Abstract
Background
Evidence of the genetic interconnectedness between PD-1/PD-L1 and circulating biomarkers related to physiological and pathological processes is largely unclear. Understanding these genetic links is crucial for gaining insights into the underlying mechanisms and potential implications in cancer immunotherapy.
Methods
To shed light on potential roles of 90 circulating biomarkers in PD-1/PD-L1, we conducted a comprehensive Mendelian randomization (MR) analysis, leveraging genetic data from large-scale genome-wide association studies.
Results
Our results revealed negative associations between EN-RAGE and TRAIL-R2 with PD-1 levels. Additionally, we observed that PD-1 levels were positively associated with TRAIL, VEGF, and ANPEP, indicating their potential role in PD-1 upregulation. Furthermore, our analysis revealed causal associations between several circulating proteins and PD-L1 levels. Thrombomodulin, PSGL-1, TNFSF14, renin, follistatin, β-NGF, KLK6, and MMP-7 demonstrated significant effects on PD-L1 regulation, suggesting their potential inhibitory role in immune checkpoint regulation. Eventually, we confirmed the potential roles of key genes involved in above circulating proteins in influencing the response to immunotherapy.
Conclusions
Our findings provide valuable evidence of the genetic interconnectedness between PD-1/PD-L1 and circulating proteins related to physiological and pathological processes, shedding light on their potential roles in disease progression and therapeutic interventions.
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Data availability
The original data are available in the open GWAS project (https://gwas.mrcieu.ac.uk/).
Abbreviations
- ICB:
-
Immune checkpoint blockade
- PD-1:
-
Programmed cell death protein 1
- PD-L1:
-
Programmed cell death ligand 1
- MR:
-
Mendelian randomization
- SNPs:
-
Single nucleotide polymorphisms
- ORs:
-
Odd ratios
- CIs:
-
Confidence intervals
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Acknowledgements
We appreciate the work of the open GWAS project (https://gwas.mrcieu.ac.uk/).
Funding
This work was supported by the National Natural Science Foundation of China Grant (82172642 to W. Wang) and Natural Science Foundation of Guangdong Province (2021A1515011683 to W. Wang).
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WL, WW: conceptualization, methodology, data curation, software and writing—review and editing. The work reported in the paper has been performed by the authors, unless clearly specified in the text.
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Li, W., Wang, W. Unraveling the genetic associations between PD-1/PD-L1 and 13 circulating biomarkers linked to physiological and pathological processes. Clin Transl Oncol 26, 1157–1169 (2024). https://doi.org/10.1007/s12094-023-03333-z
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DOI: https://doi.org/10.1007/s12094-023-03333-z