Effects of Thyroid Function on Hemostasis, Coagulation, and Fibrinolysis: A Mendelian Randomization Study
Por:
Ellervik, C, Mora, S, Kus, A, Asvold, B, Marouli, E, Deloukas, P, Sterenborg, RBTM, Teumer, A, Burgess, S, Sabater-Lleal, M, Huffman, J, Johnson, AD, Tregouet, DA, Smith, NL, Medici, M, DeVries, PS, Chasman, DI, Kjaergaard, AD
Publicada:
1 sep 2021
Ahead of Print:
1 ago 2021
Resumen:
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 x 9 outcomes)] was Bonferroni significant for the main MR analysis. Results: Genetically increased TSH was associated with decreased VWF [beta(SE) = -0.020(0.006), p = 0.001] and with decreased fibrinogen [beta(SE) = -0.008(0.002), p = 0.001]. Genetically increased fT4 was associated with increased VWF [beta(SE) = 0.028(0.011), p = 0.012]. Genetically predicted hyperthyroidism was associated with increased VWF [beta(SE) = 0.012(0.004), p = 0.006] and increased FVIII [beta(SE) = 0.013(0.005), p = 0.007]. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA [beta(SE) = -0.009(0.024), p = 0.024] and increased TPA [beta(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.
Filiaciones:
Ellervik, C:
Boston Childrens Hosp, Dept Lab Med, 300 Longwood Ave, Boston, MA 02115 USA
Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA
Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark
Reg Zealand, Dept Data & Data Support, Soro, Denmark
Mora, S:
Brigham & Womens Hosp, Ctr Lipid Metabol, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA
Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA
Kus, A:
Erasmus MC, Dept Internal Med, Acad Ctr Thyroid Dis, Rotterdam, Netherlands
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Med Univ Warsaw, Dept Internal Med & Endocrinol, Warsaw, Poland
Asvold, B:
Norwegian Univ Sci & Technol NTNU, KG Jebsen Ctr Genet Epidemiol, Dept Publ Hlth & Nursing, Trondheim, Norway
Trondheim Reg & Univ Hosp, Dept Endocrinol, Med Clin, St Olavs Hosp, Trondheim, Norway
Marouli, E:
Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England
Deloukas, P:
Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England
King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia
Sterenborg, RBTM:
Erasmus MC, Dept Internal Med, Acad Ctr Thyroid Dis, Rotterdam, Netherlands
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Radboud Univ Nijmegen Med Ctr, Dept Internal Med, Radboud Inst Hlth Sci, Nijmegen, Netherlands
Teumer, A:
Univ Med Greifswald, Inst Community Med, Greifswald, Germany
DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany
Burgess, S:
Univ Cambridge, MRC Biostat Unit, Cambridge, England
Univ Cambridge, Cardiovasc Epidemiol Unit, Dept Publ Hlth & Primary Care, Cambridge, England
Sabater-Lleal, M:
Hosp Santa Creu & Sant Pau, Genom Complex Dis Grp, Res Inst, IIB St Pau, Barcelona, Spain
Karolinska Inst, Cardiovasc Med Unit, Dept Med, Ctr Mol Med, Stockholm, Sweden
Huffman, J:
VA Boston Healthcare Syst, Sci Director Genom Res, Ctr Populat Genom, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA
Johnson, AD:
NHLBI, Framingham Heart Study, Populat Sci Branch, Div Intramural Res, Framingham, MA USA
Tregouet, DA:
Univ Bordeaux, INSERM U1219, Bordeaux Populat Hlth Res Ctr, Bordeaux, France
Smith, NL:
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Kaiser Permanente Washington, Kaiser Permamente Washington Hlth Res Inst, Seattle, WA USA
Dept Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA
Medici, M:
Erasmus MC, Dept Internal Med, Acad Ctr Thyroid Dis, Rotterdam, Netherlands
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Radboud Univ Nijmegen Med Ctr, Dept Internal Med, Radboud Inst Hlth Sci, Nijmegen, Netherlands
DeVries, PS:
Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA
Chasman, DI:
Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA
Kjaergaard, AD:
Aarhus Univ Hosp, Steno Diabet Ctr Aarhus, Aarhus, Denmark
Harvard Med Sch, Boston, MA 02115 USA.
Open Access
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