病的风险，但需要识别16个高优先级PF基因座中的特定变异(S)和基因(S)，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。我们从R01的初始周期中发现，IPF是由一些风险基因中罕见的、不常见的和常见的变异引起的，这些变异单独和/或与吸烟或不吸烟协同作用，影响发生家族性和散发性的IPF的风险，IPF的遗传学可能帮助我们更早地识别疾病，了解这种疾病的生物学和临床异质性。基于这些发现，我们推测，吸烟或不吸烟导致IPF独特的病原学、生物学和临床表型的是特定的基因变异和基因变异x基因变异的相互作用。在目标1中，我们将在1500例特发性肺纤维化(200例家族性和1300例散发性)和1500例对照中对这些靶区(16个基因座；6.17Mb DNA)进行测序；从而识别可能与特发性肺纤维化相关的广泛的序列变异。在目标2中，我们将在散发性IPF患者(200个家族性和1300个散发性)和未受影响的对照组(N=1500)的独立人群中验证这些新的序列变异。目标3的目的是了解AIMS 1和2中确定的特定遗传变异如何与MUC5B变异相互作用，然后探索MUC5B x基因变异、基因x和吸烟的相互作用，以及遗传变异和相互作用与IPF独特的生物学和临床表现的关系。在目标4中，我们计划检查遗传风险变异对其他种族群体的普适性。

 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.