https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Schleswig-Holstein Institut für Kardiogenetik Lübeck, Deutschland; 2A.I. Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio, Finnland; 3Turku Bioscience Centre University of Turku and Åbo Akademi University Turku, Finnland
Cardiovascular diseases (CVD) are influenced by genetic factors, yet the mechanisms remain incompletely understood, particularly regarding smooth muscle cells (SMCs), which play a central role in vascular remodeling and plaque stability. By colocalizing quantitative trait loci (QTLs) with genome-wide association study (GWAS) data, we aimed to identify regulatory genes influencing SMC function and linked to vascular disease risk, thereby advancing our understanding of CVD pathogenesis.
Methods:
SMCs were isolated from the ascending aortas of 151 heart transplant donors of various genetic ancestries and cultured under quiescent and proliferative conditions. Expression QTLs (eQTLs) and splicing QTLs (sQTLs) were analyzed to identify genes associated with vascular diseases, including coronary artery disease (CAD), stroke, and hypertension. Bayesian colocalization (COLOC) and eCAVIAR analyses were employed to assess shared genetic architecture with GWAS loci, while candidate genes were validated in cell culture and zebrafish through gene knockdown and knockout experiments.
Results:
We identified 336 eQTL and 580 sQTL genes colocalized with CVD loci, indicating significant genetic regulation of mRNA expression and splicing in SMCs. Notably, MAP3K7CL colocalized with CAD, heart attack, and blood pressure GWAS loci, showing elevated expression in proliferative SMCs. MAP3K7CL modulates SMC migration, proliferation, and calcification. Functional knockdown of in zebrafish revealed CVD-relevant phenotypes, including altered heart rhythm and reduced vascular integrity, underscoring its role in vascular remodeling. Additionally, the sQTL rs79237883 impacted splicing of NT5C2, with associations to CAD and blood pressure, highlighting the role of alternative splicing in CVD susceptibility.
Conclusions:
This study demonstrates the potential of colocalization analyses in identifying SMC-specific genes implicated in CVD, such as MAP3K7CL and NT5C2. Our findings offer insight into the genetic mechanisms of SMC function in vascular diseases, presenting promising therapeutic targets. Integrating molecular QTL and GWAS data enables prioritization of functionally relevant genes in SMCs, aiding in precision medicine efforts for CVD.
Funding:
This work was supported by Finnish Foundation for Cardiovascular Research, DZHK and the CORONA Foundation.