The causal relationships between inflammatory cytokines, blood metabolites, and thyroid cancer: a two-step Mendelian randomization analysis.

Background: Thyroid cancer is a prevalent malignant tumor, especially with a higher incidence in women. Tumor microenvironment changes induced by inflammation and alterations in metabolic characteristics are critical in the development of thyroid cancer. Nevertheless, their causal relationships remain unclear.

Methods: We utilized thyroid cancer GWAS data from the Global Biobank Meta-Analysis Initiative and GWAS data of 91 inflammatory cytokines and 1400 blood metabolites obtained from the GWAS Catalog to evaluate the causality between inflammatory cytokines, blood metabolites, and thyroid cancer using Mendelian randomization (MR). Initially, we identified inflammatory cytokines having a significant causal effect on thyroid cancer. Subsequently, for the identified positive blood metabolites, we applied a two-step mediation MR method to examine their mediating role in the causal effect of specific inflammatory cytokines on thyroid cancer.

Results: Our forward MR analysis identified suggestive associations between 7 inflammatory cytokines and thyroid cancer risks, and found that tumor necrosis factor ligand superfamily member 14 (TNFSF14) (IVW-OR: 1.25, 95% CI 1.10-1.42, p = 0.0004) is a significant risk factor in thyroid cancer, and this causal relationship remained significant after Bonferroni correction. The reverse MR analysis identified suggestive causal associations between thyroid cancer and 3 inflammatory cytokines and ruled out the reverse causality between TNFSF14 and thyroid cancer. Then, we identified suggestive associations between 35 blood metabolites and 24 blood metabolite ratios with thyroid cancer, and found that 5-hydroxymethyl-2-furoylcarnitine (IVW-OR: 1.38, 95% CI 1.19-1.61, p = 0.00003) is a significant risk factor for thyroid cancer, with this causality remaining significant after Bonferroni correction. Finally, our two-step MR analysis indicated that Lactosyl-N-palmitoyl-sphingosine (d18:1/16:0) and X-12013 have a mediating effect in the causal relationship between TNFSF14 and thyroid cancer, with mediation proportions of 8.55% and 5.78%, respectively. Our MR analysis did not identify significant heterogeneity or horizontal pleiotropy.

Conclusion: This study identified some inflammatory cytokines and blood metabolites associated with thyroid cancer risk and revealed the mediating role of specific blood metabolites between TNFSF14 and thyroid cancer, highlighting the critical role of inflammatory and metabolic pathways in the pathogenesis of thyroid cancer.