Causal Relationships Between High-Altitude Adaptation, Metabolic Traits, and Tumors: Insights from Mendelian Randomization.

Zhang, Xingkai, Liang He, Kai Li, Wen Li, Li Wang, Ling Chen, and Qinghai Shi. Causal relationships between high-altitude adaptation, metabolic traits, and tumors: Insights from Mendelian randomization. High Alt Med Biol. 00:00-00, 2025. Background and Objectives: Previous studies suggest that high-altitude adaptation (HAA) and metabolic traits in high-altitude populations correlate with tumor risk, but causal mechanisms remain unclear. This Mendelian randomization (MR) study investigated genetic links between HAA, metabolic traits, and tumor susceptibility while exploring potential mediation effects. Methods: Genome-wide association studies data for HAA, metabolic traits, and tumors were sourced from public databases. Inverse variance weighting served as the primary analytical method, supplemented by weighted mode, MR-Egger, and weighted median. Sensitivity analyses and two-step MR (TSMR) assessed robustness and mediation pathways. Results: We identified a potential association between HAA and a decreased risk of pancreatic cancer (odds ratio [OR] = 8.94e-8, p = 0.011) and cervical cancer (OR = 8.04e-6, p = 0.005). In contrast, HAA showed a potential link to an increased risk of esophageal cancer (OR = 3230.25, p = 0.03) and hepatocellular carcinoma (OR = 2080.07, p = 0.015). Several metabolic traits, particularly platelet-related indices, were identified as potentially associated with tumorigenesis. However, although possible mediating pathways were suggested, no metabolic trait demonstrated a statistically significant mediating effect. Conclusion: These findings highlight HAA's complex role in tumor susceptibility and provide a genetic framework for understanding tumor disparities in high-altitude regions.