Chronic Obstructive Pulmonary Disease Influence on Lung Cancer Risk Through Blood Metabolite Mediation: A Two-Sample Mendelian Randomisation and Mediation Analysis.

PURPOSE: Lung cancer (LC) risk is increased by chronic obstructive pulmonary disease (COPD) through metabolic and inflammatory processes. In addition to identifying possible inflammatory or blood metabolite mediators, this study explores the causal link between LC and COPD.

PATIENTS AND

METHODS

To determine whether COPD and LC are causally related, as well as whether inflammatory variables and blood metabolites mediate this relationship, we used two-sample and two-step Mendelian randomization (MR) analyses based on summary data from published genome-wide association studies (GWAS). Directionality and robustness were investigated using reverse MR and sensitivity analyses, primarily using the inverse variance weighted (IVW) method.

RESULTS

Two-sample MR analyses revealed that COPD was a risk factor for the occurrence of LC (P = 0.002, OR = 1.114 [1.042-1.191]). Moreover, 113 blood metabolites and six inflammatory factors showed nominally significant causal associations with LC risk (P < 0.05). Conversely, LC had no casual effect on COPD, while LC had significant causal associations with six blood metabolites. Mediation analysis demonstrated that three blood metabolites enhanced the promoted effect of COPD on the occurrence of LC, namely 1-stearoyl-2-arachidonoyl-gpc (18:0/20:4) levels, Epiandrosterone sulfate levels, and 1-palmitoyl-2-arachidonoyl-gpc (16:0/20:4n6) levels. However, there was no casual effect of COPD on inflammatory factors. Sensitivity analyses confirmed that all results were reliable.

CONCLUSION

These findings shed light on the underlying mechanisms that link COPD and LC and highlight the fact that COPD is a risk factor for the development of LC, with blood metabolites partially mediating this effect.