Genetic insights into repurposing statins for hyperthyroidism prevention: a drug-target Mendelian randomization study

Area of Science:

• Endocrinology and Metabolic Diseases
• Pharmacogenomics
• Genetic Epidemiology

Background:

• Current treatments for thyroid dysfunction have limitations and side effects.
• Statins, used for lipid lowering, have shown potential in reducing thyroid eye disease risk.

Purpose of the Study:

• To investigate the causal relationship between genetically proxied lipid-lowering drugs and thyroid dysfunction.
• To explore potential biomarkers mediating the association between lipid-lowering drug targets and thyroid dysfunction.

Main Methods:

• A drug-target Mendelian randomization (MR) study using genetic variants from genome-wide association studies (GWAS).
• Utilized genetic data for low-density lipoprotein (LDL) or triglyceride (TG) targets and thyroid dysfunction outcomes.
• Employed inverse-variance-weighted MR (IVW-MR) and colocalization analysis, followed by two-step MR for mediation analysis.

Main Results:

• Genetic mimicry of 3-hydroxy-3-methylglutarylcoenzyme reductase (HMGCR) inhibitors (statins) was significantly associated with a reduced risk of hyperthyroidism.
• Insulin-like growth factor 1 (IGF-1) was identified as a potential mediator, explaining 2.108% of the HMGCR inhibition-hyperthyroidism association.

Conclusions:

• HMGCR inhibition represents a promising therapeutic strategy for hyperthyroidism, with mechanisms potentially extending beyond lipid metabolism.
• Further laboratory and clinical studies are required to validate these findings and elucidate the underlying mechanisms.