Genetic Risk Factors for Idiopathic Pulmonary Fibrosis: Insights into Immunopathogenesis.
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ABSTRACT:
SUBMITTER: Michalski JE
PROVIDER: S-EPMC7801923 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Genetic Risk Factors for Idiopathic Pulmonary Fibrosis: Insights into Immunopathogenesis.
Michalski Jacob E JE Schwartz David A DA
Journal of inflammation research 20200101
Idiopathic pulmonary fibrosis is an etiologically complex interstitial lung disease characterized by progressive scarring of the lungs with a subsequent decline in lung function. While much of the pathogenesis of IPF still remains unclear, it is now understood that genetic variation accounts for at least one-third of the risk of developing the disease. The single-most validated and most significant risk factor, genetic or otherwise, is a gain-of-function promoter variant in the <i>MUC5B</i> gene ...[more]
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-07-01 | GSE175459 | GEO
Project description:BackgroundSurveys and retrospective studies of patients with idiopathic pulmonary fibrosis (IPF) have shown a significant diagnostic delay. However, the causes and risk factors for this delay are not known.MethodsDates at six time points before the IPF diagnosis (onset of symptoms, first contact to a general practitioner, first hospital contact, referral to an interstitial lung disease (ILD) centre, first visit at an ILD centre, and final diagnosis) were recorded in a multicentre cohort of 204 incident IPF patients. Based on these dates, the delay was divided into specific patient-related and healthcare-related delays. Demographic and clinical data were used to determine risk factors for a prolonged delay, using multivariate negative binomial regression analysis.ResultsThe median diagnostic delay was 2.1 years (IQR: 0.9-5.0), mainly attributable to the patients, general practitioners and community hospitals. Male sex was a risk factor for patient delay (IRR: 3.84, 95% CI: 1.17-11.36, p = 0.006) and old age was a risk factor for healthcare delay (IRR: 1.03, 95% CI: 1.01-1.06, p = 0.004). The total delay was prolonged in previous users of inhalation therapy (IRR: 1.99, 95% CI: 1.40-2.88, p < 0.0001) but not in patients with airway obstruction. Misdiagnosis of respiratory symptoms was reported by 41% of all patients.ConclusionDespite increased awareness of IPF, the diagnostic delay is still 2.1 years. Male sex, older age and treatment attempts for alternative diagnoses are risk factors for a delayed diagnosis of IPF. Efforts to reduce the diagnostic delay should focus on these risk factors.Trial registrationThis study was registered at http://clinicaltrials.gov (NCT02772549) on May 10, 2016.
| S-EPMC6534848 | 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 | GSE175457 | GEO
Project description:Purpose of reviewIdiopathic pulmonary fibrosis (IPF) is an invariably progressive disease. Current treatment options simply slow disease progression and better therapeutic options are needed. We aimed to review emerging literature on risk factors associated with the development of IPF.Recent findingsThere is increasing data to support the role of intrinsic risk factors (e.g. genetics, aging, sex, lung microbiome), co-morbidities (e.g. gastroesophageal reflux, obstructive sleep apnea, diabetes mellitus, herpes virus infection), and extrinsic risk factors (e.g. cigarette smoking, environmental exposures, air pollution) in IPF development. These risk factors may independently increase susceptibility for IPF or act in a synergistic fashion to contribute to increased risk for disease development.SummaryVarious risk factors have been identified in IPF development that fit within the current paradigm of disease pathogenesis. Further investigation in to these risk factors may help us better understand the pathophysiology of IPF and may guide future therapeutic interventions.
| S-EPMC6777743 | 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:Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.
| S-EPMC6884045 | biostudies-literature
Project description:Throughout the past decade, there have been substantial advances in understanding the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recently, several large genome-wide association and linkage studies have identified common genetic variants in more than a dozen loci that appear to contribute to IPF risk. In addition, family-based studies have led to the identification of rare genetic variants in genes related to surfactant function and telomere biology, and mechanistic studies suggest pathophysiological derangements associated with these rare genetic variants are also found in sporadic cases of IPF. Current evidence suggests that rather than existing as distinct syndromes, sporadic and familial cases of IPF (familial interstitial pneumonia) probably reflect a continuum of genetic risk. Rapidly evolving bioinformatic and molecular biology techniques, combined with next-generation sequencing technologies, hold great promise for developing a comprehensive, integrated approach to defining the fundamental molecular mechanisms that underlie IPF pathogenesis.
| S-EPMC4849867 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a complex, heterogeneous genetic disorder that is associated with rare and common sequence variants in many genes (MUC5B, SFTPC, SFTPA2, RTEL1, TERT, and hTR), 11 novel loci, and multiple emerging epigenetic and transcriptional profiles. In the past 5 years, we have found that: 1) genetic risk variants play major and similar roles in the development of both familial and sporadic fibrotic idiopathic interstitial pneumonia, accounting for up to 35% of the risk of idiopathic interstitial pneumonia (a disease that was previously thought to be idiopathic); 2) a promoter variant in MUC5B rs35705950 is the strongest risk factor for the development of IIP and IPF; however, rs35705950 has a low penetrance; and 3) IPF is a complex genetic disease with 11 independent loci contributing to the development of this disease, pronounced changes in DNA methylation, and transcriptional subtypes. In aggregate, these findings suggest that IPF is a heterogeneous disease and that genetic and molecular subtypes of IPF will provide essential clues to disease pathogenesis, prognosis, treatment, and survival, all of which remain major problems in understanding and treating patients with IPF. Although the basic biological mechanisms involved in IPF are emerging, the disease is heterogeneous pathologically and the final common pathways of fibrogenesis are not well understood. These observations lead us to postulate that the etiology and severity/extent of this complex condition will best be understood through an integrated approach that accounts for inherited factors, epigenetic marks, and dynamic changes in the transcriptome.
| S-EPMC5216513 | biostudies-literature
Project description:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown cause associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP). Occupational risk factors have been proposed to be associated with UIP. The aim of this case-control study is to evaluate the relationship between UIP pattern and occupational exposure in Southern Europe. METHODS:Sixty nine cases with a UIP radiological pattern at CT-scan were selected from a clinical database of the University Hospital of Perugia, Umbria, between January 2010 and December 2013. Controls (n?=?277) not reporting doctor diagnosed pulmonary fibrosis, were ascertained casually among general population from the same catching area of cases. Data were collected by a questionnaire used previously in a similar study. Logistic regression models, adjusted for gender, age and smoking, were performed to evaluate the association between UIP and occupational exposure. RESULTS:Farmers, veterinarians and gardeners (OR?=?2.73, 95%CI?=?1.47-5.10), metallurgical and steel industry workers (OR?=?4.80, 95%CI?=?1.50-15.33) were occupations associated with UIP. Metal dust and fumes and organic dust were risk factors for UIP. Increasing the length of occupational exposure in jobs at risk of pulmonary fibrosis, increased the risk of having UIP. CONCLUSIONS:This case control study confirm partially the results from previous similar studies. Some discrepancies could be explained by the different geographical origins of the population under study, reflecting also different occupational exposures.
| S-EPMC5963078 | biostudies-literature
Project description:Functional Validation of Common Idiopathic Pulmonary Fibrosis Genetic Risk Variants
| PRJNA732440 | ENA