Cancer Causes Control. 2026 Jul 22;37(8):131. doi: 10.1007/s10552-026-02219-z.
ABSTRACT
OBJECTIVES: Observational studies examining the association between vitamin D and head and neck cancer (HNC) have reported conflicting results. We conducted a two-sample MR study to investigate the causal association between genetically predicted serum 25-hydroxyvitamin D (25(OH)D) levels and the risk of HNC and its major subtypes: oral cavity, laryngeal, hypopharyngeal, and HPV-negative oropharyngeal cancers.
DESIGN: Genetic instruments were selected from GWAS of 441,291 individuals (UK Biobank). Cancer outcomes were obtained from the HEADSpAcE consortium. Multiple sclerosis (MS) was analyzed as a positive control. We identified 115 independent genetic instruments for serum 25(OH)D. Causal estimates were primarily derived using inverse variance weighted (IVW) MR, supported by MR-Egger, weighted median, and mode-based methods. Extensive sensitivity analyses assessed heterogeneity, pleiotropy, and directionality.
RESULTS: We identified 115 independent genetic instruments for serum 25(OH)D levels, which explained 5.12% of the total phenotypic variance. The mean F-statistic was 198.3 and satisfied MR assumptions. Only 17 of 682 (2.5%) SNP-confounder associations reached nominal significance (p < 5 × 10⁻8), and none remained significant after Bonferroni correction, indicating no systematic confounding. Higher 25(OH)D levels were associated with a reduced risk of MS (IVW OR = 0.84, 95% CI 0.71-0.99, p = 0.038; weighted median OR = 0.82, 95% CI 0.70-0.96, p = 0.015), while no evidence of a causal association was observed between 25(OH)D and risk of HNC or any subtype (all IVW p > 0.05; ORs ranging from 0.95 to 1.25). Sensitivity analyses revealed no evidence of horizontal pleiotropy, influential outliers, or reverse causation for any cancer outcome.
CONCLUSIONS: This study provides robust genetic evidence that circulating 25(OH)D levels are not a major causal determinant of HNC risk and that our instruments are not confounded by major lifestyle or UV-related factors.
PMID:42484911 | DOI:10.1007/s10552-026-02219-z
