Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity - PubMed (original) (raw)

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity

João Fadista et al. EBioMedicine. 2021 Mar.

Abstract

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.

Keywords: Covid-19; Idiopathic pulmonary fibrosis; MUC5B; Mendelian randomization; Mucin.

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

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Conflict of interest statement

Declaration of Competing Interest 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.

Figures

Fig 1

Fig. 1

Forest plot of IVW causal estimates, omitting each variant in turn. The estimate with the first labelled SNP includes all variants except the labelled variant, and so on. The IVW estimate including all variants ("IVW estimate") is also provided for reference. Estimates are in ln(OR).

Fig 2

Fig. 2

Genetic association estimates of the 14 non-MUC5B instrumental variables not detected to be outliers. Horizontal error bars regards standard errors of IPF estimates, while vertical error bars regards standard errors of COVID-19 severity estimates. The line represents the IVW causal estimate of IPF on COVID-19 severity. IPF, idiopathic pulmonary fibrosis. Estimates are in ln(OR).

Fig 3

Fig. 3

Forest plot of the effect estimates of the association of rs35705950 IPF T risk allele at the MUC5B locus on various COVID-19 outcomes using different control population. A2 (Very severe respiratory confirmed covid vs. population) has 4336 cases and 623,902 controls. B1 (Hospitalized covid vs. not hospitalized covid) has 2430 cases and 8478 controls. B2 (Hospitalized covid vs. population) has 6406 cases and 902,088 controls. C1 (Covid vs. lab/self-reported negative) has 24,057 cases and 218,062 controls. C2 (Covid vs. population) has 14,134 cases and 1284,876 controls.

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