BACKGROUND

This study utilized Mendelian randomization (MR) to investigate the causal relationship between circulating plasma proteins and lung adenocarcinoma.

METHODS

We obtained 734 circulating plasma protein data from genome-wide association studies (GWAS) as exposure factors and extracted single nucleotide polymorphisms (SNPs) as instrumental variables. And we obtained lung adenocarcinoma data (including 11,245 cases and 54,619 controls) from the IEU Open GWAS database as the outcome factor. The main analytical methods used are inverse-variance weighted (IVW) or Wald ratio to assess the causal relationship between circulating plasma protein levels and lung adenocarcinoma. Sensitivity analysis (leave one out method, heterogeneity and pleiotropy tests), external validation analysis, and meta-analysis after MR were used to evaluate the reliability of MR results. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the final screened plasma proteins.

RESULTS

Through the preliminary and external validation stages, ICAM5 (OR = 0.92, 95%CI: 0.89-0.95, P = 2.31 × 10), PCYOX1 (OR = 0.89, 95%CI: 0.85-0.93, P = 5.31 × 10), and TYMP (OR = 0.76, 95%CI: 0.66-0.87, P = 5.79 × 10) are negatively correlated with lung adenocarcinoma. Sensitivity analyses, external validation, and post-MR meta-analysis indicated that the MR results were robust. GO and KEGG pathway enrichment analyses demonstrated that these plasma proteins were primarily enriched in pathways such as "pyrimidine deoxyribonucleoside monophosphate metabolic process", "deoxyribonucleoside monophosphate catabolic process", "mitochondrial genome maintenance", and "Pyrimidine metabolism".

CONCLUSIONS

ICAM5, PCYOX1 and TYMP are associated with a decreased risk of lung adenocarcinoma. Plasma proteins may become new biological markers for lung adenocarcinoma, providing new insights into the prevention and treatment of this disease.