Causal role of immune traits and inflammatory proteins in autoimmune thyroid disease: Mendelian randomization study

Abstract Purpose Despite the large-scale discovery of new subpopulations of immune cells and inflammatory proteins, along with their functions in the pathogenesis of autoimmune thyroid disease (AITD), the etiology of AITD remains a mystery in many aspects. We aimed to investigate the causal relationships between the immune traits, inflammatory proteins and AITD. Methods We performed bidirectional and multivariable Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of 731 immune traits (N = 3,757), 91 inflammatory proteins (N = 14,824), and AITD obtained from the FinnGen consortium R9 release data (N = 399,034). Next, we conducted colocalization analysis to enhance the association and performed linkage disequilibrium score regression (LDSC) to estimate genetic correlation. Finally, a two-step MR analysis was employed to identify potential mediating proteins. Results Sixteen immune traits and five inflammatory proteins are suggestively associated with AITD causally. In multivariable MR analysis, after incorporating smoking status and 25-hydroxyvitamin D levels, some immune traits showed non-significant effects on AITD, albeit with minimal changes in effect sizes. The MR-BMA analysis showed that the five inflammatory proteins played an equal role. Our findings indicate a suggestive genetic correlation between IL-1 alpha and AITD. The mediation MR analysis showed that STAMBP and IL-10 mediated the causal effects of the absolute count of CD33 + HLA-DR + CD14- cells and AITD. Conclusion The current MR study provides evidence supporting the causal relationships between several specific immune traits and AITD and potential mediating inflammatory proteins.