Assessment of the Relationship between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study

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Christina Ellervik, Carolina Roselli, Ingrid E. Christophersen, Alvaro Alonso, Maik Pietzner, Collen M. Sitlani, Stella Trompet, Dan E. Arking, Bastiaan Geelhoed, Xiuqing Guo, Marcus E. Kleber, Henry J. Lin, Honghuang Lin, Peter Macfarlane, Elizabeth Selvin, Christian Shaffer, Albert V. Smith, Niek Verweij, Stefan Weiss, Anne R. Cappola & 26 others Marcus Dörr, Vilmundur Gudnason, Susan Heckbert, Simon Mooijaart, Winfried März, Bruce M. Psaty, Paul M. Ridker, Dan Roden, David J. Stott, Henry Völzke, Emelia J. Benjamin, Graciela Delgado, Patrick Ellinor, Georg Homuth, Anna Köttgen, Johan W. Jukema, Steven A. Lubitz, Samia Mora, Michiel Rienstra, Jerome I. Rotter, M. Benjamin Shoemaker, Nona Sotoodehnia, Kent D. Taylor, Pim Van Der Harst, Christine M. Albert, Daniel I. Chasman

Importance: Increased free thyroxine (FT 4 ) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear. Objective: To evaluate the potential direct involvement of thyroid traits on AF. Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55114 AF cases and 482295 referents, all of European ancestry. Exposures: Genomewide significant variants were used as instruments for standardized FT 4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT 3 ):FT 4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data. Main Outcomes and Measures: Prevalent and incident AF. Results: The study-level analysis included 7679 individuals with AF and 49233 referents (mean age [standard error], 62 [3] years; 15859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT 4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P =.02; I 2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P =.003; I 2 = 64%) in multivariable-adjusted analyses. The FT 4 genetic risk score was associated with an increase in FT 4 by 0.082 SD (standard error, 0.007; P <.001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P =.27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P =.46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT 4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P =.88). However, gene-based increased FT 3 :FT 4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P =.006), 0.88 (95% CI, 0.84-0.92; P <.001), and 0.94 (95% CI, 0.90-0.99; P =.009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P =.02) with evidence of horizontal pleiotropy (P =.045). Conclusions and Relevance: Genetically increased FT 3 :FT 4 ratio and hyperthyroidism, but not FT 4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

Original languageEnglish
JournalJAMA Cardiology
Volume4
Issue number2
Pages (from-to)144-152
Number of pages9
ISSN2380-6583
DOIs
Publication statusPublished - 2019

ID: 223192189