TY - JOUR
T1 - Assessment of the Relationship between Genetic Determinants of Thyroid Function and Atrial Fibrillation
T2 - A Mendelian Randomization Study
AU - Ellervik, Christina
AU - Roselli, Carolina
AU - Christophersen, Ingrid E.
AU - Alonso, Alvaro
AU - Pietzner, Maik
AU - Sitlani, Collen M.
AU - Trompet, Stella
AU - Arking, Dan E.
AU - Geelhoed, Bastiaan
AU - Guo, Xiuqing
AU - Kleber, Marcus E.
AU - Lin, Henry J.
AU - Lin, Honghuang
AU - Macfarlane, Peter
AU - Selvin, Elizabeth
AU - Shaffer, Christian
AU - Smith, Albert V.
AU - Verweij, Niek
AU - Weiss, Stefan
AU - Cappola, Anne R.
AU - Dörr, Marcus
AU - Gudnason, Vilmundur
AU - Heckbert, Susan
AU - Mooijaart, Simon
AU - März, Winfried
AU - Psaty, Bruce M.
AU - Ridker, Paul M.
AU - Roden, Dan
AU - Stott, David J.
AU - Völzke, Henry
AU - Benjamin, Emelia J.
AU - Delgado, Graciela
AU - Ellinor, Patrick
AU - Homuth, Georg
AU - Köttgen, Anna
AU - Jukema, Johan W.
AU - Lubitz, Steven A.
AU - Mora, Samia
AU - Rienstra, Michiel
AU - Rotter, Jerome I.
AU - Shoemaker, M. Benjamin
AU - Sotoodehnia, Nona
AU - Taylor, Kent D.
AU - Van Der Harst, Pim
AU - Albert, Christine M.
AU - Chasman, Daniel I.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
KW - Aged
KW - Atrial Fibrillation/diagnosis
KW - European Continental Ancestry Group/genetics
KW - Female
KW - Genome-Wide Association Study/methods
KW - Humans
KW - Hyperthyroidism/blood
KW - Hypothyroidism/blood
KW - Iodide Peroxidase/immunology
KW - Male
KW - Mendelian Randomization Analysis/methods
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
KW - Risk Factors
KW - Thyroid Function Tests/methods
KW - Thyroid Gland/metabolism
KW - Thyrotropin/blood
KW - Thyroxine/blood
KW - Triiodothyronine/blood
UR - http://www.scopus.com/inward/record.url?scp=85060579441&partnerID=8YFLogxK
U2 - 10.1001/jamacardio.2018.4635
DO - 10.1001/jamacardio.2018.4635
M3 - Article
C2 - 30673084
AN - SCOPUS:85060579441
VL - 4
SP - 144
EP - 152
JO - JAMA Cardiology
JF - JAMA Cardiology
SN - 2380-6583
IS - 2
ER -