Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity
João Fadista, Luke M. Kraven, Juha Karjalainen, Shea J. Andrews, Frank Geller, J. Kenneth Baillie, Louise V. Wain, Gísli Jenkins, Bjarke Feenstra
Abstract
<h2>Abstract</h2><h3>Background</h3> 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. <h3>Methods</h3> 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 (<i>P</i><5 × 10<sup>−8</sup>) 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). <h3>Findings</h3> We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04–0·57], <i>P</i> = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92–1·20], <i>P</i> = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at <i>MUC5B</i> 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], <i>P</i> = 4·24 × 10<sup>−3</sup>). Furthermore, the IPF risk-allele at <i>MUC5B</i> showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73–1·00], <i>P</i> = 2·99 × 10<sup>−2</sup>) . <h3>Interpretation</h3> The strongest genetic determinant of IPF, rs35705950 at <i>MUC5B</i>, 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 <i>MUC5B</i> and other IPF genetic risk factors. <h3>Funding</h3> Novo Nordisk Foundation and Oak Foundation.