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.
ObjectiveTo identify causal effects and potential mechanisms of oxidative stress (OS)-related genes in lung cancer. MethodsOS-related genes were extracted from the GeneCards database. Integration analysis of genome-wide association study (GWAS) data for lung cancer with gene expression and DNA methylation quantitative trait locus (QTL), including eQTL and mQTL in blood was performed using the summary data-based Mendelian randomization (SMR) approach to determine the causal relationship between OS-related genes and lung cancer risk. Colocalization analysis of OS-related gene QTL and lung cancer risk locus was performed to gain insight into the potential regulatory mechanisms of lung cancer risk. ResultsA total of 1 188 OS-related genes were obtained from the GeneCards database. A potential causal relationship between OS-related genes and lung cancer was identified by SMR analysis. AGER expression level [OR=1.944, 95%CI (1.431, 2.640), P<0.001], and ATF6B expression level [OR=1.508, 95%CI (1.287, 1.767), P<0.001] were associated with lung cancer risk. Meanwhile, ATF6B methylation level was also associated with lung cancer risk. ConclusionOS-related genes are associated with lung cancer, which may be a potential target of anti-cancer drugs.
Objective To explore the causal relationship between the Collagen VI (COL6) family proteins COL6A1, A2, and A3 and bronchiectasis using the Mendelian randomization (MR) method.MethodsThe primary analysis was conducted using MR combined with summary-data-based Mendelian randomization (SMR) analysis. COL6 family proteins were used as exposure data, and bronchiectasis was used as outcome data. Cis-protein quantitative trait locus (cis-pQTL) data were extracted for analysis, and the results were meta-analyzed. Subsequently, COL6A3-cis-pQTL data from the UK Biobank plasma proteome study were used for further validation. Colocalization analysis was also performed to further explore the association between COL6 proteins and bronchiectasis.Results MR and SMR results revealed a negative causal relationship between COL6A3 and bronchiectasis (p-MRmeta = 0.005, OR = 0.30; p-SMRmeta = 0.004, OR = 0.26). The validation phase also confirmed the negative causal relationship between COL6A3 and bronchiectasis (p-MRmeta = 0.000007, OR = 0.27; p-SMRmeta = 0.0003, OR = 0.29). Colocalization analysis supported the presence of a shared causal variant (rs972974) between COL6A3 and bronchiectasis (PP.H4 = 0.967/0.876).Conclusion There is an inverse causal relationship between COL6A3 and bronchiectasis. Low expression of COL6A3 increases the risk of developing bronchiectasis, making COL6A3 a potential biomarker and therapeutic target for drug development in bronchiectasis.
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.