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, ß-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.
ABSTRACT
BACKGROUND: Lung cancer is the primary cause of cancer-related mortality worldwide. Hemoglobin (Hb) represents the most widely utilized test parameter in clinical settings. However, few articles have examined the causal relationship between Hb concentration and lung cancer incidence. METHODS: Mendelian randomization (MR) was first conducted to investigate the potential causality between Hb and lung cancer. Sensitivity analyses were applied to validate the reliability of MR results. Then, the National Health and Nutrition Examination Survey (NHANES) database was used to verify the effect of Hb on the prognosis of lung cancer. RESULTS: The MR analysis demonstrated that Hb was casually associated with the decreased risk of lung cancer in the European population (ORIVW 0.84, 95% CI 0.75-0.95, p = 0.006; ORWeighted-median 0.78, 95% CI 0.65-0.94, p = 0.008; ORMR-Egger 0.82, 95% CI 0.64-1.04, p = 0.11). The results from the NHANES database showed that a high value of Hb was associated with better outcomes for patients with lung cancer (HR 0.45, 95% CI 0.26-0.79, p = 1.6E-03). CONCLUSIONS: Our study provides further evidence for the relationship between Hb levels and lung cancer, highlighting the potential significance of Hb as a biomarker for predicting the risk and prognosis of lung cancer.