Download PDF
CC BY-NC-ND 4.0 · Thromb Haemost
DOI: 10.1055/a-2313-0311
Stroke, Systemic or Venous Thromboembolism

Exploring the Two-Way Link between Migraines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study

Yang Wang 
1   Vascular Surgery, Shandong Public Health Clinical Center, Shandong University, Jinan, China
,
Xiaofang Hu
2   Department of Neurology, Shandong Public Health Clinical Center, Shandong University, Jinan, China
,
Xiaoqing Wang
3   Interventional Department, Shandong Public Health Clinical Center, Shandong University, Jinan, China
,
Lili Li
3   Interventional Department, Shandong Public Health Clinical Center, Shandong University, Jinan, China
,
Peng Lou
1   Vascular Surgery, Shandong Public Health Clinical Center, Shandong University, Jinan, China
,
Zhaoxuan Liu
4   Vascular Surgery, Shandong First Medical University affiliated Central Hospital, Jinan, China
› Author Affiliations
› Further Information
   Permissions and Reprints


Abstract

Background The objective of this study is to utilize Mendelian randomization to scrutinize the mutual causality between migraine and venous thromboembolism (VTE) thereby addressing the heterogeneity and inconsistency that were observed in prior observational studies concerning the potential interrelation of the two conditions.

Methods Employing a bidirectional Mendelian randomization approach, the study explored the link between migraine and VTE, incorporating participants of European descent from a large-scale meta-analysis. An inverse-variance weighted (IVW) regression model, with random-effects, leveraging single nucleotide polymorphisms (SNPs) as instrumental variables was utilized to endorse the mutual causality between migraine and VTE. SNP heterogeneity was evaluated using Cochran's Q-test and to account for multiple testing, correction was implemented using the intercept of the MR-Egger method, and a leave-one-out analysis.

Results The IVW model unveiled a statistically considerable causal link between migraine and the development of VTE (odds ratio [OR] = 96.155, 95% confidence interval [CI]: 4.342–2129.458, p = 0.004), implying that migraine poses a strong risk factor for VTE development. Conversely, both IVW and simple model outcomes indicated that VTE poses as a weaker risk factor for migraine (IVW OR = 1.002, 95% CI: 1.000–1.004, p = 0.016). The MR-Egger regression analysis denoted absence of evidence for genetic pleiotropy among the SNPs while the durability of our Mendelian randomization results was vouched by the leave-one-out sensitivity analysis.

Conclusion The findings of this Mendelian randomization assessment provide substantiation for a reciprocal causative association between migraine and VTE within the European population.

Keyword

Mendelian randomization - migraine - venous thromboembolism - bidirectional - causality

