Genetic Analysis of Airflow Obstruction After Stem Cell Transplantation

干细胞移植后气流阻塞的遗传分析

基本信息

批准号：
7619610
负责人：
JASON W CHIEN
金额：
$ 44万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7619610
关键词：
Affect Allogenic Asthma Biological Markers Bone Marrow Transplantation Bronchiolitis Obliterans Cell Transplants Cessation of life Chest Chronic Obstructive Airway Disease Clinical Clinical Data Clinical Research Complement Complex Complication DNA Data Development Devices Disease Electronics Epidemiologic Studies Evaluation Future Genes Genetic Genetic Markers Genetic Variation Goals Hematopoietic Image Immunity Inflammatory Long-Term Survivors Lung Matrix Metalloproteinases Measurement Metalloproteinase Gene Modeling Monitor Natural Immunity Nature Obstruction Pathogenesis Pathway interactions Patients Phase II Clinical Trials Phenotype Population Protocols documentation Quality of life Respiratory physiology Retrospective Studies Risk Specimen Stem cell transplant Symptoms Syndrome Transplantation Validation Work base chemokine clinical phenotype cohort diaries genetic analysis genetic association genetic variant graft vs host disease human leukocyte antigen gene insight new therapeutic target prospective public health relevance pulmonary function

项目摘要

DESCRIPTION (provided by applicant): Severe airflow obstruction (AFO) was first recognized in the early 1980s as a serious and often fatal complication of bone marrow transplantation. Known as bronchiolitis obliterans syndrome in its severest form, this syndrome is now estimated to affect up to 26% of patients who receive an allogeneic hematopoietic cell transplant (HCT), representing the most common pulmonary complication among long-term survivors. While epidemiologic studies suggest HCT-related AFO is a form of graft versus host disease (GVHD) in the lung resulting from alloreactivity, these same studies have also indicated the risk attributable to GVHD is less than anticipated, suggesting other variables likely influence the risk of developing HCT-related AFO. Preliminary genetic studies that we have conducted indicate that genetic variation in the innate immunity pathway significantly influences the risk of developing this complication. However, given the complex nature of this phenotype, it is likely there are many other pathways involved in the pathogenesis of HCT-related AFO. We hypothesize that genetic variants in key biologic pathways involved in the development of HCT-related AFO significantly influences the risk for developing this syndrome. The primary goal of this proposal is to identify these genetic variants and document their clinical utility as biomarkers in the management of patients at risk for developing HCT-related AFO. In Specific Aim 1, using a discovery and validation cohort, we will conduct a tagSNP based genetic association study to systematically screen innate immunity, adaptive immunity, chemokine, remodeling, and matrix metalloproteinase genes to identify a panel of genetic variants that are most informative for predicting the risk of developing HCT-related AFO. In Specific Aim 2, we will implement a patient directed protocol for monitoring lung function in a prospective cohort to characterize in detail the HCT-related AFO clinical phenotype. This protocol will prospectively characterize the clinical profile HCT-related AFO and provide a prospective validation cohort that will overcome the limitations of retrospective studies. Finally, we will use the genetic data from Aim 1 to identify a highly informative panel of genetic markers that will be predictive of this well-characterized phenotype. These genetic markers will also be combined with pretransplant clinical predictors of AFO to develop a predictor model that can identify patients at risk for developing HCT-related AFO accurately. These studies will result in genetic biomarkers useful for identifying populations for future phase II clinical trials, provide new insights into the disease pathobiology, and serve as novel therapeutic targets. These findings will also be applicable to other airways diseases such as asthma, COPD, and bronchiolitis obliterans after lung transplant. PUBLIC HEALTH RELEVANCE: The primary goal of this proposal is to identify these genetic variants and document their clinical utility as biomarkers in the management of patients at risk for developing HCT related AFO. We hypothesize that genetic variants in key biologic pathways involved in the development of airways diseases likely influence the risk of developing HCT-related AFO and when identified, will reveal key biologic mechanisms by which this syndrome occurs.

描述（由申请人提供）：严重气流阻塞 (AFO) 在 20 世纪 80 年代初首次被认为是骨髓移植的严重且往往致命的并发症。这种综合征被称为最严重的闭塞性细支气管炎综合征，目前估计会影响高达 26% 接受同种异体造血细胞移植 (HCT) 的患者，是长期幸存者中最常见的肺部并发症。虽然流行病学研究表明 HCT 相关的 AFO 是一种由同种异体反应引起的肺部移植物抗宿主病 (GVHD)，但这些研究也表明 GVHD 的风险低于预期，这表明其他变量可能会影响 AFO 的风险。开发与 HCT 相关的 AFO。我们进行的初步遗传学研究表明，先天免疫途径的遗传变异显着影响发生这种并发症的风险。然而，鉴于这种表型的复杂性，HCT 相关 AFO 的发病机制可能涉及许多其他途径。我们假设，参与 HCT 相关 AFO 发生的关键生物途径中的遗传变异显着影响发生该综合征的风险。该提案的主要目标是识别这些遗传变异，并记录它们作为生物标志物在管理有发生 HCT 相关 AFO 风险的患者中的临床效用。在具体目标 1 中，我们将使用发现和验证队列进行基于 tagSNP 的遗传关联研究，系统地筛选先天免疫、适应性免疫、趋化因子、重塑和基质金属蛋白酶基因，以确定一组最能提供信息的遗传变异。预测发生 HCT 相关 AFO 的风险。在具体目标 2 中，我们将实施一项针对患者的方案，用于监测前瞻性队列中的肺功能，以详细描述 HCT 相关的 AFO 临床表型。该方案将前瞻性地描述 HCT 相关 AFO 的临床特征，并提供前瞻性验证队列，以克服回顾性研究的局限性。最后，我们将使用目标 1 的遗传数据来识别一组信息丰富的遗传标记，这些标记将预测这种明确表征的表型。这些遗传标记还将与 AFO 移植前临床预测因子相结合，开发一个预测模型，可以准确识别有发生 HCT 相关 AFO 风险的患者。这些研究将产生可用于识别未来二期临床试验人群的遗传生物标志物，为疾病病理学提供新的见解，并作为新的治疗靶点。这些发现也适用于其他气道疾病，如肺移植后的哮喘、慢性阻塞性肺病和闭塞性细支气管炎。公共卫生相关性：该提案的主要目标是识别这些遗传变异并记录其作为生物标志物在管理有发生 HCT 相关 AFO 风险的患者中的临床效用。我们假设，参与气道疾病发展的关键生物途径中的遗传变异可能会影响发生 HCT 相关 AFO 的风险，并且一旦确定，将揭示发生这种综合征的关键生物学机制。