PDF herunterladen
Semin Thromb Hemost
DOI: 10.1055/s-0044-1800980
Review Article

Comprehensive Mendelian Randomization Analysis of Smoking and Its Effects on Venous Thromboembolism

Yuhong Li   *
1   Department of Trauma Hand and Foot Surgery, The First Affiliated Hospital of Yangtze University, the First People's Hospital of Jingzhou, Jingzhou, Hubei Province, People's Republic of China
,
Ling Tong   *
1   Department of Trauma Hand and Foot Surgery, The First Affiliated Hospital of Yangtze University, the First People's Hospital of Jingzhou, Jingzhou, Hubei Province, People's Republic of China
,
Youqian Zhang
2   Health Science Center, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
,
Birun Huang
3   Department of Vascular Surgery, The First Affiliated Hospital of Yangtze University, the First People's Hospital of Jingzhou, Jingzhou, Hubei Province, People's Republic of China
,
Liping Zhu
1   Department of Trauma Hand and Foot Surgery, The First Affiliated Hospital of Yangtze University, the First People's Hospital of Jingzhou, Jingzhou, Hubei Province, People's Republic of China
› Institutsangaben Funding This study received finding from the Jingzhou Healthcare Science and Technology Programme 2023 [2023HC20].
› Weitere Informationen
    Lizenzen und Reprints

Abstract

An increasing number of Mendelian randomization (MR) studies have evaluated the causal link between smoking and venous thromboembolism (VTE). However, previous studies often rely on single genetic variants related to smoking quantity and exhibit various other shortcomings, making them prone to pleiotropy and potentially leading to imprecise causal estimates. Thus, the deeper causal mechanisms remain largely unexplored. This MR study reassessed the causal relationship between smoking and VTE, including its subtypes—deep vein thrombosis (DVT) and pulmonary embolism (PE). Data on VTE were sourced from the FinnGen consortium with nonoverlapping sample sizes. The smoking phenotypes analyzed included smoking initiation, lifetime smoking, the number of cigarettes smoked per day by both current and former smokers (CigDay), and total pack-years of smoking in adulthood. The primary analytical method was inverse-variance-weighted (IVW), supplemented by multiple verification methods to ensure robust results. Statistical rigor was ensured through LDtrait pruning and Steiger filtering for reverse causation, with comprehensive sensitivity analyses including RadialMR confirming the findings' robustness. After Bonferroni correction, this study demonstrates significant causal evidence linking lifetime smoking with the incidence of VTE (odds ratio [OR]IVW = 1.50, 95% confidence interval [CI] 1.21–1.85, p = 1.75 × 10−4) and PE (ORIVW = 1.69, 95% CI 1.25–2.28, p = 6.55 × 10−4), and suggestive evidence with DVT, consistent in direction with previous studies but showing considerable differences in effect sizes and significance. Additionally, CigDay (past and current) increases the risks of VTE and DVT, while no causal link was found between smoking initiation and VTE or its subtypes (p < 0.05), both directly contradicting previous conclusions. Furthermore, our study is the first to suggest a causal link between pack-years and an increased risk of VTE. This MR study employed rigorous statistical pruning of its instrumental variables, using the most comprehensive smoking phenotype to date. It successfully mitigated biases such as winner's curse, yielding causal effect results distinct from previous studies.

Keywords

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

Statement of Ethics

Each investigation incorporated within the GWAS framework was sanctioned by the relevant ethical review panels. Please see the original article citing the GWAS article for the specific approval documents. No ethics approval was necessary for this research.


Data Availability Statement

Data sources are detailed in [Table 1]. VTE and its subtypes can be downloaded from the FinnGen consortium as version R10 (https://www.finngen.fi/en), and smoking phenotypes can be downloaded from https://www.ebi.ac.uk/gwas/ according to their PMIDs.


Authors' Contributions

Y.L.: Conceptualization, data curation, formal analysis, investigation, methodology, visualization, writing – original draft, and writing – review and editing.


L.T.: Conceptualization, data curation, formal analysis, investigation, methodology, software, validation, writing – original draft, and writing – review and editing.


Y.Z.: Data curation, investigation, resources, software, validation, visualization, and writing – review and editing.


B.H.: Conceptualization, funding acquisition, project administration, supervision, writing – original draft, and writing – review and editing.


