Abstract
BACKGROUND: Current therapeutic measures for thyroid dysfunction are limited and often accompanied by adverse effects. The use of lipid-lowering drugs like statins has recently been associated with lower thyroid eye diseases risk. OBJECTIVE: To investigate the implications of genetically proxied lipid-lowering drugs on thyroid dysfunction. METHODS: In this drug-target Mendelian randomization (MR) study, we utilized genetic variants within drug target genes associated with low-density lipoprotein (LDL) or triglyceride (TG), derived from a genome-wide association study (GWAS) meta-analysis (N ≤ 188,577), to simulate lifelong drug interventions. Genetic summary statistics for thyroid dysfunction outcomes were retrieved from GWAS datasets of Thyroid Omics Consortium (N ≤ 54,288) and UK Biobank (N = 484,598). Inverse-variance-weighted MR (IVW-MR) method was performed as primary analysis, followed by validation in colocalization analysis. A subsequent two-step MR analysis was conducted to identify biomarkers mediating the identified drug-outcome association. RESULTS: In IVW-MR analysis, genetic mimicry of 3-hydroxy-3-methylglutarylcoenzyme reductase (HMGCR) inhibitors (e.g. statins) was significantly associated with lower risk of hyperthyroidism in two independent datasets (OR(1), 0.417 per 1-mmol/L lower in LDL-C; 95% CI 0.262 to 0.664; P(1 = )2.262 × 10(-4); OR(2) 0.996; 95% CI 0.993-0.998; P(2 = )0.002). Two-step MR analysis revealed eighteen biomarkers linked to genetic mimicry of HMGCR inhibition, and identified insulin-like growth factor 1 (IGF-1) levels mediating 2.108% of the negative causal relationship between HMGCR inhibition and hyperthyroidism. CONCLUSION: This study supports HMGCR inhibition as a promising therapeutic strategy for hyperthyroidism and suggests its underlying mechanisms may extend beyond lipid metabolism. Further investigations through laboratory studies and clinical trials are necessary to confirm and elucidate these findings.