Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation
Year: 2019
Type: article
Abstract: Importance: Increased free thyroxine (FT4) 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 55 114 AF cases and 482 295 referents, all of European ancestry. Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 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 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 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 FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 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 FT3:FT4 ratio and hyperthyroidism, but not FT4 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.
Source: JAMA Cardiology
Authors: 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, 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
Institutions: University of Copenhagen, Boston Children's Hospital, Harvard University, Broad Institute, Oslo University Hospital, Vestre Viken Hospital Trust, Emory University, Universitätsmedizin Greifswald, Universität Greifswald, German Centre for Cardiovascular Research, University of Washington, Leiden University Medical Center, Johns Hopkins University, University Medical Center Groningen, University of Groningen, University of California, Los Angeles, The Lundquist Institute, Los Angeles Medical Center, Harbor–UCLA Medical Center, Heidelberg University, Medizinische Fakultät Mannheim, Boston University, Framingham Heart Study, University of Glasgow, Vanderbilt University Medical Center, University of Michigan, Icelandic Heart Association, University of Pennsylvania, University of Iceland, Synlab (Germany), Kaiser Permanente Washington Health Research Institute, Brigham and Women's Hospital, Massachusetts General Hospital, University of Freiburg, Netherlands Heart Institute
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Rare variants and NHLBI traits in deeply phenotyped cohorts, G232264632, G2583962150, G296654838, Rare variants and NHLBI traits in deeply phenotyped cohorts, G4429312988, G50080621, Atrial fibrillation: epidemiology, prevention, and outcomes, Diabetes and Prediabetes in Older Adults in ARIC, G8473394137, Mentored Patient-Oriented Research for Preventing ASCVD Events
OpenAlex ID: W2912012956