L.Z.: Conceptualization, funding acquisition, project administration, supervision, writing – original draft, and writing – review and editing.


* Both The Authors Are Co-First Authors.


Supplementary Material



Publikationsverlauf

Artikel online veröffentlicht:
17. Dezember 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Lutsey PL, Zakai NA. Epidemiology and prevention of venous thromboembolism. Nat Rev Cardiol 2023; 20 (04) 248-262
    CrossrefPubMedSuche in Google Scholar
  • 2 Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet 2021; 398 (10294): 64-77
    CrossrefPubMedSuche in Google Scholar
  • 3 Søgaard KK, Schmidt M, Pedersen L, Horváth-Puhó E, Sørensen HT. 30-year mortality after venous thromboembolism: a population-based cohort study. Circulation 2014; 130 (10) 829-836
    CrossrefPubMedSuche in Google Scholar
  • 4 Ortel TL, Neumann I, Ageno W. et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19) 4693-4738
    CrossrefPubMedSuche in Google Scholar
  • 5 Folsom AR, Cushman M. Exploring opportunities for primary prevention of unprovoked venous thromboembolism: ready for prime time?. J Am Heart Assoc 2020; 9 (23) e019395
    CrossrefPubMedSuche in Google Scholar
  • 6 Tapson VF. The role of smoking in coagulation and thromboembolism in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005; 2 (01) 71-77
    CrossrefPubMedSuche in Google Scholar
  • 7 Elisia I, Lam V, Cho B. et al. The effect of smoking on chronic inflammation, immune function and blood cell composition. Sci Rep 2020; 10 (01) 19480
    CrossrefPubMedSuche in Google Scholar
  • 8 Mahmoodi BK, Cushman M, Anne Næss I. et al. Association of traditional cardiovascular risk factors with venous thromboembolism: an individual participant data meta-analysis of prospective studies. Circulation 2017; 135 (01) 7-16
    CrossrefPubMedSuche in Google Scholar
  • 9 Murad MH, Asi N, Alsawas M, Alahdab F. New evidence pyramid. Evid Based Med 2016; 21 (04) 125-127
    CrossrefPubMedSuche in Google Scholar
  • 10 Skrivankova VW, Richmond RC, Woolf BAR. et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ 2021; 375 (2233) n2233
    CrossrefPubMedSuche in Google Scholar
  • 11 Katan MB. Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet 1986; 1 (8479) 507-508
    CrossrefPubMedSuche in Google Scholar
  • 12 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
    CrossrefPubMedSuche in Google Scholar
  • 13 Hu M, Li X, Yang Y. Causal associations between cardiovascular risk factors and venous thromboembolism. Semin Thromb Hemost 2023; 49 (07) 679-687
    Thieme ConnectPubMedSuche in Google Scholar
  • 14 Du H-C, Zheng Y-F, Shen M-Q, Deng B-Y. No genetic causality between tobacco smoking and venous thromboembolism: a two-sample Mendelian randomization study. Thromb Haemost 2024; •••: s-0044-s-1781425
    PubMedSuche in Google Scholar
  • 15 Skrivankova VW, Richmond RC, Woolf BAR. et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: the STROBE-MR statement. JAMA 2021; 326 (16) 1614-1621
    CrossrefPubMedSuche in Google Scholar
  • 16 Lawlor DA, Harbord RM, Sterne JAC, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008; 27 (08) 1133-1163
    CrossrefPubMedSuche in Google Scholar
  • 17 Carrasquilla GD, García-Ureña M, Romero-Lado MJ, Kilpeläinen TO. Estimating causality between smoking and abdominal obesity by Mendelian randomization. Addiction 2024; 119 (06) 1024-1034
    CrossrefPubMedSuche in Google Scholar
  • 18 Liu M, Jiang Y, Wedow R. et al; 23andMe Research Team, HUNT All-In Psychiatry. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet 2019; 51 (02) 237-244
    CrossrefPubMedSuche in Google Scholar
  • 19 Conroy MC, Lacey B, Bešević J. et al. UK Biobank: a globally important resource for cancer research. Br J Cancer 2023; 128 (04) 519-527
    CrossrefPubMedSuche in Google Scholar
  • 20 Wootton RE, Richmond RC, Stuijfzand BG. et al. Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study. Psychol Med 2020; 50 (14) 2435-2443
