Genetic Variants in Genes Related to Lung Function and Interstitial Lung Diseases Are Associated with Worse Outcomes in Severe COVID-19 and Lung Performance in the Post-COVID-19 Condition

Genetic variants related to susceptibility to chronic respiratory conditions such as interstitial lung disease (ILD) could share critical pathways in the pathogenesis of COVID-19 and be implicated in COVID-19 outcomes and post-COVID-19. We aimed to identify the participation of genetic variants in lung function and ILD genes in severe COVID-19 outcomes and post-COVID-19 condition. We studied 936 hospitalized patients with COVID-19. The requirement of invasive mechanical ventilation (IMV) and the acute respiratory distress syndrome (ARDS) classification were considered. The mortality was assessed as the in-hospital death. The post-COVID-19 group included 102 patients evaluated for pulmonary function tests four times during the year after discharge. Five variants (<i>FAM13A</i> rs2609255, <i>DSP</i> rs2076295, <i>TOLLIP</i> rs111521887, <i>TERT</i> rs2736100, and <i>THSD4</i> rs872471) were genotyped using TaqMan assays. A multifactor dimensionality reduction method (MDR) was performed for epistasis estimation. The <i>TERT</i> rs2736100 and <i>THSD4</i> rs872471 variants were associated with differential risk for ARDS severity (moderate vs. severe, CC + CA, <i>p</i> = 0.044, OR = 0.66, 95% CI = 0.44-0.99; and GG <i>p</i> = 0.034, OR = 2.22, 95% CI = 1.04-4.72, respectively). These variants and <i>FAM13A</i> rs2609255 were also related to pulmonary function post-COVID-19. The MDR analysis showed differential epistasis and correlation of the genetic variants included in this study. The well-known variants in recognized genes related to pulmonary function worsening and interstitial disorders are related to the severity and mortality of COVID-19 and lung performance in the post-COVID-19 condition.