Abstract
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.
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Availability of data and materials
The summary statistics for genetic associations of PD-1/PD-L1 are available in the INTERVAL study (http://www.phpc.cam.ac.uk/ceu/proteins/). The summary statistics for genetic associations of smoking (i.e., cigarettes per day) are available meta-analyzed GWAS study (https://www.finngen.fi/fi). The summary genetic statistics for genetic associations of lung cancer are available in the International Lung Cancer Consortium (Ilcco.iarc.fr). The annotated QTLs are available in RegulomeDB (https://regulomedb.org/regulome-search/) and PhenoScanner (http://www.phenoscanner.medschl.cam.ac.uk/). The 1000 genomes European reference panel is available via LDlink (https://ldlink.nci.nih.gov/).
Abbreviations
- Cis-pQTLs:
-
cis Protein quantitative trait loci
- CI:
-
Confidence interval
- eQTLs:
-
Expression quantitative trait loci
- GWAS:
-
Genome-wide association study
- ILCCO:
-
International Lung Cancer Consortium
- MR:
-
Mendelian randomization
- MVMR:
-
Multivariable Mendelian randomization
- OR:
-
Odds ratio
- PD-1:
-
Programmed death protein-1
- PD-L1:
-
Programmed death-ligand 1
- RFU:
-
Relative fluorescent unit
- SD:
-
Standard deviation
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Acknowledgements
We acknowledge participants and investigators of INTERVAL, FinnGen, and ILCCO study, and those of RegulomeDB, PhenoScanner, LDlink, and 1000 genomes European reference panel.
Funding
This work was supported by the Beijing Municipal Science & Technology Commission (Z181100001718192), the National Natural Science Foundation (82073333), and the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding (XMLX201842).
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Conception/design: ZY, WW. Collection and/or assembly of data: ZY, RY, WD. Data analysis and interpretation: ZY, RY, WD, WW. Manuscript writing: ZY, WD. Final approval of manuscript: all authors.
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Yang, Z., Yu, R., Deng, W. et al. Genetic evidence for the causal association between programmed death-ligand 1 and lung cancer. J Cancer Res Clin Oncol 147, 3279–3288 (2021). https://doi.org/10.1007/s00432-021-03740-1
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DOI: https://doi.org/10.1007/s00432-021-03740-1