Supplementary material for “Genetic insights into causal effects of serum lipids and lipid-lowering drug target genes on autoimmune thyroid disease”

<b>Abstract</b>Context: The role of serum lipids or lipid-lowering drugs in AITD patients remains confusing.Objective: To investigate the causal association between lipid traits, as well as lipid-lowering drug target genes and AITD.Methods: Mendelian randomization (MR) analysis was used to assess the effects of lipid traits, as well as 10 lipid-lowering drug target genes on AITD. Summary statistics data for AITD in European ancestry were obtained from FinnGen R10, including Graves' disease (GD), Graves' ophthalmology (GO) and autoimmune thyroiditis. To further explore the generality in other races, we supplemented the analysis of lipid-lowering drug targets in East Asian ancestry. IVW-MR was used to calculate the causal effects primarily and SMR was conducted as validation analysis. Furthermore, sensitivity test, heterogeneity test and positive control were performed to validate the robustness of the results.Results: Our findings did not support dyslipidemia as a causal factor for AITD risk. However, after multiple testing correction, we observed risk relevance between APOB and autoimmune thyroiditis (OR=2.18, 95%CI=1.30-3.64; P=0.003). SMR analysis also showed that APOB expression in subcutaneous adipose tissue is linked to a higher risk of autoimmune thyroiditis. In addition, we also found other target genes had suggestive correlation with autoimmune thyroiditis, such as ANGPTL3 (OR=5.26,95%CI=1.54-17.94; P=0.008), LPL (OR=2.15,95%CI=1.31-3.53; P=0.003) and CETP (OR=0.10,95%CI=0.02-0.48; P=0.005). In cross-ancestry analysis, we found that CETP had a potential protective effect in GD (OR=0.43, 95%CI=0.21-0.86; P=0.018). However, these effects did not pass multiple corrections, nor replicated in SMR analyses.Conclusions: Our study suggested that genetically proxies inhibition of APOB might decrease the risk of autoimmune thyroiditis. However, further pharmacological validation and clinical trials are needed to confirm this association and explain the underlying mechanisms.