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
› Author Affiliations
Funding This study received finding from the Jingzhou Healthcare Science and Technology Programme 2023 [2023HC20].
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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.

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.




Publication History

Article published online:
17 December 2024

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