Role of OAF and smoking initiation in COPD risk: Insights from Mendelian randomization

Chronic Obstructive Pulmonary Disease (COPD) is a complex condition influenced by both genetic and environmental factors. This study aims to identify potential biomarkers and explore the associations between specific maker genes, smoking initiation, and COPD.

We used Mendelian randomization (MR) with inverse variance weighting (IVW) to identify significant associations (p<0.05). Genetic instruments for smoking initiation (Genome-Wide Association Study [GWAS]: ieu-b-4877) and Out at First (OAF) (cis-expression Quantitative Trait Locus [eQTL] GWAS) were selected based on single nucleotide polymorphisms (SNPs) with p<5×10^-8. COPD GWAS data served as the outcome. Two-sample MR analysis estimated causal effects of smoking initiation/OAF on COPD. Mediation analysis explored the role of 731 immune cell phenotypes in these associations.

We identified OAF as a key genetic marker associated with COPD risk, with the eQTL analysis yielding an odds ratio (OR) of 1.09 (95% CI: 1.02-1.17, p=0.01). The IVW analysis for smoking initiation-COPD indicated an OR of 1.89 (95% CI: 1.69-2.11, p<0.001). Mediation analysis revealed that the immune cell phenotype CD14- CD16- absolute count (AC) (GCST90001581) accounted for 30.16% and 4.27% of the mediation in the OAF-COPD and smoking initiation-COPD associations, respectively.

The MR results suggest that OAF may be a genetic risk factor for COPD, with immune cell phenotypes, particularly CD14-CD16-AC, potentially playing a mediating role in COPD development. Smoking initiation is also positively correlated with COPD, playing an important role in its pathogenesis.