Pathways analysis of molecular markers in chronic sinusitis with polyps

Abstract

Objective: To perform a comprehensive molecular pathways analysis of genes identified through genome-wide expression profiling and the published literature for chronic sinusitis with polyps.

Study design: Molecular pathways analysis.

Setting: Academic medical center.

Methods: A molecular pathways analysis of gene biomarkers discovered through hypothesis-driven and high-throughput molecular studies was performed. Genes identified with a PubMed literature search were analyzed with Ingenuity Pathways Analysis software to identify central molecules implicated in the pathogenesis of chronic sinusitis with polyps. The central pathways were then compared with those identified through genome-wide expression profiling of ethmoid polyps.

Results: A total of 97 molecules were investigated with Ingenuity Pathways Analysis based on 55 studies that evaluated differences in gene expression (39), genetic variation (12), or proteomics (4). The analysis revealed 9 statistically significant molecular networks containing central nodes that included transcription factors, protein kinases, cytokines, and growth factors/receptors. The highest scoring networks implicated nuclear factor kappa-B, tumor necrosis factor, and mitogen-activated protein kinases. The majority of pathways in the literature review analysis overlapped with those identified through a single genome-wide expression study.

Conclusions: Chronic sinusitis with polyps is a complex disease with suspected contribution of multiple genetic and environmental factors. The search for causative genes has led to the discovery of numerous candidates. Pathways analysis applied to these candidate genes identified common central molecules that are likely to be key mediators of the disease process. Novel therapies targeting these molecules may be applicable for the treatment of chronic sinusitis with polyps.

Figure 1

The highest ranked biologic functions of molecular markers identified through (A) literature review pathways analysis and (B) genome-wide expression pathways analysis. Threshold of significance: P < .05.

Figure 2

Network 1 of pathway analysis generated from literature review. Tumor necrosis factor (TNF) was the central, nodal molecule of the highest scoring network (P = 1 × 10^{^–41}). Shaded molecules were specifically identified by literature review and input into the pathways analysis. See Appendix B at otojournal.org for complete list of gene abbreviations.

Figure 3

Network 1 of pathway analysis generated from genome-wide expression pathway analysis. Nuclear factor kappa B (NFκB) was the central, nodal molecule of the highest scoring network (P = 1 × 10^{^–41}). Shaded molecules were differentially expressed in the genome-wide data set and input into the pathways analysis. See Appendix B at otojournal.org for complete list of gene abbreviations.

Figure 4

Location and function of nodal genes found in both literature review and genome-wide expression pathways analyses. See Appendix B at otojournal.org for complete list of gene abbreviations.