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Updated: Jul 1, 2025
Drug Repurposing Hypothesis Generation Using the "RE:fine Drugs" System
Published on: December 11, 2016
Genetic insights into repurposing statins for hyperthyroidism prevention: a drug-target Mendelian randomization study
Anqi Huang1,2, Xinyi Wu1,2, Jiaqi Lin1,2
1Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
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 (OR1, 0.417 per 1-mmol/L lower in LDL-C; 95% CI 0.262 to 0.664; P1 = 2.262 × 10-4; OR2 0.996; 95% CI 0.993-0.998; P2 = 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.
Insights
Statins (HMGCR inhibitors) may reduce hyperthyroidism risk, suggesting novel therapeutic avenues beyond lipid lowering. Insulin-like growth factor 1 (IGF-1) may mediate this effect, warranting further research.
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.
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