Susanna C Larsson1,2, Elias Allara3, Amy M Mason3, Karl Michaëlsson1, Stephen Burgess3,4. 1. Department of Surgical Sciences, Uppsala University, Sweden (S.C.L., K.M.). 2. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L.). 3. Department of Public Health and Primary Care (E.A., A.M.M., S.B.). 4. MRC Biostatistics Unit, University of Cambridge, United Kingdom (S.B.).
Abstract
BACKGROUND: Subclinical thyroid dysfunction, defined as thyroid-stimulating hormone levels outside the reference range with normal free thyroxine levels in asymptomatic patients, is associated with alterations in cardiac hemodynamics. We used Mendelian randomization to assess the role of thyroid dysfunction for cardiovascular disease (CVD). METHODS: Single-nucleotide polymorphisms associated with thyroid function were identified from a genome-wide association meta-analysis in up to 72 167 individuals. Data for genetic associations with CVD were obtained from meta-analyses of genome-wide association studies of atrial fibrillation (n=537 409 individuals), coronary artery disease (n=184 305 individuals), and ischemic stroke (n=438 847) as well as from the UK Biobank (n=367 703 individuals). RESULTS: Genetically predicted thyroid-stimulating hormone levels and hyperthyroidism were statistically significantly associated with atrial fibrillation but no other CVDs at the Bonferroni-corrected level of significance ( P<7.8×10-4). The odds ratios of atrial fibrillation were 1.15 (95% CI, 1.11-1.19; P=2.4×10-14) per genetically predicted 1 SD decrease in thyroid-stimulating hormone levels and 1.05 (95% CI, 1.03-1.08; P=5.4×10-5) for genetic predisposition to hyperthyroidism. Genetically predicted free thyroxin levels were not statistically significantly associated with any CVD. CONCLUSIONS: This Mendelian randomization study supports evidence for a causal association of decreased thyroid-stimulating hormone levels in the direction of a mild form of hyperthyroidism with an increased risk of atrial fibrillation but no other CVDs.
BACKGROUND: Subclinical thyroid dysfunction, defined as thyroid-stimulating hormone levels outside the reference range with normal free thyroxine levels in asymptomatic patients, is associated with alterations in cardiac hemodynamics. We used Mendelian randomization to assess the role of thyroid dysfunction for cardiovascular disease (CVD). METHODS: Single-nucleotide polymorphisms associated with thyroid function were identified from a genome-wide association meta-analysis in up to 72 167 individuals. Data for genetic associations with CVD were obtained from meta-analyses of genome-wide association studies of atrial fibrillation (n=537 409 individuals), coronary artery disease (n=184 305 individuals), and ischemic stroke (n=438 847) as well as from the UK Biobank (n=367 703 individuals). RESULTS: Genetically predicted thyroid-stimulating hormone levels and hyperthyroidism were statistically significantly associated with atrial fibrillation but no other CVDs at the Bonferroni-corrected level of significance ( P<7.8×10-4). The odds ratios of atrial fibrillation were 1.15 (95% CI, 1.11-1.19; P=2.4×10-14) per genetically predicted 1 SD decrease in thyroid-stimulating hormone levels and 1.05 (95% CI, 1.03-1.08; P=5.4×10-5) for genetic predisposition to hyperthyroidism. Genetically predicted free thyroxin levels were not statistically significantly associated with any CVD. CONCLUSIONS: This Mendelian randomization study supports evidence for a causal association of decreased thyroid-stimulating hormone levels in the direction of a mild form of hyperthyroidism with an increased risk of atrial fibrillation but no other CVDs.
