Effects of Thyroid Function on Hemostasis, Coagulation, and Fibrinolysis: A Mendelian Randomization Study
Year: 2021
Type: article
Study design: Observational Study
Abstract: Background: Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on hemostasis, coagulation, and fibrinolysis are unknown. Methods: In a two-sample Mendelian randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism ( N = 134,641), normal-range thyrotropin (TSH; N = 54,288) and free thyroxine (fT4) ( N = 49,269), hyperthyroidism ( N = 51,823), and thyroid peroxidase antibody positivity ( N = 25,821) on coagulation (activated partial thromboplastin time, von Willebrand factor [VWF], factor VIII [FVIII], prothrombin time, factor VII, fibrinogen) and fibrinolysis (D-dimer, tissue plasminogen activator [TPA], plasminogen activator inhibitor-1) from the CHARGE Hemostasis Consortium ( N = 2583–120,246). Inverse-variance-weighted random effects were the main MR analysis followed by sensitivity analyses. Two-sided p < 0.05 was nominally significant, and p < 0.0011[ = 0.05/(5 exposures × 9 outcomes)] was Bonferroni significant for the main MR analysis. Results: Genetically increased TSH was associated with decreased VWF [β(SE) = −0.020(0.006), p = 0.001] and with decreased fibrinogen [β(SE) = −0.008(0.002), p = 0.001]. Genetically increased fT4 was associated with increased VWF [β(SE) = 0.028(0.011), p = 0.012]. Genetically predicted hyperthyroidism was associated with increased VWF [β(SE) = 0.012(0.004), p = 0.006] and increased FVIII [β(SE) = 0.013(0.005), p = 0.007]. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA [β(SE) = −0.009(0.024), p = 0.024] and increased TPA [β(SE) = 0.022(0.008), p = 0.008], respectively. MR sensitivity analyses showed similar direction but lower precision. Other coagulation and fibrinolytic factors were inconclusive. Conclusions: In the largest genetic studies currently available, genetically increased TSH and fT4 may be associated with decreased and increased synthesis of VWF, respectively. Since Bonferroni correction may be too conservative given the correlation between the analyzed traits, we cannot reject nominal associations of thyroid traits with coagulation or fibrinolytic factors.
Source: Thyroid
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
Institutions: University of Copenhagen, Boston Children's Hospital, Harvard University, Region Zealand, Brigham and Women's Hospital, Medical University of Warsaw, Erasmus MC, Norwegian University of Science and Technology, St Olav's University Hospital, Queen Mary University of London, William Harvey Research Institute, King Abdulaziz University, Radboud University Medical Center, Radboud Institute for Health Sciences, Universitätsmedizin Greifswald, German Centre for Cardiovascular Research, University of Cambridge, MRC Biostatistics Unit, Hospital de Sant Pau, Karolinska Institutet, VA Boston Healthcare System, National Heart, Lung, and Blood Institute, Framingham Heart Study, Université de Bordeaux, Inserm, Bordeaux Population Health, United States Department of Veterans Affairs, Kaiser Permanente, Kaiser Permanente Washington Health Research Institute, University of Washington, VA Office of Research and Development, Seattle Epidemiologic Information and Research Center, The University of Texas Health Science Center at Houston, Broad Institute, Aarhus University Hospital, Steno Diabetes Center Aarhus
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Heart Association, European Hematology Association, Wellcome Trust, National Institute for Health and Care Research, British Heart Foundation, Agence Nationale de la Recherche, Université de Bordeaux, Instituto de Salud Carlos III, National Heart, Lung, and Blood Institute, National Cancer Institute
Awards: Genetics and causality: towards more accessible and more reliable Mendelian randomization investigations, G1131762481, NIHR Senior Investigator Award, Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal), Population genomic variation, functional biology, and the risk of venous thrombosis, Identificación de nuevos marcadores y mecanismos genéticos implicados en Aneurisma Aórtico Abdominal, G4567598535, Initiative d’excellence de l’Université de Bordeaux, Genomic discoveries for understanding and predicting coronary heart disease incident and prognosis, The BHF Chair of Epidemiology and Medicine, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application (renewal). (Joint funding with MRC), Women's Health Study: Infrastructure support for cohort follow-up, Using genomics and functional biology to understand fibrinogen and factor XIII and their effects on thrombotic diseases, Mentored Patient-Oriented Research for Preventing ASCVD Events, Analysis of Whole Genome Sequence and Hemostasis Phenotypes
OpenAlex ID: W3173202158