Ellervik C, et al. – In this study, investigators assessed the potential direct engagement of thyroid characteristics on atrial fibrillation (AF). They observed an association of genetically increased triiodothyronine (FT₃):free thyroxine (FT₄) ratio and hyperthyroidism with increased AF. They also n oted elevated thyrotropin within the reference range and hypothyroidism were linked to reduced AF incidence, supporting the pathway for AF including the pituitary-thyroid-cardiac axis.

Methods

• Investigators included 11 studies in this study-level mendelian randomization (MR), whereas 55,114 AF cases and 482,295 referents (all of European ancestry) were involved in summary-level MR.
• They used genome-wide significant variants as instruments for standardized FT₄ and thyrotropin levels within the reference range, standardized FT₃:FT₄ ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism.
• They used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data under mendelian randomization.
• Prevalent and incident AF were the main outcomes and measures.

Results

• This analysis included 7,679 cases with AF and 49,233 referents.
• They noted that the pooled hazard ratio of FT₄ levels (nanograms per deciliter) for incident AF was 1.55 in study-level random-effects meta-analysis and the pooled odds ratio (OR) for prevalent AF was 2.80 in multivariable-adjusted analyses.
• The FT₄ genetic risk score was correlated with an increment in FT₄ by 0.082 SD but not with either incident AF or prevalent AF.
• Similarly, in summary-level inverse-variance weighted random-effects MR, they noted that gene-based FT₄ within the reference range was not linked to AF.
• Gene-based increased FT₃:FT₄ ratio, raised thyrotropin within the reference range, and hypothyroidism were found linked to AF with inverse-variance weighted random-effects OR of 1.33, 0.88, and 0.94, respectively, and robust to tests of horizontal pleiotropy.
• They recorded no association of the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels with AF.
• They reported that gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 with evidence of horizontal pleiotropy.