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Microarray Analysis of Peripheral Blood Cells in Pulmonary Arterial Hypertension, Surrogate to Biopsy* FREE TO VIEW

Todd M. Bull, MD; Chris D. Coldren; Patrick Nana-Sinkam, MD; Sylk M. Sotto-Santiago; Mark Moore, BA; Norbert F. Voelkel, MD; Mark W. Geraci, MD
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*From the Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Todd M. Bull, MD, Pulmonary Sciences, University of Colorado, 8200 E 9th Ave, Denver, CO 80262; e-mail: todd.bull@uchsc.edu

Chest. 2005;128(6_suppl):584S. doi:10.1378/chest.128.6_suppl.584S
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Pulmonary arterial hypertension (PAH) is associated with a diverse array of diseases that result in similar histologic and clinical phenotypes. The pathogenesis of PAH is complex, and it is likely that multiple modulating genes and environmental factors are involved. Such complexity lends itself to the use of microarray technology, which allows the efficient and accurate simultaneous expression measurement of thousands of genes.

Circulating blood cells may contain disease-specific information either because of inherent genomic alterations or because of local environmental changes. Furthermore, the gene expression of immune-modulating cells may provide disease-specific information due to inflammatory and autoimmune mechanisms that are putatively involved in the pathogenesis of PAH. We hypothesized that the analysis of gene expression profiles from peripheral blood mononuclear cells would distinguish patients with PAH from healthy volunteers. We also hypothesized that a subset of these genes would distinguish patients with idiopathic PAH (IPAH) from those with PAH due to secondary causes.

We identified a 106-gene signature, which discriminated between patients with PAH and healthy control subjects with high certainty (p ≤ 0.002). We found significant differences in expression in a variety of immune-modulating genes, including those regulating the expression of major histocompatibility complex (MHC) class II molecules. Microarray analysis predicted a profound difference in the expression of specific MHC class II alleles in patients with IPAH compared to those with secondary PAH. These differences were confirmed prospectively by human leukocyte antigen typing of a second cohort of patients.

Our work represents a novel approach to the identification and classification of PAH. The ability to distinguish patients with PAH by examining peripheral blood has significant implications both for diagnosis and disease screening. Differences in gene expression may also provide insight into the pathobiology of PAH. The differences in MHC class II alleles between patients with IPAH vs those with secondary PAH have implications for an autoimmune etiology of disease as well as a potential susceptibility to infectious agents that may play role in disease development.

Abbreviations: IPAH = idiopathic pulmonary arterial hypertension; MHC = major histocompatibility complex; PAH = pulmonary arterial hypertension




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