Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis.
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ABSTRACT:
SUBMITTER: Furusawa H
PROVIDER: S-EPMC9013199 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
Publications
Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis.
Furusawa Haruhiko H Peljto Anna L AL Walts Avram D AD Cardwell Jonathan J Molyneaux Philip L PL Lee Joyce S JS Fernández Pérez Evans R ER Wolters Paul J PJ Yang Ivana V IV Schwartz David A DA
Thorax 20220107 5
A subset of patients with hypersensitivity pneumonitis (HP) develop lung fibrosis that is clinically similar to idiopathic pulmonary fibrosis (IPF). To address the aetiological determinants of fibrotic HP, we investigated whether the common IPF genetic risk variants were also relevant in study subjects with fibrotic HP. Our findings indicate that common genetic variants in <i>TERC</i>, <i>DSP</i>, <i>MUC5B</i> and <i>IVD</i> were significantly associated with fibrotic HP. These findings provide ...[more]
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Project description:RationaleMany of the interstitial lung diseases represent a diagnostic and therapeutic challenge because their clinical and even histologic features are often nonspecific. Likewise, the transcriptional signatures of most of them are unknown.ObjectiveTo compare the gene expression patterns from patients with idiopathic pulmonary fibrosis (IPF) hypersensitivity pneumonitis (HP), and nonspecific interstitial pneumonia (NSIP) using custom oligonucleotide microarrays.MethodsWe profiled lung biopsies from 15 patients with IPF, 12 with HP, and eight with NSIP. Labeled complementary ribonucleic acid was hybridized to a custom Affymetrix oligonucleotide DNA microarray using standard Affymetrix protocols. The custom array, Hu03, contained 59,619 probe sets representing an estimated 46,000 gene clusters.ResultsWe identified statistically significant gene expression signatures that characterize HP and IPF. The HP gene expression signature was enriched for genes that are functionally associated with inflammation, T-cell activation, and immune responses, whereas the IPF signature was characterized by the expression of tissue remodeling, epithelial, and myofibroblast genes. We then compared these gene expression signatures to classify NSIP, a histologic pattern that is often difficult to differentiate consistently from HP and IPF. Two cases exhibited an IPF-like gene expression, another one could be more properly classified as HP, whereas others did not resemble HP or IPF, suggesting that they may represent idiopathic NSIP.ConclusionsOur results underscore the value of gene expression signatures to classify the interstitial lung diseases and to understand pathogenic mechanisms, and suggest new ways to improve the diagnosis and treatment of patients with these diseases.
| S-EPMC2662988 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-07-01 | GSE175459 | GEO
Project description:Rationale: To identify functionally relevant common genetic risk variants associated with idiopathic pulmonary fibrosis (IPF), we performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals as well as mediation analysis. Methods: Illumina MEGA genotyping arrays, mRNA sequencing, and Illumina 850k methylation arrays were performed on lung tissue of participants with IPF (234 RNA and 345 DNA samples) and non-diseased control (188 RNA and 202 DNA samples). Transcriptome and methylome datasets were normalized for unknown batch effects using Probabilistic Estimation of Expression Residuals (PEER). eQTL, cell type-interaction eQTL, and mQTL analyses were performed in FastQTL and co-localization analysis in eCAVIAR separately for cases and controls. Benjamini-Hochberg false discovery rate was used for adjustment for multiple comparisons. Results: After appropriate adjustment, we identified 4,745 genes with significant eQTLs in controls and 6,047 in cases (FDR-adjusted p<0.05). Focusing on genetic variants within 10 primary IPF-associated genetic loci, we identified 27 eQTLs in controls and 24 eQTLs in cases (FDR-adjusted p<0.05). Among these signals, we identified association of rs35705950 with expression of MUC5B (Chr11 locus) and rs2076295 with expression of DSP (Chr6 locus) in both cases and controls. To address cell specificity, we performed cell type-interaction eQTL analysis and identified an association of rs2076295 with expression of DSP in smooth muscle cells. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. eCAVIAR demonstrated strong co-localization of eQTL/mQTL and genetic signal in MUC5B (rs35705950) and DSP (rs2076295) in both cases and controls. Mediation analysis demonstrated partial mediation of the effect of common variants in MUC5B and DSP loci on disease risk though MUC5B and DSP gene expression. Functional validation of the mQTL in MUC5B demonstrates that the CpG is within a putative internal repressor element that interacts through a 3D loop with the enhancer containing the rs35705950 genetic variant. Conclusions: Using lung eQTL/mQTL, co-localization, and mediation analyses, we have established the functional validation of the common IPF genetic risk variants for MUC5B (rs35705950) and DSP (rs2076295). These results provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.
