Genetic and biological determinants of pulmonary embolism: Insights from Mendelian randomization studies

Table 1 Summary of causative factors for pulmonary embolism: Insights from Mendelian randomization studies

Ref.	Population	Sample size	Data sources	Exposure(s)	Methods	Results (effect estimates)	Main interpretation
Gong et al[5], 2025	Predominantly European ancestry GWAS (United Kingdom biobank-based; includes icelandic cohort)	500000	United Kingdom Biobank, GWAS summary statistics	MMP	Bidirectional two-sample MR (IVW, MR-PRESSO, sensitivity analyses)	MMP19 associated with increased PE risk (OR = 1.0009, P = 0.041); MMP12 associated with decreased PE risk (OR = 0.9992, P = 0.038)	MMP19 may be associated with increased PE risk; MMP12 may show an inverse association
Tong et al[21], 2024	Predominantly European ancestry GWAS (EAA n = 34467; PE 3940 cases, 480658 controls)	515000	Large-scale GWAS datasets	EAA	Bidirectional two-sample MR (IVW, MR-egger, weighted mode)	No consistent association between EAA and PE	EAA does not appear to be associated with PE risk
Xu et al[24], 2024	Predominantly European ancestry GWAS (MiBioGen, IEU Open GWAS)	378000	MiBioGen, IEU Open GWAS	Gut microbiota traits	Bidirectional two-sample MR (IVW, MR-Egger, weighted median)	Butyricicoccus associated with decreased PE risk; Clostridium innocuum associated with increased PE risk	Gut microbiota traits may be associated with PE susceptibility
Lyu et al[28], 2024	Predominantly European ancestry cohorts (CURES, CHARLS, FinnGen)	17547	CURES, CHARLS, FinnGen GWAS	Renal function (eGFR)	Nested case-control study with MR analysis	Reduced eGFR associated with increased PE risk (OR = 4.26, P < 0.001)	Renal dysfunction may be associated with increased PE risk
Jiang et al[34], 2024	Predominantly European ancestry GWAS (blood cell consortium, FinnGen)	500000	Blood cell consortium, FinnGen	Blood cell traits	Single-variable and multivariable MR (IVW, MR-egger)	Lower lymphocyte count associated with increased PE risk (OR = 0.84, P = 0.0139)	Immune cell traits may be associated with PE risk
Yang et al[42], 2024	Predominantly European ancestry GWAS (IEU Open GWAS database)	600000	IEU Open GWAS	Glycemic traits (T2DM, FG, FI, GH)	Two-sample MR (IVW, MR-PRESSO, sensitivity analyses)	No consistent association between glycemic traits and PE	No strong genetic evidence linking glycemic traits with PE
Liu et al[47], 2024	Predominantly European ancestry GWAS (AF and PE datasets)	1000000	Large European GWAS datasets	AF	Two-sample MR (IVW, MR-egger, MR-PRESSO)	No causal association between AF and PE	AF is unlikely to be a causal factor for PE
Wei et al[54], 2023	Predominantly European ancestry GWAS	1500000	Multiple European GWAS sources	BMI, smoking, HF, alcohol intake, IBD	Multivariable MR (IVW, Wald ratios, Cochran’s Q test)	BMI shows weak association with PE risk (OR = 1.002, P = 0.039); no consistent association for other exposures	BMI may have a weak association with PE risk; overall evidence is inconsistent
Feng et al[56], 2022	Predominantly European ancestry GWAS (United Kingdom biobank-based)	500000	United Kingdom Biobank GWAS, GEO	Blood metabolites	LDSC, MR, transcriptomic analysis	Hydroxytryptophan associated with increased PE risk; LIPC and NAT2 genes linked to PE	Metabolic pathways may be associated with PE risk
Cen et al[57], 2025	Predominantly European ancestry GWAS (IEU Open GWAS; MiBioGen)	360000 participants	IEU Open GWAS, MiBioGen	Gut microbiota and PE	Two-sample MR (IVW, pleiotropy/heterogeneity tests)	Several genera (e.g., Bacteroidetes, Oscillospira) associated with reduced PE risk	Gut microbiota composition may influence PE susceptibility
Zhang et al[58], 2023	Han Chinese GWAS cohorts	18000 participants	GWAS discovery + replication cohorts	Genetic susceptibility loci and PE	GWAS + MR + PRS analysis	FABP2 Locus identified; LDL-C and total cholesterol causally linked to PE	Lipid metabolism pathways may contribute to PE risk

CHARLS: China Health and Retirement Longitudinal Study; CURES: Cardiovascular and Metabolic Diseases Etiology Research Center; FABP2: Fatty acid binding protein 2; FG: Fasting glucose; FI: Fasting insulin; GEO: Gene expression omnibus; GH: Glycated hemoglobin; BMI: Body mass index; HF: Heart failure; IBD: Inflammatory bowel disease; IEU Open GWAS: Integrative Epidemiology Unit Open Genome-Wide Association Studies database; IVW: Inverse variance weighted; LDSC: Linkage disequilibrium score regression; MiBioGen: Human Microbiome Consortium Genome-Wide Association Study; MR: Mendelian randomization; MR-egger: Mendelian randomization-egger regression; MR-PRESSO: Mendelian randomization pleiotropy RESidual sum and outlier; PRS: Polygenic risk score; LDL-C: Low-density lipoprotein cholesterol; PE: Pulmonary embolism; EAA: Epigenetic age acceleration; eGFR: Estimated glomerular filtration rate; AF: Atrial fibrillation; T2DM: Type 2 diabetes mellitus.

Table 2 Pathophysiological mechanisms of pulmonary embolism in relation to Mendelian randomization evidence

Mechanism	Description	Clinical relevance	MR-informed associations
Thrombus formation	Formation of clots in deep veins driven by Virchow’s triad: Endothelial injury, hypercoagulability, and venous stasis	Risk of embolization to the pulmonary circulation; prevention primarily via anticoagulation	MR-specific associations not directly evaluated
Pulmonary vascular obstruction	Occlusion of pulmonary arteries leading to increased vascular resistance and right ventricular afterload	May result in right ventricular dysfunction and hemodynamic instability requiring urgent intervention	Renal dysfunction (reduced eGFR) associated with increased PE susceptibility
Gas exchange impairment	Ventilation-perfusion mismatch resulting in hypoxemia due to increased dead space ventilation	Manifests as dyspnea and hypoxemia; supportive oxygen therapy required	Obesity-related metabolic traits show variable MR associations
Inflammatory response	Cytokine release, NET formation, and oxidative stress contribute to thromboinflammation	Potential role of anti-inflammatory pathways in disease modulation	Reduced HLA-DR-positive NK cell traits associated with increased PE risk
Endothelial dysfunction	Endothelial injury promotes activation of coagulation pathways and thrombus formation	May contribute to chronic thromboembolic pulmonary hypertension	MMP19 associated with increased PE risk; MMP12 shows inverse association
Metabolic dysregulation	Obesity and metabolic imbalance promote a pro-inflammatory and prothrombotic state	May influence risk stratification and long-term outcomes	BMI and gut microbiota traits show variable MR associations
Coagulation cascade activation	Activation of clotting pathways through tissue factor exposure and thrombin generation	Guides use of anticoagulant therapies	Not directly evaluated in MR studies included in this review

NET: Neutrophil extracellular traps; eGFR: Estimated glomerular filtration rate; PE: Pulmonary embolism; MR: Mendelian randomization; MMP: Matrix metalloproteinases.