Causal Effects of Valine on Ovarian Cancer: A Bidirectional Mendelian Randomization Analysis.

Background: Ovarian cancer is a lethal female cancer with a rising incidence that is often diagnosed late due to a lack of symptoms, affecting survival and quality of life. Studies suggest that dietary factors, especially the levels of branched-chain amino acids such as valine, may influence its development. While valine is essential for metabolism, its specific role in ovarian cancer remains unclear, necessitating further research.

Methods: This study aimed to elucidate the causal relationship between valine and OC through a bidirectional Mendelian randomization (MR) approach. Data were sourced from the IEU OpenGWAS project, encompassing genome-wide association statistics for valine (N = 115,048) and OC (Ncase = 1,218, Ncontrol = 198,523) among European participants. Independent genetic variants associated with each phenotype at genome-wide significance were employed as instrumental variables (IVs). The primary analysis utilized the inverse variance weighted (IVW) method for two-sample MR analysis. MR‒Egger regression was applied to adjust for potential pleiotropy, whereas the weighted median method provided robust causal estimates under the assumption of valid IVs. Sensitivity analyses, including leave-one-out (LOO) analysis, heterogeneity tests, and horizontal pleiotropy assessments, were conducted to ensure the robustness of the findings.

Results: The results revealed a significant causal relationship between valine and OC, identifying valine as a risk factor for OC (p = 0.043, 95% CI = 1.00008-1.00491, OR = 1.00249) in the forward MR analysis. Sensitivity analyses confirmed the absence of heterogeneity (Q_p value >0.05) and horizontal pleiotropy (p > 0.05), and LOO analysis validated the stability of the results. Conversely, reverse MR analysis revealed no causal effect of OC on valine levels (p = 0.875, 95% CI = 0.34125-2.51495, OR = 1.08528).

Conclusions: These findings reveal a causal link between high valine levels and an increased OC risk. This research highlights the monitoring of valine levels as a preventive strategy and the significance of valine metabolism in OC. Future studies are needed to investigate the mechanisms and interventions for reducing risk, offering insights for clinical practice and public health initiatives in OC prevention.