Identification of candidate genes in scleroderma-related pulmonary arterial hypertension.
Dmitry N Grigoryev, Stephen C Mathai, Micah R Fisher, Reda E Girgis, Ari L Zaiman, Traci Housten-Harris, Christopher Cheadle, Li Gao, Laura K Hummers, Hunter C Champion, Joe G N Garcia, Fredrick M Wigley, Rubin M Tuder, Kathleen C Barnes, Paul M Hassoun
Author Information
Dmitry N Grigoryev: Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD 21224, USA.
We hypothesize that pulmonary arterial hypertension (PAH)-associated genes identified by expression profiling of peripheral blood mononuclear cells (PBMCs) from patients with idiopathic pulmonary arterial hypertension (IPAH) can also be identified in PBMCs from sclerodermapatients with PAH (PAH-SSc). Gene expression profiles of PBMCs collected from IPAH (n = 9), PAH-SSc (n = 10) patients, and healthy controls (n = 5) were generated using HG_U133A_2.0 GeneChips and were processed by the RMA/GCOS_1.4/SAM_1.21 data analysis pipeline. Disease severity in consecutive patients was assessed by functional status and hemodynamic measurements. The expression profiles were analyzed using PAH severity-stratification, and identified candidate genes were validated with real-time polymerase chain reaction (PCR). Transcriptomics of PBMCs from IPAHpatients was highly comparable with that of PMBCs from PAH-SScpatients. The PBMC gene expression patterns significantly correlate with right atrium pressure (RA) and cardiac index (CI), which are known predictors of survival in PAH. Array stratification by RA and CI identified 364 PAH-associated candidate genes. Gene ontology (GO) analysis revealed significant (Z(score) > 1.96) alterations in angiogenesis genes according to PAH severity: matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor (VEGF) were significantly upregulated in mild as compared with severe PAH and healthy controls, as confirmed by real-time PCR. These data demonstrate that PBMCs from patients with PAH-SSc carry distinct transcriptional expression. Furthermore, our findings suggest an association between angiogenesis-related gene expression and severity of PAH in PAH-SScpatients. Deciphering the role of genes involved in vascular remodeling and PAH development may reveal new treatment targets for this devastating disorder.
