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IDIOPATHIC PULMONARY FIBROSIS IS A COMPLEX GENETIC DISORDER.

ABSTRACT: 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.

SUBMITTER: Schwartz DA

PROVIDER: S-EPMC5216513 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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IDIOPATHIC PULMONARY FIBROSIS IS A COMPLEX GENETIC DISORDER.

Schwartz David A DA

Transactions of the American Clinical and Climatological Association 20160101

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 pneu ...[more]

PMID: 28066036

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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.

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IDIOPATHIC PULMONARY FIBROSIS IS A COMPLEX GENETIC DISORDER.

Publications

IDIOPATHIC PULMONARY FIBROSIS IS A COMPLEX GENETIC DISORDER.

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