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The genetic basis of idiopathic pulmonary fibrosis.

ABSTRACT: 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.

SUBMITTER: Kropski JA

PROVIDER: S-EPMC4849867 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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The genetic basis of idiopathic pulmonary fibrosis.

Kropski Jonathan A JA Blackwell Timothy S TS Loyd James E JE

The European respiratory journal 20150402 6

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 path ...[more]

PMID: 25837031

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Project description:BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis are typical interstitial lung diseases with unknown etiology that cause lethal lung damages. There are notable differences between these two pulmonary disorders, although they do share some similarities. Gene expression profiles have been reported independently, but differences on the transcriptional level between these two entities have not been investigated. METHODS/RESULTS: All expression data of lung tissue samples for IPF and sarcoidosis were from published datasets in the Gene Expression Omnibus (GEO) repository. After cross platform normalization, the merged sample data were grouped together and were subjected to statistical analysis for finding discriminate genes. Gene enrichments with their corresponding functions were analyzed by the online analysis engine "Database for Annotation, Visualization and Integrated Discovery" (DAVID) 6.7, and genes interactions and functional networks were further analyzed by STRING 9.0 and Cytoscape 3.0.0 Beta1. One hundred and thirty signature genes could potentially differentiate one disease state from another. Compared with normal lung tissue, tissue affected by IPF and sarcoidosis displayed similar signatures that concentrated on proliferation and differentiation. Distinctly expressed genes that could distinguish IPF from sarcoidosis are more enriched in processes of cilium biogenesis or degradation and regulating T cell activations. Key discriminative network modules involve aspects of bone morphogenetic protein receptor two (BMPR2) related and v-myb myeloblastosis viral oncogene (MYB) related proliferation. CONCLUSIONS: This study is the first attempt to examine the transcriptional regulation of IPF and sarcoidosis across different studies based on different working platforms. Groups of significant genes were found to clearly distinguish one condition from the other. While IPF and sarcoidosis share notable similarities in cell proliferation, differentiation and migration, remarkable differences between the diseases were found at the transcription level, suggesting that the two diseases are regulated by overlapping yet distinctive transcriptional networks.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity.MethodsThe genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10-8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls).FindingsWe detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10-3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10-2) .InterpretationThe strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors.FundingNovo Nordisk Foundation and Oak Foundation.

Dataset Information

The genetic basis of idiopathic pulmonary fibrosis.

Publications

The genetic basis of idiopathic pulmonary fibrosis.

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