TMEM106B alters vascular smooth muscle cell phenotypes and lysosomal function leading to atherosclerosis

Background Atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease (CAD), peripheral artery disease (PAD), and ischemic stroke (IS), account for the majority of global cardiovascular mortality. Although they affect distinct vascular territories, these conditions share overlapping traditional and genetic risk factors, suggesting common drivers of plaque formation across arterial beds. However, the specific loci underlying this shared susceptibility, and the biological pathways through which they contribute to arterial pathology, remain insufficiently defined. To address this gap, we performed a cross-trait genome-wide analysis to identify and characterize molecular mechanisms contributing to ASCVD. Among the prioritized loci was TMEM106B, a lysosomal trafficking regulator previously implicated in neurodegeneration, whose role in vascular biology has not been defined. Methods and Results Phenome-wide association analysis of the rs5011432_C variant, located within TMEM106B, demonstrated genome-wide significant associations with increased risk of CAD, PAD, and IS. Across independent patient cohorts, TMEM106B expression in atherosclerotic plaques was inversely associated with vulnerability and progressively reduced with lesion advancement. In ApoE-/- mice, Tmem106b levels were likewise reduced under Western diet, mirroring the human phenotype. Mendelian randomisation using plasma pQTL data further supported a protective causal effect of higher circulating TMEM106B protein levels across all three ASCVDs. Single-cell RNA sequencing of human coronary arteries identified vascular smooth muscle cells (VSMCs) as the principal arterial source of TMEM106B, with reduced expression observed in VSMCs from patients with CAD and in carriers of the rs5011432_C risk allele. To define functional consequences, TMEM106B was silenced in primary human aortic VSMCs using RNA interference. Loss of TMEM106B induced a synthetic, pro-inflammatory, and migratory transcriptional program accompanied by broad lysosomal dysregulation. Functionally, knockdown increased proliferation and migration and impaired autophagic flux. Proteome array-based secretome profiling further revealed enhanced release of pro-inflammatory mediators, consistent with a plaque-destabilizing VSMC phenotype. Conclusion Our cross-trait genome-wide analysis identified TMEM106B, a lysosomal trafficking regulator, as a shared susceptibility locus across ASCVDs and a regulator of vascular smooth muscle cell phenotype and lysosomal homeostasis. Reduced TMEM106B expression associates with plaque progression and vulnerability and promotes a synthetic, pro-inflammatory VSMC state. These convergent genetic, transcriptomic, and functional findings highlight TMEM106B and lysosomal pathways as promising therapeutic targets to prevent plaque progression and adverse events in ASCVD.