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.