Rare and Common Variants in <i>KIF15</i> Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis

Zhang, David; Povysil, Gundula; Kobeissy, Philippe H.; Li, Qi; Wang, Binhan; Amelotte, Mason; Jaouadi, Hager; Newton, Chad A.; Maher, Toby M.; Molyneaux, Philip L.; Noth, Imre; Martínez, Fernando J.; Raghu, Ganesh; Todd, Jamie L.; Palmer, Scott M.; Haefliger, Carolina; Platt, Adam; Petrovski, Steve; Garcia, Joseph A.; Goldstein, David B.; Garcia, Christine Kim

doi:10.1164/rccm.202110-2439oc

Cited by 31 publications

(29 citation statements)

References 39 publications

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“…The associations of rare variants at ADA reported here, as well as those at KIF15 reported recently in this journal ( 15 ), highlight the potential to identify additional rare IPF risk variants of large effect in adequately powered WGS or whole-exome sequencing studies. ADA plays a role in lung fibrosis in mouse models and regulates levels of adenosine, a signaling molecule important in immune function and injury response ( 16 ).…”

supporting

confidence: 71%

Identification of a Genetic Susceptibility Locus for Idiopathic Pulmonary Fibrosis in the 16p Subtelomere Using Whole-Genome Sequencing

Donoghue¹,

Stockwell²,

Neighbors³

et al. 2023

Am J Respir Crit Care Med

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supporting

confidence: 71%

Identification of a Genetic Susceptibility Locus for Idiopathic Pulmonary Fibrosis in the 16p Subtelomere Using Whole-Genome Sequencing

Donoghue¹,

Stockwell²,

Neighbors³

et al. 2023

Am J Respir Crit Care Med

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“…The increased expression of FOXM1 in the IPF small airway cultures was found to be significant when compared to cell cultures generated from normal small airway tissue (Figure 2B). Numerous studies have linked variants in the KIF15 gene to an increased risk of developing IPF (27–29). Significant genes present in our dataset reflect the characteristics seen in IPF lung tissue and IPF cell cultures.…”

Section: Discussionmentioning

confidence: 99%

Bulk RNA-Sequencing of small airway cell cultures from IPF and post-COVID lung fibrosis patients illustrates disease signatures and differential responses to TGF-β1 treatment

Uhl

Paithankar

Leshchiner

et al. 2023

Preprint

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IPF is a condition in which an injury to the lung leads to the accumulation of scar tissue. This fibrotic tissue reduces lung compliance and impairs gas exchange. Studies have shown that infection with COVID-19 significantly worsens the clinical outcomes of IPF patients. The exact etiology of IPF is unknown, but recent evidence suggests that the distal small airways, (those having a diameter less than 2 mm in adults), play a role in the early pathogenesis of IPF. TGF-β1 is a main driver of fibrosis in a variety of tissues; the binding of TGF-β1 to its receptor triggers a signaling cascade that results in inflammatory signaling, accumulation of collagen and other components of the extracellular matrix, and immune system activation. This study aimed to investigate possible mechanisms that contribute to worsening lung fibrosis in IPF patients after being diagnosed with COVID-19, with a particular focus on the role of TGF-β1. Small airway cell cultures derived from IPF and post-COVID-19 IPF patient transplant tissues were submitted for RNA-sequencing and differential gene expression analysis. The genetic signatures for each disease state were determined by comparing the differentially expressed genes present in the cells cultured under control conditions to cells cultured with TGF-β1. The genes shared between the culture conditions laid the framework for determining the genetic signatures of each disease. Our data found that genes associated with pulmonary fibrosis appeared to be more highly expressed in the post-COVID fibrosis samples, under both control and TGF-β1-treated conditions. A similar trend was noted for genes involved in the TGF-β1 signaling pathway; the post-COVID fibrosis cell cultures seemed to be more responsive to treatment with TGF-β1. Gene expression analysis, RT-PCR, and immunohistochemistry confirmed increased levels of BMP signaling in the IPF small airway cell cultures. These findings suggest that TGF-β1 signaling in IPF small airway cells could be inhibited by BMP signaling, leading to the differences in genetic signatures between IPF and post-COVID fibrosis.

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“…Among the top 10 BPs, mitosis-related pathways accounted for half. A genetic study involving 1,725 IPF patients and 23,509 controls found heterozygous deleterious variants in kinesin family member 15 ( KIF15 ), which take part in spindle separation during mitosis ( 69 ). Mitotic imbalance may be an important mechanism in the pathogenesis of IPF.…”

Section: Discussionmentioning

confidence: 99%

Construction of a TFs-miRNA-mRNA network related to idiopathic pulmonary fibrosis

Su¹,

Liu²,

Wu³

et al. 2023

Ann Transl Med

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Background The transcription factors (TFs)-microRNA (miRNA)-messenger RNA (mRNA) network plays an important role in a variety of diseases. However, the relationship between the TFs-miRNA-mRNA network and idiopathic pulmonary fibrosis (IPF) remains unclear. Methods The GSE110147 and GSE53845 datasets from the Gene Expression Omnibus (GEO) database were used to process differentially expressed genes (DEGs) analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), as well as Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The GSE13316 dataset was used to perform differentially expressed miRNAs (DEMs) analysis and TFs prediction. Finally, a TFs-miRNA-mRNA network related to IPF was constructed, and its function was evaluated by Gene Ontology (GO) and KEGG analyses. Also, 19 TFs in the network were verified by quantitative real time polymerase chain reaction (qRT-PCR). Results Through our analysis, 53 DEMs and 2,630 DEGs were screened. The GSEA results suggested these genes were mainly related to protein digestion and absorption. The WGCNA results showed that these DEGs were divided into eight modules, and the GO and KEGG analyses results of blue module genes showed that these 86 blue module genes were mainly enriched in cilium assembly and cilium organization. Moreover, a TFs-miRNA-mRNA network comprising 25 TFs, 11 miRNAs, and 60 mRNAs was constructed. Ultimately, the functional enrichment analysis showed that the TFs-miRNA-mRNA network was mainly related to the cell cycle and the phosphatidylinositol 3 kinase-protein kinase B ( PI3K-Akt ) signaling pathway. Furthermore, experimental verification of the TFs showed that ARNTL , TRIM28 , EZH2 , BCOR , and ASXL1 were sufficiently up-regulated in the transforming growth factor (TGF)-β1 treatment groups, while BCL6 , BHLHE40 , FOXA1 , and EGR1 were significantly down-regulated. Conclusions The novel TFs-miRNA-mRNA network that we constructed could provide new insights into the underlying molecular mechanisms of IPF. ARNTL , TRIM28 , EZH2 , BCOR , ASXL1 , BCL6 , BHLHE40 , FOXA1 , and EGR1 may play important roles in IPF and become effective biomarkers for diagnosis and treatment.

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Rare and Common Variants in KIF15 Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis

Cited by 31 publications

References 39 publications

Identification of a Genetic Susceptibility Locus for Idiopathic Pulmonary Fibrosis in the 16p Subtelomere Using Whole-Genome Sequencing

Identification of a Genetic Susceptibility Locus for Idiopathic Pulmonary Fibrosis in the 16p Subtelomere Using Whole-Genome Sequencing

Bulk RNA-Sequencing of small airway cell cultures from IPF and post-COVID lung fibrosis patients illustrates disease signatures and differential responses to TGF-β1 treatment

Construction of a TFs-miRNA-mRNA network related to idiopathic pulmonary fibrosis

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