Blood Manganese and Risk of Squamous Cell Carcinomas of the Head and Neck

Importance: Squamous cell carcinomas of the oral cavity (OCSCC), oropharynx (OPSCC), hypopharynx (HPSCC), and larynx (LSCC) are the most common forms of head and neck cancer globally. Epidemiological studies have identified variations in blood trace metal concentrations as potential risk factors for the development of these cancers, but these studies are susceptible to multiple biases. Objective: To determine if variations in genetically predicted blood manganese are associated with risk of OCSCC, OPSCC, HPSCC, and LSCC. Design, Setting, and Participants: This population-based 2-sample cis-mendelian randomization study used a genetic instrument for blood manganese derived from a meta-analysis of 3 individual-level genome-wide association study datasets of 6564 Scandinavian participants. Genetic associations for the development of the specified cancers were obtained from a nonoverlapping, multi-ancestral meta-analysis that combined individual-level genome-wide association study datasets comprising 38 857 healthy controls, 5596 case patients with OCSCC, 2212 case patients with human papillomavirus (HPV)-positive OPSCC, 1473 case patients with HPV-negative OPSCC, 898 case patients with HPSCC, and 4409 case patients with LSCC. Exposures: Increases in genetically predicted whole blood manganese concentration proxied by a genetic instrument including 2 cis-variants (single-nucleotide variants) selected due to their known functions in regulating manganese metabolism. Main Outcomes and Measures: The primary outcomes were the risk of OCSCC, OPSCC (HPV positive and HPV negative), HPSCC, and LSCC, evaluated by estimating the odds ratio (OR) and 95% CI of each outcome per 1-SD increase in whole blood manganese concentration after rank-based inverse normalization transformation. Results: Genetically predicted higher blood manganese was found to have a statistically significant association with increased risk of OCSCC (OR, 1.25; 95% CI, 1.10-1.43; P < .001) and HPV-positive OPSCC (OR, 1.23; 95% CI, 1.04-1.45; P = .02). Associations between blood manganese and HPV-negative OPSCC (OR, 1.20; 95% CI, 0.95-1.50; P = .13), HPSCC (OR, 1.25; 95% CI, 0.75-2.07; P = .39), and LSCC (OR, 1.10; 95% CI, 0.92-1.32; P = .28) were directionally concordant but not statistically significant. Conclusions and Relevance: This cis-mendelian randomization study demonstrates statistically significant associations between higher blood manganese concentrations and risk of OCSCC and HPV-positive OPSCC. Further work should aim to establish the pathophysiological mechanisms underlying this association to inform potential public health strategies for the prevention of these cancers.