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.
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.
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