Objective To investigate the causal effect of coronavirus disease 2019 (COVID-19) on idiopathic pulmonary fibrosis (IPF). Methods Genome-wide association studies (GWAS) data were sourced from the COVID-19 Host Genetics Initiative and published research. We employed: ① linkage disequilibrium score regression to estimate heritability of individual traits and genetic correlations between COVID-19 and IPF; ② multi-trait analysis of GWAS to identify genetic loci associated with COVID-19 and IPF; ③ Mendelian randomization (MR) to assess causal effect of COVID-19 on IPF; ④ colocalization analysis to identify shared causal variants. Results ① Three COVID-19 phenotypes showed significant positive genetic correlations with IPF (P<0.05); ② Multi-trait analysis of GWAS identified loci jointly associated with COVID-19 and IPF; ③ MR indicated that COVID-19 hospitalization may increase IPF risk (P=0.006); ④ Two causal variants were identified: rs12585036 (posterior probability>0.8, mapped to ATP11A) and rs12610495 (posterior probability>0.8, mapped to DPP9). Conclusions COVID-19 hospitalization may increase IPF risk through inflammatory pathways, providing new insights for managing COVID-19-related pulmonary diseases.
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is defined as an acute and clinically significant respiratory deterioration characterized by evidence of new, widespread alveolar abnormality. In the past, AE-IPF was considered to be idiopathic, which was hard to be prevented and its prognosis was hard to be obviously improved; the latest researches have shown that AE-IPF can be triggered by known causes, including pulmonary infection, aspiration, etc. This review summarizes the etiology or risk factors, treatment and prevention of AE-IPF according to the latest researches.
ObjectiveTo investigate the causal relationship between gut microbiota and idiopathic pulmonary fibrosis (IPF). MethodsGenome-wide association studies (GWAS) data of gut microbiota and IPF were obtained from MiBioGen and IEU OpenGWAS, respectively. Instrumental variables were screened by means of significance, linkage disequilibrium, weak instrumental variable screening, and removal of confounding factors (genetics, smoking, host characteristics). Inverse variance weighted (IVW) was used as the main Mendelian randomization (MR) analysis method, and the weighted median, simple mode, MR-Egger, and weighted mode were used to perform MR to reveal the causal effect of gut microbiota and IPF. The Cochrane's Q, leave-one-out, MR-Egger-intercept, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and Steiger tests were used to analyze the heterogeneity, horizontal pleiotropy, outliers, and directionality, respectively. ResultsIVW analysis results showed that Actinobacteria [OR=1.773, 95%CI (1.323, 2.377), P<0.001], Erysipelatoclostridium [OR=2.077, 95%CI (1.107, 3.896), P=0.023], and Streptococcus [OR=1.35, 95%CI (1.100, 1.657), P=0.004] could increase the risk of IPF. Bifidobacterium [OR=0.668, 95%CI (0.620, 0.720), P<0.001], Ruminococcus [OR=0.434, 95%CI (0.222, 0.848), P=0.015], and Tyzzerella [OR=0.479, 95%CI (0.304, 0.755), P=0.001] could reduce the risk of IPF. No significant heterogeneity, horizontal pleiotropy, outliers, and reverse causality were found. ConclusionActinobacteria, Erysipelatoclostridium and Streptococcus may increase the risk of IPF, while Bifidobacterium, Ruminococcus and Tyzzerella may reduce the risk of IPF. Regulation of the above gut microbiota may become a new direction in the study of the pathogenesis of IPF.
Objective To identify new potential drug targets for idiopathic pulmonary fibrosis (IPF) in order to improve the current situation where there are very few effective treatments for IPF. Methods This study integrates protein quantitative trait loci (pQTL) data from the deCODE cohort and the Atherosclerosis Risk in Communities (ARIC) study, expression quantitative trait loci (eQTL) data of whole blood from the GTEx-V8 and eQTLGen databases, and genome-wide association study (GWAS) data of IPF, and employs a multi-dimensional genetic epidemiology approach for analysis. Specifically, it includes: assessing the causal relationship between protein levels and IPF risk using two-sample Mendelian randomization (MR) methods; examining the potential associations between gene expression and IPF using summary-data-based Mendelian randomization (SMR) analysis; and determining the sharing of genetic variants between pQTL/eQTL and GWAS signals using Bayesian colocalization analysis. On this basis, a protein-protein interaction (PPI) network was further constructed, and target druggability assessment and potential drug prediction were performed to evaluate the biological significance and therapeutic potential of candidate targets. Results This study identified two proteins significantly associated with IPF: BRSK2 (β=1.222 7, P=1.12×10–10) and AP2A2 (β=2.854 3, P=1.22×10–7). The analysis suggests that these two proteins may participate in the occurrence and progression of IPF by affecting the balance of lung tissue injury and repair or by modulating fibrosis-related signaling pathways, and increased levels of both BRSK2 and AP2A2 proteins were significantly associated with an increased risk of IPF. Further Bayesian colocalization analysis indicated that AP2A2 shares genetic variant loci with IPF, with posterior probabilities of PPH0=1.49×10–11, PPH1=7.6×10–5, PPH2=1.99×10–10, PPH3=1.33×10–5, and PPH4=0.999 9, suggesting a high degree of genetic signal concordance between them. For external validation, analyses based on the ARIC and UK Biobank databases further supported a potential causal association between BRSK2 and IPF, showing that genetic variants leading to increased BRSK2 protein levels also increased the risk of developing IPF (P=0.004). Conclusions At the protein and gene expression levels, this study provides genetic evidence supporting a potential causal association of AP2A2 and BRSK2 with IPF. These proteins may participate in the pathogenesis and progression of IPF by influencing the balance of lung tissue injury and repair or fibrosis-related signaling pathways. They may also serve as potential therapeutic targets for IPF. However, their specific mechanisms of action require further elucidation.
