Causal associations between plasma metabolites and head and neck cancer: a bidirectional Mendelian randomization study

OBJECTIVE: Although observational studies have reported associations between plasma metabolites and Head and Neck Cancer (HNC), their causal relationships remain unclear. This study aimed to systematically evaluate the causal associations between circulating plasma metabolites and HNC risk using a bidirectional Mendelian Randomization (MR) approach. METHODS: We conducted a bidirectional two-sample MR analysis leveraging Genome-Wide Association Study (GWAS) summary statistics for 1400 plasma metabolites and HNC from the FinnGen consortium. Causal estimates were primarily derived using the Inverse Variance-Weighted (IVW) method, complemented by MR-Egger, weighted median, and weighted mode approaches. Sensitivity analyses, including heterogeneity tests, pleiotropy assessment, and leave-one-out analyses, were performed to ensure robustness. To validate the findings, significant associations were replicated using independent HNC GWAS data from the IEU OpenGWAS database. RESULTS: IVW analysis identified three plasma metabolites causally associated with increased HNC risk: 1,2-dipalmitoyl-gpc (16:0/16:0) (OR = 1.20, 95% CI 1.06-1.37, p = 0.004), P-cresol glucuronide (OR = 1.22, 95% CI 1.03-1.45, p = 0.023), and Nisinate (24:6n3) (OR = 1.15, 95% CI 1.01-1.32, p = 0.038). These associations were directionally consistent and supported by sensitivity and replication analyses. No evidence suggested reverse causality from HNC to these metabolites. CONCLUSIONS: This study provides systematic genetic evidence supporting causal roles of specific plasma metabolites in HNC development. These findings enhance the understanding of metabolic mechanisms underlying HNC and may inform future biomarker discovery and preventive or therapeutic strategies. LEVEL OF EVIDENCE: Level 3.