Download PDF
CC BY-NC-ND 4.0 · Thromb Haemost 2023; 123(09): 913-919
DOI: 10.1055/a-2040-4850
Stroke, Systemic or Venous Thromboembolism

The Causality between Diabetes and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study

Song Hu
1   Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, Center for Respiratory and Pulmonary Vascular Diseases, Department of Cardiology, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Jiang-Shan Tan
1   Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, Center for Respiratory and Pulmonary Vascular Diseases, Department of Cardiology, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Meng-Jin Hu
2   State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Fuwai Hospital, Beijing, China
,
Ting-Ting Guo
1   Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, Center for Respiratory and Pulmonary Vascular Diseases, Department of Cardiology, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Liyuan Chen
1   Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, Center for Respiratory and Pulmonary Vascular Diseases, Department of Cardiology, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Lu Hua
1   Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, Center for Respiratory and Pulmonary Vascular Diseases, Department of Cardiology, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Jian Cao
3   Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
› Author Affiliations Funding The study was supported by grants from CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&T-B-040) and the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences (NCRC2020007).
› Further Information
   Permissions and Reprints


Abstract

Background Diabetes was considered as a risk factor for venous thromboembolism (VTE), but conflicting findings have been reported from observational studies. This study aimed at investigating the causal associations of type 1 and type 2 diabetes with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE).

Methods We designed a bidirectional two-sample Mendelian randomization (MR) analysis by using summary-level data from large genome-wide association studies performed in European individuals. Inverse variance weighting with multiplicative random effect method was used to obtain the primary causal estimates, and weighted median, weighted mode, and MR egger regression were replenished as sensitivity analyses to test the robustness of the results.

Results We found no significant causal effects of type 1 diabetes on VTE (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96–1.00, p = 0.043), DVT (OR: 0.98, 95% CI: 0.95–1.00, p = 0.102), and PE (OR: 0.98, 95% CI: 0.96–1.01, p = 0.160). Similarly, no significant associations of type 2 diabetes with VTE (OR: 0.97, 95% CI: 0.91–1.03, p = 0.291), DVT (OR: 0.96, 95% CI: 0.89–1.03, p = 0.255), and PE (OR: 0.97, 95% CI: 0.90–1.04, p = 0.358) were also observed. Results from multivariable MR analysis were consistent with the findings in univariable analysis. In the other direction, the results showed no significant causal effects of VTE on type 1 and type 2 diabetes.

Conclusion This MR analysis demonstrated no significant causal associations of type 1 and type 2 diabetes with VTE in both directions, in conflict with previous observational studies reporting positive association, which provided clues for understanding the underlying pathogenesis of diabetes and VTE.

Keywords

diabetes - venous thromboembolism - deep vein thrombosis - pulmonary embolism - Mendelian randomization

