Pulmonary arterial hypertension (PAH) in children or adults is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Pulmonary arterial smooth muscle cell (PASMC) and endothelial (PAEC) proliferation are key components of the pulmonary hypertension pathophysiologic response. Although the number of vasodilator drugs has increased, still 20-30% of patients do not respond and non-responders have a poor prognosis eventually requiring lung transplantation. In essence, we lack simple, minimally invasive more lung/vascular specific, objective, repeatable, generalizable and less expensive measures of PAH to improve outcomes. Using a mass spectrometry based plasma discovery for proteins that are increased in PAH, have identified that the insulin like growth factors (IGFs) and it's binding proteins (IGFBPs) are altered in PAH. We now have pilot data that IGF2 is decreased and IGFBP2 increased in PAH. Both of these proteins are implicated in pulmonary function and disease. As these proteins are encoded by specific genes, it is possible that coding variation may contribute to altered levels of circulating protein. However, as these genes are part of highly regulated networks, regulatory variation (present in the non-coding regions) likely contributes to variation in circulating levels. The overall goal of this proposal is to determine if IGF family coding variants are associated with PAH clinical measures of severity and whether non-coding regions are associated with circulating levels. The proposed study in this application is to analyze the existing genomic data which is maintained in PAHBiobank National Biological Sample and Data Repository for Pulmonary Arterial Hypertension. The PAHBiobank is a NHLBI funded (HL105333) resource of biological samples, genetic data, and clinical data for the PAH research community. The cohorts from PAHBiobank were successfully used as validation cohorts in the preliminary study, and our goal is to take the advantage of the existing genetic and clinical data collected in the repository, analyze and demonstrate the clinical importance of the IGF targets in PAH etiology at the molecular level. The significance of the proposed studies is that by linking IGF and mutations to circulating levels and functional measures of disease severity and patient survival, a critical step in the function of these proteins in PAH is revealed and provides the basis for new therapeutic, diagnostic and prognostic strategies in PAH. Our overall goal will be addressed in the following specific aims:
Aim 1) Using existing whole exome sequencing data from the PAHBiobank, determine whether IGFs and IGFBPs coding genetic variants are associated with clinical severity and survival.
Aim 2) Perform genome wide association analyses leveraging ELISA analysis which is underway for the PAHBiobank serum samples and existing OMNI5 genotyping SNP chip data to Identify genetic variants associated with circulating IGFs and IGFBPs.
We propose a new study for the reanalysis of existing genomic and clinical data of patients with pulmonary arterial hypertension (PAH) enrolled in the NHLBI PAHBiobank to address the role of IGF and IGF binding proteins in mediating PAH severity and survival. Our goal is to take the advantage of the existing genetic and clinical data collected in the repository, analyze and demonstrate the clinical importance of the IGF targets in PAH etiology at the molecular level. The significance of the proposed studies is that by linking IGF and mutations to circulating levels and functional measures of disease severity and patient survival, a critical step in the function of these proteins in PAH is revealed and provides the basis for new therapeutic, diagnostic and prognostic strategies in PAH.
