This study aimed to investigate the causal relationship between PAH and various common cancers using (MR methods. Our findings suggest that genetically proxied PAH is significantly associated with an increased risk of liver cancer, while no substantial causal links were found with other common cancer types, including thyroid, lung, gastric, and colorectal cancers. These results have important implications for understanding how chronic conditions like PAH may influence cancer risk.

Previous epidemiological studies have also indicated a potential association between PAH and tumors. A cohort study using Danish nationwide registries that included over 5,000 PAH patients found that the risk of developing cancer in PAH patients was significantly increased in the first year, nearly doubling compared to the general population [32]. Coincidentally, another study has explored the potential association between Pulmonary hypertension and cancer within a German outpatient cohort. Utilizing the Disease Analyzer database (IQVIA), this research identified over 11,000 treated PH patients, revealing a significantly higher cancer incidence (23.2%) compared to non-PH patients (8.5%) over a 10-year period, with notable associations observed in both male and female patients, as well as specific cancer types such as respiratory and skin cancers [33]. However, our study did not find a significant causal relationship between PAH and lung cancer. This discrepancy could be explained by several factors. First, MR analysis relies on genetic variants as IVs, which may not fully capture the complexities of the relationship observed in clinical studies, where confounding factors such as smoking or environmental exposures could play a significant role. Second, clinical studies often reflect direct observational associations, which are more susceptible to bias from confounding and reverse causality. In contrast, MR analysis seeks to infer causality based on genetic variation, which may not be directly comparable to the findings of observational studies. Additionally, the absence of a significant result in our MR analysis could also be due to insufficient power or the lack of relevant genetic variants strongly associated with both PAH and lung cancer. Future studies with larger datasets and more refined genetic instruments could help clarify this relationship.

The observed association between PAH and cancer raises questions about the underlying mechanisms. One potential explanation is that chronic hypoxia, a hallmark of PAH, may promote tumorigenesis in the liver. Hypoxia could lead to the activation of hypoxia-inducible factors (HIFs), which are transcription factors that regulate various genes involved in angiogenesis, metabolism, and cell survival [34]. This process could enhance the growth and spread of liver tumors. Additionally, the hemodynamic changes associated with PAH may lead to liver dysfunction, contributing to an environment conducive to cancer development. Inflammation and fibrosis, often seen in both PAH and liver disease, may also play a role in this relationship by promoting cellular changes that facilitate cancer progression. Understanding the potential pathways linking PAH and cancer is critical for developing preventive strategies and therapeutic interventions. For instance, targeted therapies that address the underlying pathophysiology of PAH may also mitigate cancer risk. Furthermore, monitoring liver function in PAH patients could provide early indicators of increased cancer risk, enabling timely interventions. It is also important to consider the implications of genetic and environmental heterogeneity in different populations, as genetic variants and environmental exposures influencing PAH and cancer risk may vary significantly across diverse cohorts. The findings of this study, based on a European population, may not fully capture these variations. Replicating these analyses in non-European populations is essential to validate the observed associations and ensure their generalizability. Such efforts could provide a deeper understanding of the interplay between genetic predisposition, environmental factors, and disease outcomes, ultimately leading to more personalized and inclusive preventive strategies.

The use of MR in this study offers several advantages. MR is powerful for establishing causal relationships as it leverages genetic variants as IVs, which are less prone to confounding and reverse causation. This method provides more accurate causal effect estimates compared to traditional observational studies and allows exploration of the effects of long-term exposure, such as PAH, since genetic variants are fixed at conception and remain constant throughout life. However, MR is not without its limitations [35]. One significant concern is the assumption of independence among the IVs. If genetic variants are associated with confounding factors, the results may be biased. Additionally, while we did not observe evidence of horizontal pleiotropy in our analysis, this could still be a concern in MR studies. Horizontal pleiotropy occurs when genetic variants affect the outcome through pathways other than the exposure, potentially leading to misleading conclusions. The use of sensitivity analyses, such as MR-Egger regression and leave-one-out analyses, helps to address these issues, but they cannot completely eliminate the risk of bias. Another significant limitation of this study is the lack of exploration into the underlying mechanisms linking pulmonary arterial PAH to cancer. While our findings suggest a potential association between PAH and certain cancer types, the biological pathways that may mediate this relationship remain unclear.

In conclusion, this study highlights a significant association between genetically proxied PAH and an increased risk of liver cancer, suggesting that chronic conditions like PAH may have important implications for cancer risk. Understanding the underlying mechanisms linking PAH to cancer can inform preventive strategies and therapeutic approaches. While MR provides a robust framework for establishing causal relationships, researchers must remain vigilant about the potential limitations and biases inherent in this method. Further research is needed to explore the mechanisms linking PAH to cancer and to validate these findings in diverse populations. This knowledge will be critical for improving patient outcomes and informing public health strategies aimed at reducing cancer risk in individuals with chronic conditions.