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

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.

The MUC5B Promoter Polymorphism Associates With Severe COVID-19 in the European Population

“…Because severe COVID-19 is associated with substantial pneumonitis and shares multiple risk factors with IPF, Fadista et al recently investigated whether a genetic correlation between IPF and severe COVID-19 exists using a Mendelian randomization approach ( 33 ). They found that genetically increased risk of IPF indeed associated with increased COVID-19 severity, except for the MUC5B allele.…”

“…The MUC5B risk allele had a different effect compared with other IPF predisposing alleles and protected against COVID-19 hospitalization in the elderly. Because the MUC5B results contradicted their hypotheses the authors were concerned that the analysis might have been influenced by possible selection bias: 1) due to the rs35705950 T allele carriers undertaking strict self-isolation, and 2) due to survival bias of the rs35705950 non-IPF T allele carriers ( 33 ). With the unique data of the UK biobank cohort, we were able to address these questions.…”

Host genetic factors determining COVID-19 susceptibility and severity

“…However, there may have been selection bias, as IPF patients are likely to self-isolate and protect themselves from SARS-CoV-2 infection. Therefore, carriers of the T -allele might be underrepresented in the COVID-19 patients population [78] . This could, of course, also effect the HGI study.…”

A MUC5Bgene polymorphism, rs35705950-T, confers protective effects in COVID-19 infection

“…The data herein establishes that the "T" allele of rs35705950-T in MUC5B, which has been associated with an increased risk for the development of IPF, confers a decreased risk of hospitalization and pneumonia following COVID-19 infection among MVP participants of European ancestry. The protective effect of the rs35705950-T, in addition to being counterintuitive, is in stark contrast to the increased risk of severe COVID-19 disease observed for other well-established causal variants or IPF, including variants located in the TERC, DEPTOR, and FAM13A (26).…”