Exploring the cross-phenotype network region of disease modules reveals concordant and discordant pathways between chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis

Abstract

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are two pathologically distinct chronic lung diseases that are associated with cigarette smoking. Genetic studies have identified shared loci for COPD and IPF, including several loci with opposite directions of effect. The existence of additional shared genetic loci, as well as potential shared pathobiological mechanisms between the two diseases at the molecular level, remains to be explored. Taking a network-based approach, we built disease modules for COPD and IPF using genome-wide association studies-implicated genes. The two disease modules displayed strong disease signals in an independent gene expression data set of COPD and IPF lung tissue and showed statistically significant overlap and network proximity, sharing 19 genes, including ARHGAP12 and BCHE. To uncover pathways at the intersection of COPD and IPF, we developed a metric, NetPathScore, which prioritizes the pathways of a disease by their network overlap with another disease. Applying NetPathScore to the COPD and IPF disease modules enabled the determination of concordant and discordant pathways between these diseases. Concordant pathways between COPD and IPF included extracellular matrix remodeling, Mitogen-activated protein kinase (MAPK) signaling and ALK pathways, whereas discordant pathways included advanced glycosylation end product receptor signaling and telomere maintenance and extension pathways. Overall, our findings reveal shared molecular interaction regions between COPD and IPF and shed light on the congruent and incongruent biological processes lying at the intersection of these two complex diseases.

Molecular networks in Network Medicine: Development and applications

“…Recently, a PPI network‐based approach unveiled molecular network neighborhoods for chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), with a statistically significant region of intersection and network proximity (Halu et al, 2019). The shared network region involved 19 genes, including Rho GTPase activating protein 12 ( ARHGAP12 ) and butyrylcholinesterase ( BCHE ) as key nodes.…”

“…The shared network region involved 19 genes, including Rho GTPase activating protein 12 ( ARHGAP12 ) and butyrylcholinesterase ( BCHE ) as key nodes. Thus, network‐based strategies may also offer a potent means to dissect genes and pathways shared between phenotypically distinct diseases, such as COPD and IPF, thus offering novel insights into pathobiological mechanisms (Halu et al, 2019). In earlier work, by mapping the seed genes onto the human interactome via the DIAMOnD algorithm (Ghiassian et al, 2015), an asthma‐associated network neighborhood was identified (Sharma et al, 2015).…”

Molecular Mechanisms of Alveolar Epithelial Stem Cell Senescence and Senescence-Associated Differentiation Disorders in Pulmonary Fibrosis

“…Such environmental stress cues as bleomycin [ 58 , 116 , 117 ], IR [ 105 , 118 , 119 ] or H 2 O 2 [ 102 , 120 , 121 , 122 ] have been shown to induce telomere DNA damage, resulting in telomere shortening. Consistent with cigarette smoking as causing pulmonary lesions by a mechanism of telomeric DDR [ 123 , 124 , 125 ], a significant number of smokers with IPF and chronic obstructive pulmonary disease (COPD) demonstrated acceleratory shortening of telomeres [ 47 , 123 , 126 ]. We demonstrated that radiation exposure, oxidative stress (such as H 2 O 2 ) or bacterial product bleomycin each trigger telomere shelterin protein TPP1 degradation in AEC2 stem cells, provoking telomere uncapping, DDR, stem cell exhaustion, fibrogenic gene expressions, and pulmonary fibrosis [ 35 ].…”

Leveraging global multi-ancestry meta-analysis in the study of Idiopathic Pulmonary Fibrosis genetics

“…No previous associations were found for the intergenic rs76537958 at 4q32.1, while variants (LD with rs76537958: r 2 < 0.1) in RAPGEF2 have been associated with FVC in UKB Neale v2 analysis, childhood and lifetime pneumonia 22 . In addition, RAPGEF2 has been reported as a shared risk factor for both IPF and chronic obstructive pulmonary disease (COPD) in a network analysis 23 .…”