An in-depth study of the correlation between Hashimoto's thyroiditis and Sjogren's syndrome: multiple evidences from large cohorts, Mendelian randomization, and transcriptomic analysis.

The co-occurrence of Hashimoto's thyroiditis (HT) and Sjogren's syndrome (SS), two seemingly unrelated diseases that both affect huge amounts of people worldwide, has been indicated previously in several case reports. However, there is a lack of higher-level evidences proving their comorbidity, and the underlying mechanisms remain unelucidated. This in-depth study aims to provide evidences for the comorbidity between HT and SS and explore the genetic and immunological mechanisms that may underlie their occurrence. Leveraging large retrospective cohorts from the collaborative electronic health record database, matched by propensity scores, we evaluated the risk of developing SS in 190,653 patients with HT and the risk of developing HT in 73,306 patients with SS. A Mendelian randomization (MR) approach was applied to investigate the causal relationship between the two conditions. Transcriptomic analysis of GEO datasets further explored common immunological markers. Our large-scale propensity score-matched analysis revealed a significantly higher risk of SS in HT patients compared to controls, with a hazard ratio (HR) of 3.227 and a confidence interval (CI) of 2.987-3.486, over a 20-year follow-up period. Similarly, a reciprocal risk was observed, with SS patients at a higher risk of developing HT (HR, 2.780; CI, 2.568-3.009) compared to controls. In Mendelian randomization study, random-effects IVW method showed a potential causal effect of HT on SS (IVW OR = 1.871, 95% CI = 1.265-2.768; P = 0.002). Furthermore, transcriptomic analysis showed there were 127 common up-regulated differential expressed genes (DEGs) between HT and SS, accounting for 29.4% of upregulated DEGs in HT and 14.5% of upregulated DEGs. Common hub genes in HT and SS were also determined, including CD4, IFNG, CCR7, and ITGAM, suggesting a shared immunopathogenesis and highlighting potential therapeutic targets. Our findings revealed a strong correlation between HT and SS, supported by evidences from clinical cohorts, the genetical causal effect, and shared immunopathogenesis, offering new insights into the cooccurrence of the two diseases.