Authors: Peter N Taylor; Diana Albrecht; Anna Scholz; Gala Gutierrez-Buey; John H Lazarus; Colin M Dayan; Onyebuchi E Okosieme Journal: Nat Rev Endocrinol Date: 2018-03-23 Impact factor: 43.330
Authors: Nicolas Rodondi; Wendy P J den Elzen; Douglas C Bauer; Anne R Cappola; Salman Razvi; John P Walsh; Bjørn O Asvold; Giorgio Iervasi; Misa Imaizumi; Tinh-Hai Collet; Alexandra Bremner; Patrick Maisonneuve; José A Sgarbi; Kay-Tee Khaw; Mark P J Vanderpump; Anne B Newman; Jacques Cornuz; Jayne A Franklyn; Rudi G J Westendorp; Eric Vittinghoff; Jacobijn Gussekloo Journal: JAMA Date: 2010-09-22 Impact factor: 56.272
Authors: Greet L Roef; Youri E Taes; Jean-Marc Kaufman; Caroline M Van Daele; Marc L De Buyzere; Thierry C Gillebert; Ernst R Rietzschel Journal: Thyroid Date: 2013-07-17 Impact factor: 6.568
Authors: C T Sawin; A Geller; P A Wolf; A J Belanger; E Baker; P Bacharach; P W Wilson; E J Benjamin; R B D'Agostino Journal: N Engl J Med Date: 1994-11-10 Impact factor: 91.245
Authors: Carolina Roselli; Mark D Chaffin; Lu-Chen Weng; Stefanie Aeschbacher; Gustav Ahlberg; Christine M Albert; Peter Almgren; Alvaro Alonso; Christopher D Anderson; Krishna G Aragam; Dan E Arking; John Barnard; Traci M Bartz; Emelia J Benjamin; Nathan A Bihlmeyer; Joshua C Bis; Heather L Bloom; Eric Boerwinkle; Erwin B Bottinger; Jennifer A Brody; Hugh Calkins; Archie Campbell; Thomas P Cappola; John Carlquist; Daniel I Chasman; Lin Y Chen; Yii-Der Ida Chen; Eue-Keun Choi; Seung Hoan Choi; Ingrid E Christophersen; Mina K Chung; John W Cole; David Conen; James Cook; Harry J Crijns; Michael J Cutler; Scott M Damrauer; Brian R Daniels; Dawood Darbar; Graciela Delgado; Joshua C Denny; Martin Dichgans; Marcus Dörr; Elton A Dudink; Samuel C Dudley; Nada Esa; Tonu Esko; Markku Eskola; Diane Fatkin; Stephan B Felix; Ian Ford; Oscar H Franco; Bastiaan Geelhoed; Raji P Grewal; Vilmundur Gudnason; Xiuqing Guo; Namrata Gupta; Stefan Gustafsson; Rebecca Gutmann; Anders Hamsten; Tamara B Harris; Caroline Hayward; Susan R Heckbert; Jussi Hernesniemi; Lynne J Hocking; Albert Hofman; Andrea R V R Horimoto; Jie Huang; Paul L Huang; Jennifer Huffman; Erik Ingelsson; Esra Gucuk Ipek; Kaoru Ito; Jordi Jimenez-Conde; Renee Johnson; J Wouter Jukema; Stefan Kääb; Mika Kähönen; Yoichiro Kamatani; John P Kane; Adnan Kastrati; Sekar Kathiresan; Petra Katschnig-Winter; Maryam Kavousi; Thorsten Kessler; Bas L Kietselaer; Paulus Kirchhof; Marcus E Kleber; Stacey Knight; Jose E Krieger; Michiaki Kubo; Lenore J Launer; Jari Laurikka; Terho Lehtimäki; Kirsten Leineweber; Rozenn N Lemaitre; Man Li; Hong Euy Lim; Henry J Lin; Honghuang Lin; Lars Lind; Cecilia M Lindgren; Marja-Liisa Lokki; Barry London; Ruth J F Loos; Siew-Kee Low; Yingchang Lu; Leo-Pekka Lyytikäinen; Peter W Macfarlane; Patrik K Magnusson; Anubha Mahajan; Rainer Malik; Alfredo J Mansur; Gregory M Marcus; Lauren Margolin; Kenneth B Margulies; Winfried März; David D McManus; Olle Melander; Sanghamitra Mohanty; Jay A Montgomery; Michael P Morley; Andrew P Morris; Martina Müller-Nurasyid; Andrea Natale; Saman Nazarian; Benjamin Neumann; Christopher Newton-Cheh; Maartje N Niemeijer; Kjell