2022-07-01 | GSE175457 | GEO
Project description:N6-methyladenosine (m6A) modification plays a pivotal role in post-transcriptionally regulating gene expression and biological functions. Nonetheless, the roles of m6A modification in the regulation of chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remain unclear. Twenty-two significant m6A regulators were selected from differential gene analysis between the control and treatment groups from the GSE150910 dataset. Five candidate m6A regulators (insulin-like growth factor binding protein 2, insulin-like growth factor binding protein 3, YTH domain-containing protein 1, zinc finger CCCH domain-containing protein 13, and methyltransferase-like 3) were screened by the application of a random forest model and nomogram model to predict risks of pulmonary fibrosis. The consensus clustering method was applied to divide the treatment samples into two groups with different m6A patterns (clusters A and B) based on the 22 m6A regulators. Our study performed principal component analysis to obtain the m6A-related score of the 288 samples to quantify the two m6A patterns. The study reveals that cluster A was linked to T helper cell (Th) 2-type cytokines, while the immune infiltration of Th1 cytokines was higher in cluster B. Our results suggest that m6A cluster A is likely related to pulmonary fibrosis, indicating m6A regulators play notable roles in the occurrence of pulmonary fibrosis. The m6A patterns could be considered as biomarkers to identify CHP and IPF, which will be helpful to develop immunotherapy strategies for pulmonary fibrosis in the future.
| S-EPMC9329921 | biostudies-literature
Project description:Rationale: To identify functionally relevant common genetic risk variants associated with idiopathic pulmonary fibrosis (IPF), we performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals as well as mediation analysis. Methods: Illumina MEGA genotyping arrays, mRNA sequencing, and Illumina 850k methylation arrays were performed on lung tissue of participants with IPF (234 RNA and 345 DNA samples) and non-diseased control (188 RNA and 202 DNA samples). Transcriptome and methylome datasets were normalized for unknown batch effects using Probabilistic Estimation of Expression Residuals (PEER). eQTL, cell type-interaction eQTL, and mQTL analyses were performed in FastQTL and co-localization analysis in eCAVIAR separately for cases and controls. Benjamini-Hochberg false discovery rate was used for adjustment for multiple comparisons. Results: After appropriate adjustment, we identified 4,745 genes with significant eQTLs in controls and 6,047 in cases (FDR-adjusted p<0.05). Focusing on genetic variants within 10 primary IPF-associated genetic loci, we identified 27 eQTLs in controls and 24 eQTLs in cases (FDR-adjusted p<0.05). Among these signals, we identified association of rs35705950 with expression of MUC5B (Chr11 locus) and rs2076295 with expression of DSP (Chr6 locus) in both cases and controls. To address cell specificity, we performed cell type-interaction eQTL analysis and identified an association of rs2076295 with expression of DSP in smooth muscle cells. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. eCAVIAR demonstrated strong co-localization of eQTL/mQTL and genetic signal in MUC5B (rs35705950) and DSP (rs2076295) in both cases and controls. Mediation analysis demonstrated partial mediation of the effect of common variants in MUC5B and DSP loci on disease risk though MUC5B and DSP gene expression. Functional validation of the mQTL in MUC5B demonstrates that the CpG is within a putative internal repressor element that interacts through a 3D loop with the enhancer containing the rs35705950 genetic variant. Conclusions: Using lung eQTL/mQTL, co-localization, and mediation analyses, we have established the functional validation of the common IPF genetic risk variants for MUC5B (rs35705950) and DSP (rs2076295). These results provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.
2022-07-01 | GSE175458 | GEO
Project description:Chronic hypersensitivity pneumonitis (CHP) is caused by an immune response to antigen inhalation and is characterized by variable histopathological and clinical features. A subset of CHP subjects have usual interstitial pneumonia and appear to be clinically similar to subjects with idiopathic pulmonary fibrosis (IPF). However, the molecular relationship between CHP and IPF is not well understood. We report an RNA-seq based transcriptomic analysis for whole lung tissues from CHP, IPF and control subjects.
