Association between hyperthyroidism, subacute thyroiditis and twenty common cancers: A bidirectional mendelian randomization study

Abstract Objective: The epidemiological evidence regarding the causal relationship between hyperthyroidism, subacute thyroiditis (SAT), and tumors remains inconclusive. Therefore, we conducted a two-sample bidirectional Mendelian randomization (MR) study to establish the causal relationship between these conditions. Methods: We conducted a bi-directional MR study using publicly available GWAS summary statistics to explore the causality between genetically predicted hyperthyroidism, SAT and the risk of 20 common cancers. The analysis was performed using inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. The primary results were based on the IVW (random effects), followed by sensitivity analysis. Furthermore, maximum likelihood, penalized weighted median and IVW (fixed effects) were used to confirm the robustness of the findings. Results: IVW analysis revealed a significant positive causal association between hyperthyroidism and breast cancer (OR = 2.20E+05, 95% CI: 7.7733–6.23E+09, P = 0.0187), ovarian cancer (OR =1.0949, 95% CI: 1.0250–1.1696, P = 0.0071), thyroid cancer (OR =3.05E+11, 95% CI: 1.06E+01–8.84E+21, P = 0.0314), and colorectal cancer (OR =1.1345, 95% CI: 1.0293–1.2505, P = 0.0110) ; while hyperthyroidism had an inverse association with bladder cancer (OR =0.9446, 95% CI: 0.9017–0.9896, P = 0.0164), prostate cancer (OR =0.6174, 95% CI: 0.4879–0.7813, P = 5.97E-05), liver and bile duct cancer (OR =0.9723, 95% CI: 0.9540–0.9910, P = 0.0038), brain cancer (OR =0.9699, 95% CI: 0.9460–0.9945, P = 0.0166), and malignant neoplasm of male genital organs (OR =0.8593, 95% CI: 0.7868–0.9385, P = 0.0007). Furthermore, the IVW analysis supported a positive causal relationship between SAT and endometrial cancer (OR =1.031, 95% CI: 1.0032–1.0596, P = 0.0288), while SAT had an inverse association with kidney cancer (OR =0.9015, 95% CI: 0.8255–0.9844, P = 0.0209) and thyroid cancer (OR =0.9143, 95% CI: 0.8390–0.9962, P =0.0407). However, we only observed an inverse association between malignant neoplasm of male genital organs and SAT in the reverse MR analyses. Conclusions: The current investigation offers genetic evidence that hyperthyroidism could potentially elevate the risk of developing breast, ovarian, thyroid, and colorectal cancers. Likewise, SAT is identified as a possible risk factor for endometrial cancer. In light of these findings, further studies are necessary to uncover the underlying mechanisms that establish causal links between hyperthyroidism, SAT, and malignancies.