Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity
Background: Idiopathic 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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-03-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396421000700 |
| _version_ | 1818847863892869120 |
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| author | João Fadista Luke M. Kraven Juha Karjalainen Shea J. Andrews Frank Geller J Kenneth Baillie Louise V. Wain R.Gisli Jenkins Bjarke Feenstra |
| author_facet | João Fadista Luke M. Kraven Juha Karjalainen Shea J. Andrews Frank Geller J Kenneth Baillie Louise V. Wain R.Gisli Jenkins Bjarke Feenstra |
| author_sort | João Fadista |
| collection | DOAJ |
| description | Background: Idiopathic 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. Methods: The 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). Findings: We 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) . Interpretation: The 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. Funding: Novo Nordisk Foundation and Oak Foundation. |
| first_indexed | 2024-12-19T06:08:13Z |
| format | Article |
| id | doaj.art-6bc29d65502544a9a139615dc9b960a5 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-19T06:08:13Z |
| publishDate | 2021-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-6bc29d65502544a9a139615dc9b960a52022-12-21T20:33:04ZengElsevierEBioMedicine2352-39642021-03-0165103277Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severityJoão Fadista0Luke M. Kraven1Juha Karjalainen2Shea J. Andrews3Frank Geller4J Kenneth Baillie5Louise V. Wain6R.Gisli Jenkins7Bjarke Feenstra8Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Corresponding author at: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.Department of Health Sciences, University of Leicester, Leicester, United KingdomInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Massachusetts General Hospital, Boston, MA, United States; Broad Institute of Harvard and MIT, Cambridge, MA, United StatesDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United StatesDepartment of Epidemiology Research, Statens Serum Institut, Copenhagen, DenmarkRoslin Institute, University of Edinburgh, Edinburgh, United Kingdom; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, United KingdomDepartment of Health Sciences, University of Leicester, Leicester, United Kingdom; NIHR, Leicester Respiratory, Biomedical Research Centre, Glenfield Hospital, Leicester, United KingdomNottingham University Hospitals NHS Trust, City Campus, Nottingham, United Kingdom; NIHR Biomedical Research Centre, University of Nottingham, Nottingham, United KingdomDepartment of Epidemiology Research, Statens Serum Institut, Copenhagen, DenmarkBackground: Idiopathic 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. Methods: The 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). Findings: We 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) . Interpretation: The 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. Funding: Novo Nordisk Foundation and Oak Foundation.http://www.sciencedirect.com/science/article/pii/S2352396421000700Mendelian randomizationCovid-19Idiopathic pulmonary fibrosisMUC5BMucin |
| spellingShingle | João Fadista Luke M. Kraven Juha Karjalainen Shea J. Andrews Frank Geller J Kenneth Baillie Louise V. Wain R.Gisli Jenkins Bjarke Feenstra Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity EBioMedicine Mendelian randomization Covid-19 Idiopathic pulmonary fibrosis MUC5B Mucin |
| title | Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity |
| title_full | Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity |
| title_fullStr | Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity |
| title_full_unstemmed | Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity |
| title_short | Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity |
| title_sort | shared genetic etiology between idiopathic pulmonary fibrosis and covid 19 severity |
| topic | Mendelian randomization Covid-19 Idiopathic pulmonary fibrosis MUC5B Mucin |
| url | http://www.sciencedirect.com/science/article/pii/S2352396421000700 |
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