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

Song Hu; Jiang-Shan Tan; Meng-Jin Hu; Ting-Ting Guo; Liyuan Chen; Lu Hua; Jian Cao

doi:10.1055/a-2040-4850

Thrombosis and Haemostasis, Table of Contents

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

¹Key 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

¹Key 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

²State 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

¹Key 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

¹Key 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

¹Key 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

³Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China

› Author Affiliations

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

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References

References
1 Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet 2021; 398 (10294): 64-77
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
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
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
5 Piazza G, Goldhaber SZ. Venous thromboembolism and atherothrombosis: an integrated approach. Circulation 2010; 121 (19) 2146-2150
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
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
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
9 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262 (02) 157-172
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
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
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
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
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
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
16 Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA 2017; 318 (19) 1925-1926
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
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
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
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
21 Elsworth B, Lyon M, Alexander T. et al. The MRC IEU OpenGWAS data infrastructure. 2020
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
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
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
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
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
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
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
29 Maddatu J, Anderson-Baucum E, Evans-Molina C. Smoking and the risk of type 2 diabetes. Transl Res 2017; 184: 101-107
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
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
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
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
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
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
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
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

Supplementary Material

Supplementary Material