Genetic Regulation of Liver-Derived MST1 Links Systemic Inflammation to Coronary Artery Disease

M. Schwab (München)¹, I. Pugach (München)², T. Keßler (München)¹, Z. Chen (München)¹, J. Krefting (München)³, A. Moggio (München)¹, L. Ling (München)¹, F. Starnecker (München)¹, M. U. Kaikkonen (Kuopio)⁴, S. Bankier (Bergen)⁵, M. Mokry (Utrecht)⁶, G. Pasterkamp (Utrecht)⁷, S. Doppler (München)⁸, H. Lahm (München)⁹, M. Dreßen (München)⁸, M. Krane (München)⁹, J. Björkegren (New York)¹⁰, S. Steigerwald (Martinsried)¹¹, M. Mann (Martinsried)¹², S. W. van der Laan (Utrecht)¹³, H. Schunkert (München)¹, M. von Scheidt (München)^1
1Deutsches Herzzentrum München Klinik für Herz- und Kreislauferkrankungen München, Deutschland; ²Deutsches Herzzentrum München, TUM Universitätsklinikum München, Deutschland; ³Deutsches Herzzentrum München Klink für Herzkreislauferkrankungen München, Deutschland; ⁴A.I. Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio, Finnland; ⁵Computational Biology Unit Department of Informatics Bergen, Norwegen; ⁶Central Diagnostics Laboratory, University Medical Center Utrecht Utrecht, Niederlande; ⁷University Medical Center Utrecht Department of Experimental Cardiology Utrecht, Niederlande; ⁸Deutsches Herzzentrum München Klinik für Herz- und Gefäßchirurgie München, Deutschland; ⁹Deutsches Herzzentrum München München, Deutschland; ¹⁰Department of Genetics & Genomic Sciences Institute of Genomics and Multiscale Biology New York, USA; ¹¹Max-Plack-Institut für Biochemie Proteomics und Signaltransduktion Martinsried, Deutschland; ¹²Max-Planck-Institut für Biochemie Martinsried, Deutschland; ¹³PhD Laboratory of Experimental Cardiology Department of Cardiology Utrecht, Deutschland

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 GTEx, proteomic and clinical data from the UK Biobank, and plaque RNA and protein data from the AtheroExpress biobank. 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. (Funded by DigiMed Bayern; PRECAD2 clinical trial registration number, DRKS00020960).