Purpose: Hypothyroidism has been associated with atrial fibrillation (AF) in some studies. This study aimed to characterize thyroid related genetic variants that may change susceptibility to AF in patients on thyroid hormone replacement therapy (levothyroxine).
Methods: A case-control study was done among patients of European Caucasian ethnicity from the Genetics of Diabetes Audit and Research Tayside (GoDARTS) recruited in Tayside (Scotland, UK). Electronic medical records (biochemistry, prescribing, hospital admissions and demographics) were used to ascertain patients with atrial fibrillation and their controls as well as patients with hypothyroidism, and linked to genetic biobank data. Genetic tests of association were performed by means of logistic regression models adjusted for age, gender and average thyroid-stimulating hormone.
Results: We analysed 1,031 cases of AF and 10,757 controls. Loci on chromosomes 3 (Thyroid Hormone Receptor Beta-THRβ), 6 (human leukocyte antigen-HLA), and 14 (Thyroid Stimulating Hormone Receptor- TSHR) were associated to AF in patients on levothyroxine. A significant interaction between HLA-rs2517532 and levothyroxine use was found (OR=1.32, 95%CI: 1.031.67, P=2.6e02). A significant interaction was also found between TSHR-2234919 and levothyroxine use (OR=0.48, 95%CI: 0.240.97, P=4.2e02). Fifteen unlinked single-nucleotide polymorphisms (SNPs) located on chromosome 3 at THRβ showed interactions with similar size effect estimates (OR= 1.31.5, P<5e02), and two SNPs at THRβ (rs7652234 and rs826219) showed larger size estimates (OR=1.92.0, P<2e02).
Conclusions: This study provides evidence that genetic factors, such as polymorphisms in the THRβ, HLA, and TSHR genes, might contribute to inter-individual variations in susceptibility to AF in patients on levothyroxine.