Supplementary Material



Publication History

Received: 10 June 2023

Accepted: 10 April 2024

Accepted Manuscript online:
24 April 2024

Article published online:
20 May 2024

© 2024. 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 Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015; 12 (08) 464-474
    CrossrefPubMedGoogle Scholar
  • 3 Headache Classification Committee of the International Headache Society (IHS). Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38 (01) 1-211
    CrossrefPubMedGoogle Scholar
  • 4 Adelborg K, Szépligeti SK, Holland-Bill L. et al. Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ 2018; 360: k96
    CrossrefPubMedGoogle Scholar
  • 5 Peng KP, Chen YT, Fuh JL, Tang CH, Wang SJ. Association between migraine and risk of venous thromboembolism: a nationwide cohort study. Headache 2016; 56 (08) 1290-1299
    CrossrefPubMedGoogle Scholar
  • 6 Sacco S, Carolei A. Burden of atherosclerosis and risk of venous thromboembolism in patients with migraine. Neurology 2009; 72 (23) 2056-2057 , author reply 2057
    CrossrefPubMedGoogle Scholar
  • 7 Folsom AR, Lutsey PL, Misialek JR, Cushman M. A prospective study of migraine history and venous thromboembolism in older adults. Res Pract Thromb Haemost 2019; 3 (03) 357-363
    CrossrefPubMedGoogle Scholar
  • 8 Elgendy IY, Nadeau SE, Bairey Merz CN, Pepine CJ. American College of Cardiology Cardiovascular Disease in Women Committee† , American College of Cardiology Cardiovascular Disease in Women Committee† . Migraine headache: an under-appreciated risk factor for cardiovascular disease in women. J Am Heart Assoc 2019; 8 (22) e014546
    CrossrefPubMedGoogle Scholar
  • 9 Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA 2017; 318 (19) 1925-1926
    CrossrefPubMedGoogle Scholar
  • 10 Karlsson T, Hadizadeh F, Rask-Andersen M, Johansson Å, Ek WE. Body mass index and the risk of rheumatic disease: linear and nonlinear Mendelian randomization analyses. Arthritis Rheumatol 2023; 75 (11) 2027-2035
    CrossrefPubMedGoogle Scholar
  • 11 Lawler T, Warren Andersen S. Serum 25-hydroxyvitamin D and cancer risk: a systematic review of mendelian randomization studies. Nutrients 2023; 15 (02) 422
    CrossrefPubMedGoogle Scholar
  • 12 Burgess S, Butterworth AS, Thompson JR. Beyond Mendelian randomization: how to interpret evidence of shared genetic predictors. J Clin Epidemiol 2016; 69: 208-216
    CrossrefPubMedGoogle Scholar
  • 13 Sudlow C, Gallacher J, Allen N. et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med 2015; 12 (03) e1001779
    CrossrefPubMedGoogle Scholar
  • 14 Lyon MS, Andrews SJ, Elsworth B, Gaunt TR, Hemani G, Marcora E. The variant call format provides efficient and robust storage of GWAS summary statistics. Genome Biol 2021; 22 (01) 32
    CrossrefPubMedGoogle Scholar
  • 15 Kurki MI, Karjalainen J, Palta P. et al; FinnGen. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 2023; 613 (7944) 508-518
    CrossrefPubMedGoogle Scholar
  • 16 Sanderson E, Glymour MM, Holmes MV. et al. Mendelian randomization. Nat Rev Methods Primers 2022; 2: 6
    CrossrefPubMedGoogle Scholar
  • 17 Staley JR, Blackshaw J, Kamat MA. et al. PhenoScanner: a database of human genotype-phenotype associations. Bioinformatics 2016; 32 (20) 3207-3209
    CrossrefPubMedGoogle Scholar
  • 18 Kamat MA, Blackshaw JA, Young R. et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics 2019; 35 (22) 4851-4853
    CrossrefPubMedGoogle Scholar
  • 19 Burgess S, Thompson SG. Mendelian Randomization: Methods for Causal Inference Using Genetic Variants. New York, NY: CRC Press; 2021
    CrossrefGoogle Scholar
  • 20 May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol 2016; 12 (08) 455-464
    CrossrefPubMedGoogle Scholar
  • 21 Dodick DW. Migraine. Lancet 2018; 391 (10127): 1315-1330
    CrossrefPubMedGoogle Scholar
  • 22 Khorana AA, Mackman N, Falanga A. et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers 2022; 8 (01) 11
    CrossrefPubMedGoogle Scholar
  • 23 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
  • 24 Bhoelan S, Borjas Howard J, Tichelaar V. et al. Recurrence risk of venous thromboembolism associated with systemic lupus erythematosus: a retrospective cohort study. Res Pract Thromb Haemost 2022; 6 (08) e12839
    CrossrefPubMedGoogle Scholar
  • 25 Pengo V, Denas G. Antiphospholipid syndrome in patients with venous thromboembolism. Semin Thromb Hemost 2023; 49 (08) 833-839
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Maitrot-Mantelet L, Horellou MH, Massiou H, Conard J, Gompel A, Plu-Bureau G. Should women suffering from migraine with aura be screened for biological thrombophilia?: results from a cross-sectional French study. Thromb Res 2014; 133 (05) 714-718
    CrossrefPubMedGoogle Scholar
  • 27 Tietjen GE, Collins SA. Hypercoagulability and migraine. Headache 2018; 58 (01) 173-183
    CrossrefPubMedGoogle Scholar
  • 28 Schwaiger J, Kiechl S, Stockner H. et al Burden of atherosclerosis and risk of venous thromboembolism in patients with migraine. Neurology 2008; 71 (12) 937-943
    CrossrefPubMedGoogle Scholar
  • 29 Bushnell CD, Jamison M, James AH. Migraines during pregnancy linked to stroke and vascular diseases: US population based case-control study. BMJ 2009; 338: b664
    CrossrefPubMedGoogle Scholar
  • 30 Ding WY, Protty MB, Davies IG, Lip GYH. Relationship between lipoproteins, thrombosis, and atrial fibrillation. Cardiovasc Res 2022; 118 (03) 716-731
    CrossrefPubMedGoogle Scholar
  • 31 Gupta RM, Hadaya J, Trehan A. et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 2017; 170 (03) 522-533.e15
    CrossrefPubMedGoogle Scholar
  • 32 Kumari B, Prabhakar A, Sahu A. et al. Endothelin-1 gene polymorphism and its level predict the risk of venous thromboembolism in male indian population. Clin Appl Thromb Hemost 2017; 23 (05) 429-437
    CrossrefPubMedGoogle Scholar
  • 33 Zhang Y, Liu J, Jia W. et al. AGEs/RAGE blockade downregulates Endothenin-1 (ET-1), mitigating Human Umbilical Vein Endothelial Cells (HUVEC) injury in deep vein thrombosis (DVT). Bioengineered 2021; 12 (01) 1360-1368
    CrossrefPubMedGoogle Scholar
  • 34 Padilla J, Carpenter AJ, Das NA. et al. TRAF3IP2 mediates high glucose-induced endothelin-1 production as well as endothelin-1-induced inflammation in endothelial cells. Am J Physiol Heart Circ Physiol 2018; 314 (01) H52-H64
    CrossrefPubMedGoogle Scholar
  • 35 Liu L, Jouve C, Sebastien Hulot J, Georges A, Bouatia-Naji N. Epigenetic regulation at LRP1 risk locus for cardiovascular diseases and assessment of cellular function in hiPSC derived smooth muscle cells. Cardiovasc Res 2022; 118 (01) cvac066.193
    CrossrefPubMedGoogle Scholar
  • 36 Vormittag R, Bencur P, Ay C. et al. Low-density lipoprotein receptor-related protein 1 polymorphism 663 C > T affects clotting factor VIII activity and increases the risk of venous thromboembolism. J Thromb Haemost 2007; 5 (03) 497-502
    CrossrefPubMedGoogle Scholar
  • 37 Chun H, Kurasawa JH, Olivares P. et al. Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts. J Thromb Haemost 2022; 20 (10) 2255-2269
    CrossrefPubMedGoogle Scholar