2020-07-01 | GSE150910 | GEO
Project description:Rationale: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises after repeated exposure and sensitization to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease, but, to date, no study has investigated the composition of microbial communities in the lower airways in CHP.Objectives: To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects.Methods: We prospectively recruited individuals with a CHP diagnosis (n = 110), individuals with an IPF diagnosis (n = 45), and control subjects (n = 28). Subjects underwent BAL and bacterial DNA was isolated, quantified by quantitative PCR and the 16S ribosomal RNA gene was sequenced to characterize the bacterial communities in the lower airways.Measurements and Main Results: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both subjects with IPF and subjects with CHP included Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. However, in IPF, Firmicutes dominated, whereas the percentage of reads assigned to Proteobacteria in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the Staphylococcus burden was increased in CHP, and Actinomyces and Veillonella burdens were increased in IPF. The lower airway bacterial burden in subjects with CHP was higher than that in control subjects but lower than that of those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP.Conclusions: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF, and, notably, the bacterial burden in individuals with CHP fails to predict survival.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by an abnormal activation of lung epithelium and fibroblasts, as well as an excessive accumulation of extracellular matrix. Pirfenidone was introduced as a therapeutic option for IPF and chronic hypersensitive pneumonitis (cHP), a related disease. However, high plasma concentrations, which can be achieved even at recommended doses, are frequently associated with adverse events. Hence, an extended release formulation (XP), yielding lower peak plasma concentrations, has been developed. The aim of this study was to compare the pharmacokinetic properties of XP with those of the immediate (IR) formulation in patients with IPF or cHP. Data were analyzed using two pharmacokinetic approaches, conventional non compartmental analysis and a population analysis using the nonlinear mixed effects model technique. Results observed with both approaches were consistent. Drug exposure was similar with both formulations. However, XP exhibited less concentration fluctuations and a longer mean resident time. These results suggest that XP could be a feasible option to reduce adverse events associated to pirfenidone elevated concentrations. Nevertheless, efficacy studies are required to fully document the therapeutic potential of XP.
| S-EPMC7610245 | biostudies-literature
Project description:BackgroundPatients with interstitial lung disease (ILD) have poor health-related quality of life (HRQL). However, whether HRQL differs among different subtypes of ILD is unclear. The aim of this study was to determine whether HRQL was different among patients with idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (CHP).MethodsWe identified patients from an ongoing longitudinal cohort of patients with ILD. HRQL was assessed using the Short Form (SF)-36 medical outcomes form (version 2.0). Regression analysis was used to determine the association between clinical covariates and HRQL, primarily the physical component summary (PCS) and mental component summary (MCS) score. A multivariate regression model was created to identify potential covariates that could help explain the association between the ILD subtype and HRQL.ResultsPatients with IPF (n = 102) were older, more likely to be men, and more likely to have smoked. Pulmonary function was similar between the groups. The patients with CHP (n = 69) had worse HRQL across all eight domains of the SF-36, as well as the PCS and MCS, compared with patients with IPF (P < .01-.09). This pattern remained after controlling for age and pulmonary function (P < .01-.02). Covariates explaining part of the relationship between disease subtype and PCS score included severity of dyspnea (P < .01) and fatigue (P < .01). Covariates explaining part of the relationship between disease subtype and MCS score included severity of dyspnea (P < .01), female sex (P = .02), and fatigue (P = .02).ConclusionsHRQL is worse in CHP compared with IPF. HRQL differences between ILD subtypes are explained in part by differences in sex, dyspnea, and fatigue.
| S-EPMC4042514 | biostudies-literature
Project description:5-methyladenosine (m5C) modification regulates gene expression and biological functions in oncologic areas. However, the effect of m5C modification in chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remains unknown. Expression data for 12 significant m5C regulators were obtained from the interstitial lung disease dataset. Five candidate m5C regulators, namely tet methylcytosine dioxygenase 2, NOP2/Sun RNA methyltransferase 5, Y-box binding protein 1, tRNA aspartic acid methyltransferase 1, and NOP2/Sun RNA methyltransferase 3 were screened using random forest and nomogram models to predict risks of pulmonary fibrosis. Next, we applied the consensus clustering method to stratify the samples with different m5C patterns into two groups (cluster A and B). Finally, we calculated immune cell infiltration scores via single-sample gene set enrichment analysis, then compared immune cell infiltration, related functions as well as the expression of programmed cell death 1 (PD-1, PDCD1) and programmed death protein ligand-1 (PD-L1, CD274) between the two clusters. Principal component analysis of m5C-related scores across the 288 samples revealed that cluster A had higher immune-related expression than B. Notably, T helper cell (Th) 2 type cytokines and Th1 signatures were more abundant in clusters A and B, respectively. Our results suggest that m5C is associated with and plays a crucial role in development of pulmonary fibrosis. These m5C patterns could be potential biomarkers for identification of CHP and IPF, and guide future development of immunotherapy or other new drugs strategies for pulmonary fibrosis.
| S-EPMC10097674 | biostudies-literature