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.
【저자키워드】 COVID-19, mendelian randomization, Idiopathic pulmonary fibrosis, MUC5B, Mucin., 【초록키워드】 severe COVID-19, Older adults, SARS-COV-2 infection, susceptibility, mendelian randomization, severity, pulmonary fibrosis, Genetic, variant, COVID-19 severity, lung, Lung disease, fibrosis, risk factor, airway, Idiopathic pulmonary fibrosis, Protective effects, survival, Patient, Genome-wide association study, COVID-19 hospitalization, genetic variants, GWAS, mucin, Pneumonitis, estimate, correlation, Selection bias, protective effect, association, MUC5B, IPF, Evidence, Analysis, Linkage disequilibrium, genetic association, airways, the strongest, genetic determinant, combined effect, Self-isolation, instrumental variables, Older, causal variant, increased risk, carriers, other variants, complex, foundation, COVID-19 Host Genetics Initiative, variance, risk allele, explanation, positive, genetic risk factors, idiopathic, outlier, initiative, risk loci, Effect, risk of COVID-19, controls, instrumental variable, performed, provided, characterized, were used, determine, excluded, GWAS meta-analysis, Oak, scarring, selection bia, with COVID-19, 【제목키워드】 pulmonary fibrosis, Idiopathic pulmonary fibrosis, genetic etiology,