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

TitleAssessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study.
Publication TypeJournal Article
Year of Publication2019
AuthorsEllervik C, Roselli C, Christophersen IE, Alonso A, Pietzner M, Sitlani CM, Trompet S, Arking DE, Geelhoed B, Guo X, Kleber ME, Lin HJ, Lin H, MacFarlane P, Selvin E, Shaffer C, Smith AV, Verweij N, Weiss S, Cappola AR, Dörr M, Gudnason V, Heckbert S, Mooijaart S, März W, Psaty BM, Ridker PM, Roden D, Stott DJ, Völzke H, Benjamin EJ, Delgado G, Ellinor P, Homuth G, Köttgen A, Jukema JW, Lubitz SA, Mora S, Rienstra M, Rotter JI, M Shoemaker B, Sotoodehnia N, Taylor KD, van der Harst P, Albert CM
Secondary AuthorsChasman DI
JournalJAMA Cardiol
Date Published2019 02 01
KeywordsAged, Atrial Fibrillation, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hyperthyroidism, Hypothyroidism, Iodide Peroxidase, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Thyroid Function Tests, Thyroid Gland, Thyrotropin, Thyroxine, Triiodothyronine

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 

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.

Alternate JournalJAMA Cardiol
PubMed ID30673084
PubMed Central IDPMC6396813
Grant ListR01 DK089174 / DK / NIDDK NIH HHS / United States
16EIA26410001 / AHA / American Heart Association-American Stroke Association / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL116690 / HL / NHLBI NIH HHS / United States
R01 DK112940 / DK / NIDDK NIH HHS / United States
K24 HL136852 / HL / NHLBI NIH HHS / United States
R01 HL134811 / HL / NHLBI NIH HHS / United States