Genome-wide association study of amidoarone-induced hypothyroidism

Abstract Background Amiodarone is a commonly prescribed antiarrhythmic drug used to manage supraventricular and ventricular arrhythmias. The use of amiodarone is associated with a broad range of adverse effects across several organ systems. As many as 10-20% of all patients treated with amiodarone develop thyroid dysfunction, most commonly amiodarone induced hypothyroidism (AIH). (1) Purpose We examined if AIH may have a genetic predisposition. Methods We conducted the first genome-wide association study of AIH using data from a large biobank. Cases were defined as individuals who within one year of amiodarone initiation were given a diagnosis of hypothyroidism or treated with thyroid hormone replacement. Controls were defined as individuals who were continuously treated with amiodarone, without any history of hypothyroidism. Odds Ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic mixed model regression. Results In total, we identified 339 cases of AIH and 2,296 amiodarone-treated controls (Table 1). We found two risk loci, residing at chromosome 9q22.33 and 20p11.21. The lead variant at the first locus, rs9696968-G, was an intron variant located in PTCSC2 (OR: 2.32; 95% CI 1.91 – 2.83, P = 8.17 × 10-18). The other lead variant, rs1543443-A, was located 82 kb upstream to FOXA2 and was at borderline genome-wide significance (OR 1.77, 95% CI 1.44 – 2.19, P = 5.19 × 10-8; Figure 1). The locus in PTCSC2 is a top hit in thyroid cancer (OR 1.69) and hypothyroidism (OR 1.3). (2) FOXA2, a critical transcription factor, is recognized in mice for its role during development, in regulation of mature tissues, and once mutated also involved in cancer. (3) Conclusions We found two risk loci located in PTCSC2 and FOXA2 that were significantly associated with AIH, but replication is needed in order to confirm these associations. Indeed, it seems that individuals with genetic susceptibility to hypothyroidism are more likely to develop AIH, hence the PTCSC2 locus is a known high impact rick locus for hypothyroidism. These findings add to the potentials of pharmacogenetics in cardiology. Cases are individuals with hypothyroidism within one year after initiation of amiodarone therapy. Controls are disease free individuals who are continuously taking amiodarone. The Y-axis is the negative log10 of the P-value for each single nucleotide polymorphism. The X-axis is the chromosome, with positions on each chromosome ranging from lower to higher (left to right). Each novel locus is presented in red color. The dotted line marks the threshold for genome-wide significance.Table 1.Characteristics of study group.Figure 1.Manhattan plot of amiodarone induced hypothyroidism.