Why the study?
The upstream genetic mechanisms linking hepatic inflammatory pathways to CAD remain incompletely defined, prompting investigation into whether genetic variation regulating MST1 expression contributes to CAD risk through a liver-vascular inflammatory axis.
Does genetically modulated hepatic MST1 expression and circulating MST1 protein level increase the risk of coronary artery disease and major adverse cardiovascular events?
Observational (n=278)
Yes
Does genetically modulated hepatic MST1 expression and circulating MST1 protein level increase the risk of coronary artery disease and major adverse cardiovascular events?
Genetic regulation of liver-derived MST1 causally influences circulating protein levels, vascular inflammation, and atherosclerotic cardiovascular events, identifying MST1 as a potential biomarker and therapeutic target for CAD.
Background Chronic inflammation contributes causally to atherosclerosis, but the upstream genetic mechanisms linking hepatic inflammatory pathways to coronary artery disease (CAD) remain incompletely defined. This study investigated whether genetic variation regulating macrophage-stimulating protein 1 (MST1) expression contributes to CAD risk through a liver–vascular inflammatory axis. Methods Genomic, transcriptomic, and proteomic data from 278 patients with established CAD in the PRECAD2 cohort were integrated to identify protein quantitative trait loci (pQTL) in plasma and arterial tissue. Validation was performed using liver and arterial expression and splicing QTL (eQTL/sQTL) data from GTEx1, proteomic and clinical data from the UK Biobank3, and plaque RNA and protein data from the AtheroExpress biobank2. Causal inference was assessed by colocalization and two-sample Mendelian randomization (MR) analyses. Results Variants at the MST1 locus (lead SNP rs11709525) regulated hepatic MST1 expression and splicing, leading to concordant effects on circulating MST1 protein levels (β = –0.83, p = 2.1 × 10⁻¹⁹). MR supported a causal relationship between liver MST1 expression and CAD risk (β = 0.116 ± 0.011, p = 1.2 × 10⁻²⁶). In the UK Biobank (~7 500 events), higher plasma MST1 concentrations were associated with increased body-mass index, LDL cholesterol, NLRP3-inflammasome, and higher incidence of myocardial infarction and stroke (log-rank p < 10⁻⁴). In AtheroExpress, plaque MST1 protein abundance correlated with 3-year major adverse cardiovascular events (hazard ratio 1.31 [95% CI 1.01–1.71], p = 0.046). Conclusion Genetic regulation of liver-derived MST1 alters circulating protein levels that associate with vascular inflammation and increased atherosclerotic risk. MST1 represents a potential biomarker and therapeutic target linking hepatic gene regulation to plaque inflammation and cardiovascular events.Graphical AbstractUKBB_outcome
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Schwab et al. (2026) conducted an observational in Coronary artery disease (CAD) (n=278). Genetically regulated hepatic/circulating and plaque MST1 (macrophage-stimulating protein 1) expression/levels vs. Lower MST1 expression/protein levels was evaluated on 3-year major adverse cardiovascular events (MACE) and coronary artery disease risk (HR 1.31, 95% CI 1.01-1.71, p=0.046).
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