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

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

doi:10.1001/jamacardio.2018.4635

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

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. CappolaMarcus 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^*

^*Corresponding author for this work

Department of Clinical Medicine

25 Citations (Scopus)

Abstract

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 language	English
Journal	JAMA Cardiology
Volume	4
Issue number	2
Pages (from-to)	144-152
Number of pages	9
ISSN	2380-6583
DOIs	https://doi.org/10.1001/jamacardio.2018.4635
Publication status	Published - 2019

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10.1001/jamacardio.2018.4635

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Ellervik, C., Roselli, C., Christophersen, I. E., Alonso, A., Pietzner, M., Sitlani, C. M., Trompet, S., Arking, D. E., Geelhoed, B., Guo, X., Kleber, M. E., Lin, H. J., Lin, H., Macfarlane, P., Selvin, E., Shaffer, C., Smith, A. V., Verweij, N., Weiss, S., ... Chasman, D. I. (2019). Assessment of the Relationship between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study. JAMA Cardiology, 4(2), 144-152. https://doi.org/10.1001/jamacardio.2018.4635

Ellervik, 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, Shoemaker, MB, Sotoodehnia, N, Taylor, KD, Van Der Harst, P, Albert, CM & Chasman, DI 2019, 'Assessment of the Relationship between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study', JAMA Cardiology, vol. 4, no. 2, pp. 144-152. https://doi.org/10.1001/jamacardio.2018.4635

@article{21505ccfa9b84946baa4228ab3c29f11,

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

abstract = " 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. ",

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

year = "2019",

doi = "10.1001/jamacardio.2018.4635",

language = "English",

volume = "4",

pages = "144--152",

journal = "JAMA Cardiology",

issn = "2380-6583",

publisher = "American Medical Association",

number = "2",

}

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

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1001/jamacardio.2018.4635

DO - 10.1001/jamacardio.2018.4635

M3 - Journal article

C2 - 30673084

AN - SCOPUS:85060579441

SN - 2380-6583

VL - 4

SP - 144

EP - 152

JO - JAMA Cardiology

JF - JAMA Cardiology

IS - 2

ER -

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

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