Dataset Information

Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10^-7, odds ratio = 2.87, 95% confidence interval: 2.03-4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10^-20), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.

SUBMITTER: Dhindsa RS

PROVIDER: S-EPMC7988141 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

Dhindsa Ryan S RS Mattsson Johan J Nag Abhishek A Wang Quanli Q Wain Louise V LV Allen Richard R Wigmore Eleanor M EM Ibanez Kristina K Vitsios Dimitrios D Deevi Sri V V SVV Wasilewski Sebastian S Karlsson Maria M Lassi Glenda G Olsson Henric H Muthas Daniel D Monkley Susan S Mackay Alex A Murray Lynne L Young Simon S Haefliger Carolina C Maher Toby M TM Belvisi Maria G MG Jenkins Gisli G Molyneaux Philip L PL Platt Adam A Petrovski Slavé S

Communications biology 20210323 1

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association betwee ...[more]

PMID: 33758299

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Project description:BackgroundTyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF).MethodsThirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC).ResultsGene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions.ConclusionsWe performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is characterized by the insidious onset of dyspnea or cough. However, a subset of patients has a short duration of symptoms with rapid progression to end-stage disease. In this study, we evaluated clinical and molecular features of "rapid" and "slow" progressors with IPF.Methods and findings26 patients with <6 months of symptoms before first presentation [rapid progressors] and 88 patients with >24 months of symptoms [slow progressors] were studied. Survival was analyzed by the Kaplan-Meyer method and proportional hazard's model. Lung microarrays and tissue proteins were measured in a subset of patients. No differences were found in age, physiologic impairment and bronchoalveolar lavage (BAL) cellular profile. There were more males (OR = 6.5; CI:1.4-29.5; p = 0.006) and smokers (OR = 3.04; CI:1.1-8.3; p = 0.04) in the rapid progressors group. Survival from the beginning of symptoms was significantly reduced in rapid progressors (HR = 9.0; CI:4.48-18.3; p<0.0001) and there was a tendency for decreased survival from the time of diagnosis (HR = 1.5; CI:0.81-2.87; p = 0.18). We identified 437 differentially expressed genes. Lungs of rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration/proliferation, and genes from fibroblasts/smooth muscle cells. Upregulation of two of these genes, adenosine-2B receptor and prominin-1/CD133, was validated by immunohistochemistry and were expressed by alveolar epithelial cells. BAL from rapid progressors showed a >2-fold increase of active matrix metalloproteinase-9, and induced a higher fibroblast migration compared with slow progressors and controls [238+/-98% versus 123+/-29% (p<0.05) and 30+/-17% (p<0.01)].Conclusions/significanceA subgroup of IPF patients, predominantly smoking males, display an accelerated clinical course and have a gene expression pattern that is different from those with slower progression and longer survival. These findings highlight the variability in the progression of IPF, and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease, characterized by a decline in lung function. To date, the pathophysiologic mechanisms associated with lung dysfunction remain unclear, and no effective therapy has been identified to improve lung function.MethodsIn the present study, we used weighted gene co-expression network analysis (WGCNA) to identify key modules and hub genes associated with lung function in IPF. Three datasets, containing clinical information, were downloaded from Gene Expression Omnibus. WGCNA was performed on the GSE32537 dataset. Differentially expressed gene s (DEGs) between IPF patients and healthy controls were also identified to filter hub genes. The relationship between hub genes and lung function was then validated using the GSE47460 and GSE24206 datasets.ResultsThe red module, containing 267 genes, was positively correlated with the St. George's Respiratory Questionnaire score (r = 0.37, p < 0.001) and negatively correlated with the percent predicted forced vital capacity (FVC% predicted) (r = - 0.46, p < 0.001) and the percent predicted diffusion capacity of the lung for carbon monoxide (Dlco% predicted) (r = - 0.42, p < 0.001). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that the genes in the red module were primarily involved in inflammation and immune pathways. Based on Module Membership and Gene Significance, 32 candidate hub genes were selected in the red module to construct a protein-protein interaction network . Based on the identified DEGs and the degree of connectivity in the network, we identified three hub genes, including interleukin 6 (IL6), suppressor of cytokine signaling-3 (SOCS3), and serpin family E member 1 (SERPINE1). In the GSE47460 dataset, Spearman correlation coefficients between Dlco% predicted and expression levels of IL6, SERPINE1, SOCS3 were -0.32, -0.41, and -0.46, respectively. Spearman correlation coefficients between FVC% predicted and expression levels of IL6, SERPINE1, SOCS3 were -0.29, -0.33, and -0.27, respectively. In the GSE24206 dataset, all three hub genes were upregulated in patients with advanced IPF.ConclusionWe identified three hub genes that negatively correlated with the lung function of IPF patients. Our results provide insights into the pathogenesis underlying the progressive disruption of lung function, and the identified hub genes may serve as biomarkers and potential therapeutictargets for the treatment of IPF patients.

Dataset Information

Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

Publications

Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

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