Conference: 2012 International PHA Conference and Scientific Sessions
Release Date: 06.22.2012
Presentation Type: Abstracts
BACKGROUND: Approximately 6-10% of PAH cases have a positive family history, inherited as an autosomal dominant trait. The primary gene underlying heritable forms of PAH is the bone morphogenetic protein receptor 2 (BMPR2), with several other genes in the same pathway also implicated in a smaller number of families. One the central questions that remains unanswered is why only about 20% of individuals who inherit a predisposing mutation actually go on develop PAH.
Little is known about the factors that influence this reduced gene penetrance. Previous studies have demonstrated elevated levels of bone marrow-derived circulating CD34+/CD133+ proangiogenic progenitor cells in PAH and myeloid abnormalities in the bone marrow of the both PAH patients and unaffected gene carriers. In this study, we performed expression array analysis of circulating CD34+/CD133+ progenitors to determine whether gene expression profiles of cells from unaffected mutation carriers could be used as a marker of early disease.
METHODS: Circulating CD34+/CD133+ progenitor cells were isolated from peripheral blood samples of 8 patients and 3 unaffected gene carriers from 3 PAH families, together with 11 controls. Cells were cultured for 7 days, then harvested for RNA extraction and analyzed on Illumina gene expression arrays. Data were analyzed using Genespring software.
RESULTS: A total of 102 genes showed three-fold or greater difference between PAH patients and controls, including apolipoproteins C and E, von Willebrand factor and matrix metallopeptidase 7. Cluster analysis of both the entire gene set and the subset of 102 differentially expressed genes showed that unaffected mutation carriers clustered much more closely with PAH patients than controls.
CONCLUSIONS: While the possibility of some clustering on the basis of family relatedness independent of PAH cannot be excluded, our data suggest that the expression profile of circulating CD34+/CD133+ progenitor cells from unaffected carriers closely resemble those of PAH patients. Altered expression profiles may therefore be determined by the primary genetic mutation and pre-date development of the disease. A subset of genes showed intermediate expression in carriers as compared with controls or affected patients and will be followed up in larger group to determine whether they may be useful markers of disease susceptibility.
FUNDING: AHA Scientist Development Grant #0835146N.