Nikus; Peter Nilsson; Raymond Noordam; Heidi Oellers; Morten S Olesen; Marju Orho-Melander; Sandosh Padmanabhan; Hui-Nam Pak; Guillaume Paré; Nancy L Pedersen; Joanna Pera; Alexandre Pereira; David Porteous; Bruce M Psaty; Sara L Pulit; Clive R Pullinger; Daniel J Rader; Lena Refsgaard; Marta Ribasés; Paul M Ridker; Michiel Rienstra; Lorenz Risch; Dan M Roden; Jonathan Rosand; Michael A Rosenberg; Natalia Rost; Jerome I Rotter; Samir Saba; Roopinder K Sandhu; Renate B Schnabel; Katharina Schramm; Heribert Schunkert; Claudia Schurman; Stuart A Scott; Ilkka Seppälä; Christian Shaffer; Svati Shah; Alaa A Shalaby; Jaemin Shim; M Benjamin Shoemaker; Joylene E Siland; Juha Sinisalo; Moritz F Sinner; Agnieszka Slowik; Albert V Smith; Blair H Smith; J Gustav Smith; Jonathan D Smith; Nicholas L Smith; Elsayed Z Soliman; Nona Sotoodehnia; Bruno H Stricker; Albert Sun; Han Sun; Jesper H Svendsen; Toshihiro Tanaka; Kahraman Tanriverdi; Kent D Taylor; Maris Teder-Laving; Alexander Teumer; Sébastien Thériault; Stella Trompet; Nathan R Tucker; Arnljot Tveit; Andre G Uitterlinden; Pim Van Der Harst; Isabelle C Van Gelder; David R Van Wagoner; Niek Verweij; Efthymia Vlachopoulou; Uwe Völker; Biqi Wang; Peter E Weeke; Bob Weijs; Raul Weiss; Stefan Weiss; Quinn S Wells; Kerri L Wiggins; Jorge A Wong; Daniel Woo; Bradford B Worrall; Pil-Sung Yang; Jie Yao; Zachary T Yoneda; Tanja Zeller; Lingyao Zeng; Steven A Lubitz; Kathryn L Lunetta; Patrick T Ellinor Journal: Nat Genet Date: 2018-06-11 Impact factor: 38.330
Authors: Estefanía Lozano-Velasco; Rosemary Wangensteen; Andrés Quesada; Carlos Garcia-Padilla; Julia A Osorio; María Dolores Ruiz-Torres; Amelia Aranega; Diego Franco Journal: PLoS One Date: 2017-12-01 Impact factor: 3.240
Authors: Sabrina Sales Martinez; Margaret Gutierrez; Ivan Delgado-Enciso; Jezabel Maisonet; Aydevis Jean Pierre; Adriana Campa; Laura Kallus; Janet Diaz Martinez Journal: Int J Environ Res Public Health Date: 2022-07-02 Impact factor: 4.614
Authors: Eirini Marouli; Aleksander Kus; Fabiola Del Greco M; Layal Chaker; Robin Peeters; Alexander Teumer; Panos Deloukas; Marco Medici Journal: J Clin Endocrinol Metab Date: 2020-08-01 Impact factor: 5.958
Authors: Christina Ellervik; Samia Mora; Aleksander Kuś; Bjørn Åsvold; Eirini Marouli; Panos Deloukas; Rosalie B T M Sterenborg; Alexander Teumer; Stephen Burgess; Maria Sabater-Lleal; Jennifer Huffman; Andrew D Johnson; David-Alexandre Trégouet; Nicolas L Smith; Marco Medici; Paul S DeVries; Daniel I Chasman; Alisa D Kjaergaard Journal: Thyroid Date: 2021-08-05 Impact factor: 6.506
Authors: Alice Giontella; Luca A Lotta; John D Overton; Aris Baras; Andrea Sartorio; Pietro Minuz; Dipender Gill; Olle Melander; Cristiano Fava Journal: J Pers Med Date: 2021-12-06
Authors: Enrique Soto-Pedre; Moneeza K Siddiqui; Cyrielle Maroteau; Adem Y Dawed; Alex S Doney; Colin N A Palmer; Ewan R Pearson; Graham P Leese Journal: Front Genet Date: 2021-06-23 Impact factor: 4.599
Authors: Shuai Yuan; Siddhartha Kar; Mathew Vithayathil; Paul Carter; Amy M Mason; Stephen Burgess; Susanna C Larsson Journal: Int J Cancer Date: 2020-04-03 Impact factor: 7.316