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. We performed a Mendelian randomisation (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5x10-8) 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. The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. 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 = 4.24x10-3). 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 = 2.99x10-2) . 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 a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors.

中文翻译：

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特发性肺纤维化与COVID-19严重程度之间的共同遗传病因

背景。特发性肺纤维化（IPF）是一种复杂的肺部疾病，其特征是进行性肺瘢痕形成。严重的COVID-19与严重的肺炎有关，并且与IPF有许多共同的主要危险因素。这项研究旨在确定IPF与严重COVID-19之间的遗传相关性，并评估IPF遗传风险增加对COVID-19严重程度的潜在因果作用。方法。我们对COVID-19中的IPF因果关系进行了孟德尔随机（MR）研究。在以前的全基因组关联研究（GWAS）中，与IPF敏感性相关的遗传变异（P <5x10-8）被用作工具变量（IVs）。这些IV对COVID-19严重性的影响估计是通过COVID-19宿主遗传学计划从GWAS荟萃分析中收集的。IPF和COVID-19严重程度之间的遗传相关性通过连锁不平衡（LD）评分回归来估算。发现。我们检测到IPF与COVID-19严重程度呈正相关（rg = 0.31 [95％CI 0.04-0.57]，P = 0.023）。严重COVID-19的MR估算未显示任何遗传关联（OR 1.05，[95％CI 0.92-1.20]，P = 0.43）。但是，离群值分析显示，与其他变体相比，MUC5B的IPF风险等位基因rs35705950具有不同的作用。当排除rs35705950时，MR结果提供了证据，即遗传上增加的IPF风险对COVID-19严重性具有因果关系（OR 1.21，[95％CI 1.06-1.38]，P = 4.24x10-3）。此外，MUC5B的IPF风险等位基因仅在老年人中显示出明显的抗COVID-19住院的保护作用（OR 0.86，[95％CI 0.73-1.00]，P = 2。99x10-2）。解释。IPF的最强遗传决定因素，MUC5B的rs35705950，似乎赋予了针对COVID-19的保护，而所有其他IPF风险基因座的综合作用似乎赋予了COVID-19严重性的风险。观察到的rs35705950的作用可能是由于粘蛋白过量产生对气道的保护作用，也可能是由于对rs35705950 T进行严格自我隔离的患者群体非常丰富而导致的选择偏见。由于IPF因果变异对SARS-CoV-2感染具有多种影响，因此需要进一步研究以解决MUC5B变异与其他IPF遗传危险因素之间的这种明显矛盾。而所有其他IPF风险基因座的综合作用似乎赋予了COVID-19严重程度的风险。观察到的rs35705950的作用可能是由于粘蛋白过量产生对气道的保护作用，也可能是由于对rs35705950 T进行严格自我隔离的患者群体非常丰富而导致的选择偏见。由于IPF因果变异对SARS-CoV-2感染具有多种影响，因此需要进一步研究以解决MUC5B变异与其他IPF遗传危险因素之间的这种明显矛盾。而所有其他IPF风险基因座的综合作用似乎赋予了COVID-19严重程度的风险。观察到的rs35705950的作用可能是由于粘蛋白过量产生对气道的保护作用，也可能是由于对rs35705950 T进行严格自我隔离的患者群体大量富集而导致的选择偏见。由于IPF因果变异对SARS-CoV-2感染具有多种影响，因此需要进一步研究以解决MUC5B变异与其他IPF遗传危险因素之间的这种明显矛盾。观察到的rs35705950的作用可能是由于粘蛋白过量产生对气道的保护作用，也可能是由于对rs35705950 T进行严格自我隔离的患者群体大量富集而导致的选择偏见。由于IPF因果变异对SARS-CoV-2感染具有多种影响，因此需要进一步研究以解决MUC5B变异与其他IPF遗传危险因素之间的这种明显矛盾。观察到的rs35705950的作用可能是由于粘蛋白过量产生对气道的保护作用，也可能是由于对rs35705950 T进行严格自我隔离的患者群体大量富集而导致的选择偏见。由于IPF因果变异对SARS-CoV-2感染具有多种影响，因此需要进一步研究以解决MUC5B变异与其他IPF遗传危险因素之间的这种明显矛盾。