Genetic analysis the causal associations between metal elements and thyroid cancer: a bidirectional Mendelian...

Thyroid cancer is the most common endocrine malignancy worldwide, and recent studies suggest that environmental metal exposure may influence its development. However, existing evidence is mostly observational and lacks causal inference.

We performed a two-sample Mendelian randomization (MR) analysis to assess the causal relationships between 21 metal elements and thyroid cancer risk in East Asian populations. Genetic instruments were selected from a GWAS of 2488 individuals, and thyroid cancer summary statistics were obtained from 361 cases and 178,362 controls. The inverse-variance weighted (IVW) method was used as the primary analysis, with MR-Egger, weighted median, MR-PRESSO, and sensitivity analyses to assess robustness.

IVW results identified a positive causal association between serum lead levels, OR = 1.608 (95% CI: 1.165-2.219; P = 0.004) and plasma manganese levels, OR = 1.332 (95% CI: 1.087-1.633; P = 0.006) with thyroid cancer. In contrast, plasma titanium levels were inversely associated with thyroid cancer risk, OR = 0.834 (95% CI: 0.697-0.997; P = 0.046). No evidence of reverse causation was found. Sensitivity analyses showed no significant heterogeneity or pleiotropy, supporting the robustness of the findings.

This study provides the first genetic evidence for causal links between specific metal exposures and thyroid cancer. Elevated lead and manganese levels may increase cancer risk, while titanium may have a protective effect. These findings warrant further validation through mechanistic and longitudinal studies across diverse populations.