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Original Investigation
January 23, 2019

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

Author Affiliations
  • 1Department of Laboratory Medicine, Boston Children’s Hospital, Boston, Massachusetts
  • 2Harvard Medical School, Boston, Massachusetts
  • 3Division of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 4Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
  • 5Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 6Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway
  • 7Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
  • 8Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
  • 9DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
  • 10Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle
  • 11Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
  • 12Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
  • 13McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 14University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  • 15Division of Genomic Outcomes, Institute for Translational Genomics and Population Sciences, Torrance, California
  • 16Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance
  • 17Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles
  • 18Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
  • 19Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
  • 20National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, Massachusetts
  • 21Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
  • 22Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 23Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 24School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor
  • 25Icelandic Heart Association, Kopavogur, Iceland
  • 26Interfaculty Institute for Genetics and Functional Genomics, University Medicine and University Greifswald, Greifswald, Germany
  • 27Smilow Center for Translational Research, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 28Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
  • 29Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  • 30Department of Epidemiology, University of Washington, Seattle
  • 31Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
  • 32Institute for Evidence-Based Medicine in Old Age, Leiden, the Netherlands
  • 33Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany
  • 34Cardiovascular Health Research Unit, Department of Medicine, Epidemiology, and Health Services, University of Washington, Seattle
  • 35Kaiser Permanente Washington Health Research Institute, Seattle
  • 36Division of Cardiovascular, Brigham and Women’s Hospital, Boston, Massachusetts
  • 37Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 38Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
  • 39Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
  • 40Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
  • 41Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts
  • 42Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts
  • 43University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany
  • 44Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
  • 45Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands
  • 46Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands
  • 47Cardiovascular Research Center, Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston
JAMA Cardiol. 2019;4(2):144-152. doi:10.1001/jamacardio.2018.4635
Key Points

Question  Are free thyroxine (FT4) and thyrotropin levels within the reference range, triiodothyronine (FT3):FT4 ratio, hypothyroidism, thyroid peroxidase antibody levels, or hyperthyroidism on a direct pathway for atrial fibrillation (AF)?

Findings  This mendelian randomization study of 55 114 individuals with AF and 482 295 referents found that genetically increased FT3:FT4 ratio and hyperthyroidism were associated with increased risk of AF, and thyrotropin within the reference range and hypothyroidism were inversely associated with risk of AF. There was no support for a direct involvement of FT4 within the reference range or thyroid peroxidase antibody levels in AF.

Meaning  Low thyrotropin, as an early sign of an overactive thyroid gland, with a concomitant increased FT3:FT4 ratio are genetically associated with AF.

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.

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