Genetically modulated regulation of liver-derived MST1 links systemic inflammation to coronary artery disease risk
M Schwab, I P Pugach, T K Kessler, Z C Chen, J K Krefting, C A Abrahamian, M K Kaikkonen Maatta, M M Mokry, S W Wei, G P Pasterkamp, S S steigerwald, M M Mann, M K Krane, H S Schunkert, MvS von ScheidtAbstract
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