GWAS of amiodarone-induced thyroid dysfunction: Applications for genotype-guided risk stratification

Summary Background Amiodarone is a widely used antiarrhythmic which frequently induces thyroid dysfunction, including both amiodarone-induced hypothyroidism (AIH) and thyrotoxicosis (AIT). Whether genetic factors contribute to these adverse drug reactions is unknown. In this study, we aimed to identify genetic variants that influence the risk of amiodarone-induced thyroid dysfunction and to evaluate their potential to support genotype-guided risk screening. Methods This pharmacogenetic study comprised two genome-wide meta-analyses of AIH and AIT using five datasets (Copenhagen Hospital Biobank, The Danish Blood Donor Study, Estonian Biobank, deCODE genetics, and Mass General Brigham Biobank). Key measures included the odds ratio (OR) per risk allele, the variants’ effects on spontaneous thyroid disease and biomarkers, and their clinical predictive ability, assessed by the area under the receiver operating curve (AUC), positive and negative predictive values (PPV and NPV). Findings The AIH meta-analysis (880 cases, 4,031 controls) identified three genome-wide significant loci in: FOXE1 (rs36052460; OR 2.58, allele frequency [AF] = 64.3%, P = 2.55 × 10 −44 ), FOXA2 (rs2424459; OR 1.67, AF = 71.3%, P = 2.59 × 10 −14 ), and ADAM32 (rs12681571; OR 1.49, AF = 61.8%, P = 3.05 × 10 −9 ). The AIT meta-analysis (385 cases, 4,936 controls) identified one locus in CAPZB (rs867355; OR 1.63, AF = 66.1%, P = 3.49 × 10 −8 ). In risk prediction models, a polygenic risk score (PRS) of the AIH variants increased the AUC by 9.2% (95% CI 6.6 – 11.9%), which outperformed a genome-wide hypothyroidism PRS (1.5% AUC increase, 95%CI 0.0 – 2.9%). Similarly, the CAPZB variant improved AIT prediction (AUC increase of 4.0%, 95% CI 0.4 – 7.5%) beyond a hyperthyroidism PRS (0.2% AUC increase, 95%CI -0.8 – 1.2%). Genotype-guided screening would identify individuals at low risk (NPVs ranging from 90-95% and PPVs 2-20%). Interpretation We identified genetic variants that influence the risk of developing amiodarone-induced thyroid dysfunction. Genotype-guided screening offers a potential complement to current strategies and personalize pre-treatment risk assessment for patients initiating amiodarone therapy.