GWAS in Fibrosing Interstitial Lung Disease

纤维化间质性肺疾病中的 GWAS

基本信息

批准号：
8508282
负责人：
David Albert Schwartz
金额：
$ 158.3万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508282
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 response telomere

项目摘要

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.

该提案的目的是发现对发育至关重要的遗传变异纤维化间质性肺疾病（fILD）。由于遗传变异和环境都会增加患病风险为了了解 fiLD 疾病的发展，我们寻求通过以下方式全面鉴定与 fiLD 相关的遗传变异：在研究这组复杂疾病的遗传学时考虑环境暴露。场本提案中包括的研究人群（家族性间质性肺炎 (FIP)、散发性特发性间质性肺炎肺炎（IIP）和石棉肺）将使我们能够发现与 fILD 相关的遗传变异，同时跨越一系列赋予 fILD 易感性的基因，并且越来越有可能受到以下因素的影响环境暴露。 fILD 的遗传基础证据充足。 fILD 与多效性遗传有关至少 3% 的 IIP 病例的一级亲属患有类似疾病。罕见突变据报道，维持端粒长度的基因（TERT 和 TERC）与 FIP（定义为一个家庭中出现 2 例 IIP）和特发性肺纤维化（IPF）是最常见的疾病 IIP 的常见形式。两个患有 FIP 的家族已被证明具有与疾病相关的突变表面活性剂蛋白 C。我们对 82 个 FIP 家族进行了连锁研究，并确定了连锁 10、11 和 12 号染色体上的区域。此外，我们还发现了 MUC5AC（chr11 职位候选人）与 FIP 和 IPF 相关。大约 40% 的 FIP 家庭患有家庭成员之间的 IIP 类型不一致，表明 IIP 可能是由常见的基因变异引起的因环境暴露而发生表型改变。事实上，FIP 和 IPF 会受到以下因素的影响：环境暴露，男性更常见（可能是由于职业暴露），以及在吸烟者中。 IPF 还与接触金属或木屑有关。职业接触石棉可导致与 IPF 组织学无法区分的 FILD（通常为间质性肺纤维化）肺炎、UIP）。我们发现，在 FIP 患者中，chr11 LOD 评分受到以下因素的强烈影响：吸烟。因此，我们假设 fILD 是由多种遗传变异引起的，独立地或与环境暴露相结合，并且相同的遗传变异可以导致不同形式的 fiLD。我们计划通过进行全基因组研究来确定 fILD 的遗传原因家族性和散发性 IIP 与石棉肺的关联研究，并确定相关的遗传变异患有这些疾病。此外，我们将检查这些 fILD 遗传变异对其他疾病的普遍性种族群体和 FIP 患者的家庭。这些方法将识别遗传变异肺纤维化常见，以及石棉接触和/或吸烟所特有的基因变异抽烟。