Identification of candidate genes in scleroderma-related pulmonary arterial hypertension

Dmitry N. Grigoryev, Stephen Mathai, Micah R. Fisher, Reda E. Girgis, Ari L. Zaiman, Traci Housten-Harris, Christopher Cheadle, Li Gao, Laura Hummers, Hunter C. Champion, Joe G N Garcia, Fredrick Wigley, Rubin M. Tuder, Kathleen C. Barnes, Paul M Hassoun

Research output: Contribution to journalArticle

Abstract

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 scleroderma patients 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 IPAH patients was highly comparable with that of PMBCs from PAH-SSc patients. 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 (Zscore > 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-SSc patients. Deciphering the role of genes involved in vascular remodeling and PAH development may reveal new treatment targets for this devastating disorder.

Original languageEnglish (US)
Pages (from-to)197-207
Number of pages11
JournalTranslational Research
Volume151
Issue number4
DOIs
StatePublished - Apr 2008

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Genetic Association Studies
Pulmonary Hypertension
Blood
Genes
Gene expression
Polymerase chain reaction
Blood Cells
Matrix Metalloproteinase 9
Hemodynamics
Vascular Endothelial Growth Factor A
Ontology
Heart Atria
Pipelines
Real-Time Polymerase Chain Reaction
Gene Expression
Pressure
Gene Ontology
Gene Expression Profiling
Transcriptome

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, medical
  • Public Health, Environmental and Occupational Health

Cite this

Identification of candidate genes in scleroderma-related pulmonary arterial hypertension. / Grigoryev, Dmitry N.; Mathai, Stephen; Fisher, Micah R.; Girgis, Reda E.; Zaiman, Ari L.; Housten-Harris, Traci; Cheadle, Christopher; Gao, Li; Hummers, Laura; Champion, Hunter C.; Garcia, Joe G N; Wigley, Fredrick; Tuder, Rubin M.; Barnes, Kathleen C.; Hassoun, Paul M.

In: Translational Research, Vol. 151, No. 4, 04.2008, p. 197-207.

Research output: Contribution to journalArticle

Grigoryev, DN, Mathai, S, Fisher, MR, Girgis, RE, Zaiman, AL, Housten-Harris, T, Cheadle, C, Gao, L, Hummers, L, Champion, HC, Garcia, JGN, Wigley, F, Tuder, RM, Barnes, KC & Hassoun, PM 2008, 'Identification of candidate genes in scleroderma-related pulmonary arterial hypertension', Translational Research, vol. 151, no. 4, pp. 197-207. https://doi.org/10.1016/j.trsl.2007.12.010
Grigoryev, Dmitry N. ; Mathai, Stephen ; Fisher, Micah R. ; Girgis, Reda E. ; Zaiman, Ari L. ; Housten-Harris, Traci ; Cheadle, Christopher ; Gao, Li ; Hummers, Laura ; Champion, Hunter C. ; Garcia, Joe G N ; Wigley, Fredrick ; Tuder, Rubin M. ; Barnes, Kathleen C. ; Hassoun, Paul M. / Identification of candidate genes in scleroderma-related pulmonary arterial hypertension. In: Translational Research. 2008 ; Vol. 151, No. 4. pp. 197-207.
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AU - Cheadle, Christopher

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AU - Hummers, Laura

AU - Champion, Hunter C.

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