    CrossrefPubMedSuche in Google Scholar
  • 21 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
    CrossrefPubMedSuche in Google Scholar
  • 22 Burgess S, Thompson SG. CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol 2011; 40 (03) 755-764
    CrossrefPubMedSuche in Google Scholar
  • 23 Guan W, Steffen BT, Lemaitre RN. et al. Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology Consortium. Circ Cardiovasc Genet 2014; 7 (03) 321-331
    CrossrefPubMedSuche in Google Scholar
  • 24 Cai J, Li X, Wu S. et al. Assessing the causal association between human blood metabolites and the risk of epilepsy. J Transl Med 2022; 20 (01) 437
    CrossrefPubMedSuche in Google Scholar
  • 25 Lin S-H, Brown DW, Machiela MJ. LDtrait: an online tool for identifying published phenotype associations in linkage disequilibrium. Cancer Res 2020; 80 (16) 3443-3446
    CrossrefPubMedSuche in Google Scholar
  • 26 Hemani G, Zheng J, Elsworth B. et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife 2018; 7: e34408
    CrossrefPubMedSuche in Google Scholar
  • 27 Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 2016; 40 (04) 304-314
    CrossrefPubMedSuche in Google Scholar
  • 28 Ye T, Shao J, Kang H. Debiased inverse-variance weighted estimator in two-sample summary-data Mendelian randomization. The Annals of Statistics Institute of Mathematical Statistics 2021; 49: 2079-2100
    PubMedSuche in Google Scholar
  • 29 Zhao J, Ming J, Hu X, Chen G, Liu J, Yang C. Bayesian weighted Mendelian randomization for causal inference based on summary statistics. Bioinformatics 2020; 36 (05) 1501-1508
    CrossrefPubMedSuche in Google Scholar
  • 30 Zhao Q, Wang J, Hemani G, Bowden J, Small DS. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. The Annals of Statistics Institute of Mathematical Statistics 2020; 48: 1742-1769
    PubMedSuche in Google Scholar
  • 31 Burgess S, Foley CN, Allara E, Staley JR, Howson JMM. A robust and efficient method for Mendelian randomization with hundreds of genetic variants. Nat Commun 2020; 11 (01) 376
    CrossrefPubMedSuche in Google Scholar
  • 32 Zhang L, Mukherjee B, Ghosh M, Gruber S, Moreno V. Accounting for error due to misclassification of exposures in case-control studies of gene-environment interaction. Stat Med 2008; 27 (15) 2756-2783
    CrossrefPubMedSuche in Google Scholar
  • 33 Kulinskaya E, Dollinger MB, Bjørkestøl K. On the moments of Cochran's Q statistic under the null hypothesis, with application to the meta-analysis of risk difference. Res Synth Methods 2020; 11 (06) 920
    CrossrefPubMedSuche in Google Scholar
  • 34 Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 2017; 32 (05) 377-389
    CrossrefPubMedSuche in Google Scholar
  • 35 Wu F, Huang Y, Hu J, Shao Z. Mendelian randomization study of inflammatory bowel disease and bone mineral density. BMC Med 2020; 18 (01) 312
    CrossrefPubMedSuche in Google Scholar
  • 36 Verbanck M, Chen C-Y, 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
    CrossrefPubMedSuche in Google Scholar
  • 37 Cheng H, Garrick DJ, Fernando RL. Efficient strategies for leave-one-out cross validation for genomic best linear unbiased prediction. J Anim Sci Biotechnol 2017; 8: 38
    CrossrefPubMedSuche in Google Scholar
  • 38 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
    CrossrefPubMedSuche in Google Scholar
  • 39 Brion M-JA, Shakhbazov K, Visscher PM. Calculating statistical power in Mendelian randomization studies. Int J Epidemiol 2013; 42 (05) 1497-1501
    CrossrefPubMedSuche in Google Scholar
  • 40 Burgess S, Thompson SG. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol 2015; 181 (04) 251-260
    CrossrefPubMedSuche in Google Scholar
  • 41 Liu J, Zhang Y, Zeng B. Commentary: “no genetic causality between tobacco smoking and venous thromboembolism: a two-sample Mendelian randomization study”. Thromb Haemost 2024; 124 (12) 1169-1170
    Thieme ConnectPubMedSuche in Google Scholar