Supplementary Material



Publication History

Received: 01 November 2022

Accepted: 31 January 2023

Accepted Manuscript online:
22 February 2023

Article published online:
09 March 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet 2021; 398 (10294): 64-77
    CrossrefPubMedGoogle Scholar
  • 2 Liew NC, Alemany GV, Angchaisuksiri P. et al. Asian venous thromboembolism guidelines: updated recommendations for the prevention of venous thromboembolism. Int Angiol 2017; 36 (01) 1-20
    PubMedGoogle Scholar
  • 3 Siegal DM, Eikelboom JW, Lee SF. et al; Venous Thromboembolism Collaboration. Variations in incidence of venous thromboembolism in low-, middle-, and high-income countries. Cardiovasc Res 2021; 117 (02) 576-584
    CrossrefPubMedGoogle Scholar
  • 4 Duggirala MK, Cook DA, Mauck KF. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 349 (04) 401-402 , author reply 401–402
    CrossrefPubMedGoogle Scholar
  • 5 Piazza G, Goldhaber SZ. Venous thromboembolism and atherothrombosis: an integrated approach. Circulation 2010; 121 (19) 2146-2150
    CrossrefPubMedGoogle Scholar
  • 6 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
    CrossrefPubMedGoogle Scholar
  • 7 Lemkes BA, Hermanides J, Devries JH, Holleman F, Meijers JC, Hoekstra JB. Hyperglycemia: a prothrombotic factor?. J Thromb Haemost 2010; 8 (08) 1663-1669
    CrossrefPubMedGoogle Scholar
  • 8 Bryk AH, Prior SM, Plens K. et al. Predictors of neutrophil extracellular traps markers in type 2 diabetes mellitus: associations with a prothrombotic state and hypofibrinolysis. Cardiovasc Diabetol 2019; 18 (01) 49
    CrossrefPubMedGoogle Scholar
  • 9 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262 (02) 157-172
    CrossrefPubMedGoogle Scholar
  • 10 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117 (01) 93-102
    CrossrefPubMedGoogle Scholar
  • 11 Bai J, Ding X, Du X, Zhao X, Wang Z, Ma Z. Diabetes is associated with increased risk of venous thromboembolism: a systematic review and meta-analysis. Thromb Res 2015; 135 (01) 90-95
    CrossrefPubMedGoogle Scholar
  • 12 Bell EJ, Folsom AR, Lutsey PL. et al. Diabetes mellitus and venous thromboembolism: a systematic review and meta-analysis. Diabetes Res Clin Pract 2016; 111: 10-18
    CrossrefPubMedGoogle Scholar
  • 13 Hinton W, Nemeth B, de Lusignan S. et al. Effect of type 1 diabetes and type 2 diabetes on the risk of venous thromboembolism. Diabet Med 2021; 38 (05) e14452
    CrossrefPubMedGoogle Scholar
  • 14 Holst AG, Jensen G, Prescott E. Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study. Circulation 2010; 121 (17) 1896-1903
    CrossrefPubMedGoogle Scholar
  • 15 Heit JA, Leibson CL, Ashrani AA, Petterson TM, Bailey KR, Melton III LJ. Is diabetes mellitus an independent risk factor for venous thromboembolism?: a population-based case-control study. Arterioscler Thromb Vasc Biol 2009; 29 (09) 1399-1405
    CrossrefPubMedGoogle Scholar
  • 16 Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA 2017; 318 (19) 1925-1926
    CrossrefPubMedGoogle Scholar
  • 17 Sekula P, Del Greco M F, Pattaro C, Köttgen A. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol 2016; 27 (11) 3253-3265
    CrossrefPubMedGoogle Scholar
  • 18 Levin MG, Klarin D, Assimes TL. et al; VA Million Veteran Program. Genetics of smoking and risk of atherosclerotic cardiovascular diseases: a mendelian randomization study. JAMA Netw Open 2021; 4 (01) e2034461
    CrossrefPubMedGoogle Scholar
  • 19 Higbee DH, Granell R, Sanderson E, Davey Smith G, Dodd JW. Lung function and cardiovascular disease: a two-sample Mendelian randomisation study. Eur Respir J 2021; 58 (03) 2003196
    CrossrefPubMedGoogle Scholar
  • 20 Larsson SC, Mason AM, Bäck M. et al; Million Veteran Program. Genetic predisposition to smoking in relation to 14 cardiovascular diseases. Eur Heart J 2020; 41 (35) 3304-3310
    CrossrefPubMedGoogle Scholar
  • 21 Elsworth B, Lyon M, Alexander T. et al. The MRC IEU OpenGWAS data infrastructure. 2020
    PubMed
  • 22 Forgetta V, Manousaki D, Istomine R. et al; DCCT/EDIC Research Group. Rare genetic variants of large effect influence risk of type 1 diabetes. Diabetes 2020; 69 (04) 784-795
    CrossrefPubMedGoogle Scholar
  • 23 Xue A, Wu Y, Zhu Z. et al; eQTLGen Consortium. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun 2018; 9 (01) 2941
    CrossrefPubMedGoogle Scholar
  • 24 Bowden J, Spiller W, Del Greco M F. et al. Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression. Int J Epidemiol 2018; 47 (04) 1264-1278
    CrossrefPubMedGoogle Scholar
  • 25 Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 2018; 50 (05) 693-698
    CrossrefPubMedGoogle Scholar
  • 26 Choi Y, Lee SJ, Spiller W. et al. Causal associations between serum bilirubin levels and decreased stroke risk: a two-sample Mendelian randomization study. Arterioscler Thromb Vasc Biol 2020; 40 (02) 437-445
    CrossrefPubMedGoogle Scholar
  • 27 Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 2015; 44 (02) 512-525
    CrossrefPubMedGoogle Scholar
  • 28 Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol 2017; 46 (06) 1985-1998
    CrossrefPubMedGoogle Scholar
  • 29 Maddatu J, Anderson-Baucum E, Evans-Molina C. Smoking and the risk of type 2 diabetes. Transl Res 2017; 184: 101-107
    CrossrefPubMedGoogle Scholar
  • 30 Gregson J, Kaptoge S, Bolton T. et al; Emerging Risk Factors Collaboration. Cardiovascular risk factors associated with venous thromboembolism. JAMA Cardiol 2019; 4 (02) 163-173
    CrossrefPubMedGoogle Scholar
  • 31 Tan JS, Liu NN, Guo TT, Hu S, Hua L. Genetically predicted obesity and risk of deep vein thrombosis. Thromb Res 2021; 207: 16-24
    CrossrefPubMedGoogle Scholar
  • 32 Kaur R, Kaur M, Singh J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies. Cardiovasc Diabetol 2018; 17 (01) 121
    CrossrefPubMedGoogle Scholar
  • 33 Petrauskiene V, Falk M, Waernbaum I, Norberg M, Eriksson JW. The risk of venous thromboembolism is markedly elevated in patients with diabetes. Diabetologia 2005; 48 (05) 1017-1021
    CrossrefPubMedGoogle Scholar
  • 34 Gariani K, Mavrakanas T, Combescure C, Perrier A, Marti C. Is diabetes mellitus a risk factor for venous thromboembolism? A systematic review and meta-analysis of case-control and cohort studies. Eur J Intern Med 2016; 28: 52-58
    CrossrefPubMedGoogle Scholar
  • 35 Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002; 162 (10) 1182-1189
    CrossrefPubMedGoogle Scholar
  • 36 Van Schouwenburg IM, Mahmoodi BK, Veeger NJ. et al. Insulin resistance and risk of venous thromboembolism: results of a population-based cohort study. J Thromb Haemost 2012; 10 (06) 1012-1018
    CrossrefPubMedGoogle Scholar
  • 37 Glynn RJ, Rosner B. Comparison of risk factors for the competing risks of coronary heart disease, stroke, and venous thromboembolism. Am J Epidemiol 2005; 162 (10) 975-982
    CrossrefPubMedGoogle Scholar