Role of the cardiovascular risk gene LRCH1 in vascular inflammation

• Applicants: Dr. Yaw Asare; Professor Dr. Martin Dichgans
• Subject Area: Cardiology, Angiology ; Biochemistry
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 581263983

Common genetic variants at LRCH1 (leucine rich repeats [LRR] and calponin homology [CH] domain containing 1) are a major risk factor for human atherosclerosis, as revealed by GWAS in stroke, coronary artery disease, and other vascular disorders. rs9526212, the LRCH1 lead variant, is an expression quantitative trait locus (eQTL) for LRCH1 in multiple tissues, including the left ventricle, atherosclerotic aorta, atherosclerotic-lesion-free arteries, and blood. Data from both human and mouse studies suggest that the effects of risk alleles in the LRCH1 gene region on atherogenesis are mediated through elevated LRCH1 expression. However, the suspected link between altered LRCH1 expression and atherosclerosis remains to be established, as do the specific underlying mechanisms. Our working hypothesis is that LRCH1 orchestrates the assembly and activation of the JAK-STAT pathway in Mɸ, which in turn release factors that act on surrounding VSMCs to control atheroprogression and plaque stability. Our preliminary work indicates that Lrch1 deficiency attenuates atherosclerotic plaque burden and increases histopathological features of plaque stability, likely through modulation of pro-inflammatory cytokine production, cell adhesion, and migration. In human carotid endarterectomy samples, increased LRCH1 expression was associated with atheroprogression and clinical plaque instability. However, the cell type-specific role of LRCH1 in atherosclerotic plaque formation and stabilization and the precise mechanism linking LRCH1 to vascular inflammation, cell adhesion, and migration remain largely undefined. We propose to address the following objectives: 1) detail the effects of global and cell-specific deletion of Lrch1 on atherosclerosis; 2) scrutinize the mechanisms underlying the proatherogenic effects of LRCH1; and 3) unravel the molecular role of LRCH1 in the JAK-STAT signaling pathway. We expect these findings to provide fundamental insights into the molecular mechanisms underlying human atherosclerosis and open novel therapeutic perspectives.

• DFG Programme: Research Grants