PO06 Lysosomal Protein TMEM106B Links to Multiple Atherosclerotic Cardiovascular Disorders

Background Our cross-trait meta-analysis identified TMEM106B, a lysosomal protein, as a genetic locus shared across three atherosclerotic cardiovascular diseases (ASCVDs): coronary artery disease (CAD), peripheral artery disease (PAD), and ischemic stroke (IS). TMEM106B is primarily studied in neurodegenerative disorders(Root et al., 2021). However, the molecular mechanisms linking TMEM106B to ASCVD pathogenesis remain poorly understood. Methods and Results Phenotype association analysis of the lead variant rs5011432_C at the TMEM106B locus revealed associations not only with increased risk of three ASCVDs, but also with elevated adverse factors and reduced protective factors. Subsequent proteome-wide Mendelian randomisation (MR) analysis using plasma pQTL data from the ARIC study(Hicks et al., 2021) provided consistent evidence for causal protective roles of TMEM106B on the three ASCVDs and multiple related risk traits. Data from the ATHERO-Express database(Verhoeven et al., 2004) further demonstrated that higher TMEM106B expression is negatively associated with plaque vulnerability index, and with features indicative of plaque instability, such as intraplaque haemorrhage and lipid-rich areas. Bulk RNA sequencing data from GTEx(GTEx Consortium, 2013) showed that TMEM106B is abundantly expressed in ASCVD-relevant tissues–particularly arterial and adipose tissues–at levels comparable to those in brain tissues. The single-cell RNA sequencing (scRNA-seq) data of the coronary artery from public resources(Hu et al., 2021; Wirka et al., 2019) revealed that TMEM106B is relatively abundant in vascular smooth muscle cells (VSMCs), a finding replicated in carotid artery scRNA-seq data from two independent cohorts. Notably, TMEM106B expression is markedly reduced in VSMCs from both diseased coronary arteries and unstable carotid plaques. Functional assays demonstrated that TMEM106B knockdown in coronary VSMCs promotes cell proliferation and migration. In the coronary artery tissue, the co-expressed genes of TMEM106B are enriched in pathways related to lysosomal functions (endocytosis, SNARE interaction in vesicular transport, and RNA degradation) and vascular remodeling (MAPK signaling and SMC constructions). Specifically, in coronary VSCMs, TMEM106B is co-expressed with genes associated with SMC’s identity, stress response, and remodeling. Conclusion The protective effects of TMEM106B against the three ASCVDs are consistently supported across multiple levels, including genetic associations, phenotypic indicators of plaque stability, tissue- and single-cell–level expression data, and in vitro knockdown experiments. All data collectively support a potential molecular cascade in which TMEM106B influences lysosomal function, thereby affecting VSMCs, and ultimately contributing to atherosclerosis