TY - JOUR
T1 - Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity
AU - COVID-19 Host Genetics Initiative
AU - Fadista, João
AU - Kraven, Luke M
AU - Karjalainen, Juha
AU - Andrews, Shea J
AU - Geller, Frank
AU - Baillie, J Kenneth
AU - Wain, Louise V
AU - Jenkins, R Gisli
AU - Feenstra, Bjarke
AU - van de Beek, Diederik
N1 - Funding Information: JF works for Novo Nordisk A/S since January 2021. LVW receives funding from GSK and Orion, outside of the submitted work. RGJ Jenkins reports personal fees and other from Biogen, personal fees from Galapagos, other from Galecto, personal fees and other from GlaxoSmithKline, personal fees from Heptares, personal fees and other from MedImmune, personal fees from Boehringer Ingelheim, personal fees from Pliant, personal fees from Roche/InterMune, personal fees from MedImmune, personal fees from PharmAkea, personal fees from Bristol Myers Squibb, personal fees from Chiesi, personal fees from Roche/Promedior, other from RedX, other from NuMedii, other from Nordic Biosciences, outside the submitted work; and RGJ is supported by a National Institute of Health Research Professorship (NIHR ref: RP-2017-08-ST2-014). RGJ is a trustee for Action for Pulmonary Fibrosis. Funding Information: We thank the patients, staff and investigators who contributed to the Covid-19 HGI and the IPF GWAS consortia. JF and BF received partial support from the Novo Nordisk Foundation (NNF18OC0053228) and the Oak Foundation (OCAY-18-598).LVW holds a GSK/British Lung Foundation Chair in Respiratory Research. The research was partially supported by the NIHR Leicester Biomedical Research centre and the NIHR Nottingham Biomedical Research centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. LMK holds a Medical Research Council IMPACT studentship (MR/N013913/1). Publisher Copyright: © 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Covid-19
KW - Idiopathic pulmonary fibrosis
KW - MUC5B
KW - Mendelian randomization
KW - Mucin
UR - http://www.scopus.com/inward/record.url?scp=85103608467&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ebiom.2021.103277
DO - https://doi.org/10.1016/j.ebiom.2021.103277
M3 - Article
C2 - 33714028
SN - 2352-3964
VL - 65
SP - 103277
JO - eBioMedicine
JF - eBioMedicine
M1 - 103277
ER -