Abstract 10132: Integration of microRNA Expression Profiling and a Validated Gene Signature from Peripheral Blood Mononuclear Cells in Pulmonary Hypertension Associated with Sickle Cell Disease
Background: Pulmonary hypertension (PH) is a serious complication of sickle cell disease (SCD) associated with increased mortality. Gene expression profiles of peripheral blood mononuclear cells (PBMC) have been reported in pulmonary arterial hypertension and in SCD. We hypothesized that a gene expression signature from PBMC in patients with SCD may be utilized as a PH biomarker.
Methods & Results: 30 patients with homozygous SCD prospectively underwent transthoracic echocardiography and phlebotomy for PBMC isolation. PH was defined as estimated right ventricular systolic pressure (RVSP)>30 mmHg with a peak tricuspid regurgitation velocity (TRV)>2.5m/s. Genome-wide gene expression profiles were compared between SCD cases with PH (n=18) and without PH (n=9) and correlated against PH severity using RVSP (correlation coefficient ρR) and TRV (ρT) as surrogates. Only genes with ρR^2 and ρT^2 >0.15 were considered differentially expressed for PH yielding 631 transcripts. A support vector machine analysis was then applied identifying a 10 gene signature which discriminated patients with and without echo-defined PH in the discovery cohort with 100% accuracy. The 10 gene signature was validated in an independent cohort of SCD patients with PH confirmed by right heart catheterization (n=13) and without PH (n=16) with 90% accuracy. To further identify significant pathways involved in PH in SCD, we correlated miRNA expression profiling in the discovery cohort against PH severity (ρR^2 or ρT^2 >0.15 considered differentially expressed) yielding 12 unique miRNAs. In silico analyses of the top PH miRNAs revealed strong binding predictions for miR-301a to polypeptide N-acetylgalactosaminyltransferase 13 (GALNT13), a PH signature gene, which was further validated by microarray data confirming correlation between miR-301a expression and GALNT13 in SCD-related PH.
Conclusion: These expression data may have implications as a biomarker to screen an at-risk population in SCD for early PH diagnosis. Given the robust integration of miRNA and gene expression data yielding GALNT13, a glycosyltransferase enzyme involved in O-glycan synthesis, as a top candidate gene, we speculate that GALNT13 and glyocosylation patterns may play a novel role in SCD-related PH.
- © 2011 by American Heart Association, Inc.