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 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.