CXCL9 mediating the effect of thyroid disorders on oral and oropharyngeal cancer risk: A mediation Mendelian randomization study

The established association between thyroid disorders (TD) and its two main subtypes—hyperthyroidism and hypothyroidism—and the incidence of oral and oropharyngeal cancer (OCPC) has been substantiated. However, the direct causal relationship and potential intermediary mechanisms linking these conditions have not been clearly defined in prior studies. This study employed univariate Mendelian randomization (MR) analysis to explore those relationship. Instrumental variables from genome-wide association study (GWAS) datasets for TD (n = 218,792), hyperthyroidism (n = 460,499), hypothyroidism (n = 213,990), and OCPC (n = 12,619), along with 41 intermediary inflammatory cytokines (n = 8293), were analyzed. Inverse variance weighting (IVW) method assessed the causal relationships, while summary MR analysis with pQTL datasets from decode and 91 inflammatory cytokines explored the cytokines' roles as biomarkers and therapeutic targets for OCPC. Multivariable MR (MVMR) analysis quantified the mediation effect of these cytokines in the TD-OCPC relationship. UVMR analysis provided strong evidence for a causal relationship between TD (OR = 1.376, 95 % CI = 1.142–1.656, p = 0.001), hyperthyroidism (OR = 1.319, 95 % CI=1.129–1.541, p = 0.001), hypothyroidism (OR = 1.224, 95 % CI = 1.071–1.400, p = 0.003), and the risk of OCPC. CXCL9 was identified as a significant intermediary in mediating the risk of OCPC from TD and its two subtypes (OR = 1.218, 95 % CI = 1.016–1.461, P = 0.033), suggesting its potential as a predictive biomarker for OCPC. MVMR analysis further revealed that CXCL9 mediated 7.94 %, 14.4 %, and 18 % of the effects of TD, hyperthyroidism, and hypothyroidism on OCPC risk, respectively. This study not only elucidated the potential causal relationships between TD including its two subtypes and OCPC risk, but also highlighted CXCL9 as a pivotal mediator in this association.