Genetic evidence for the causal association between programmed death-ligand 1 and lung cancer.

PD-1/PD-L1 might have a causal role in operating lung cancer risk. However, such an association has not been investigated in the general population. We assessed whether PD-L1 has an independent effect on lung cancer risk using two-sample Mendelian randomization (MR) based on a proteomic genome-wide association study (3301 health participants) of European ancestry and the International Lung cancer Consortium (11,348 cases and 15,861 controls). Negative control analyses using chronic obstructive pulmonary disease (COPD)/asthma/interstitial lung disease (ILD)-related infection (~ 22,730 cases and ~ 112,908 controls) were also conducted to enhance the credibility of the selected instruments and MR-based estimates. This study found that genetically predicted PD-1/PD-L1 were not significantly associated with lung cancer after adjustment for multiplicity. However, suggestive evidence was observed for the total effect of higher PD-1 with decreased lung cancer risk and the direct effect (i.e., not mediated by PD-1 and smoking) of lower PD-L1 with decreased lung cancer risk. No association between genetically predicted PD-L1 and COPD/asthma/ILD related infection was noted. Taken together, our findings suggest that interventions decreasing PD-L1 might have a role in lowering lung cancer risk.