BACKGROUND AND AIMS
Autoimmune diseases (ADs) are associated with increased myocardial infarction (MI) risk, suggesting shared genetic susceptibility. We systematically investigated the shared genetic architecture, pleiotropic loci, and candidate therapeutic targets linking ADs and MI.
METHODS
We analyzed genome-wide association study summary statistics for 10 ADs and MI, primarily from European-ancestry populations. Linkage disequilibrium score regression, high-definition likelihood, stratified linkage disequilibrium score regression, pleiotropy analysis, Bayesian colocalization, and immune-trait colocalization were performed. Candidate genes were prioritized using summary-data-based Mendelian randomization and followed up using quantitative polymerase chain reaction in hypoxia-treated HL-1 cardiomyocytes and by descriptive expression profiling in single-cell RNA sequencing datasets from human atherosclerotic plaques and cardiac resident immune cells.
RESULTS
MI showed significant positive genetic correlations with Crohn's disease, rheumatoid arthritis (RA), and primary biliary cholangitis (PBC) after false discovery rate correction. We identified 49 pleiotropic loci, including 7 with colocalization evidence compatible with a shared causal variant. Integrative analyses prioritized 12 candidate genes, with SH2B3, TMEM116, and ACAD10 highlighted across multiple disease pairs. Immune-trait colocalization highlighted activated monocyte- and T-cell-related features in RA-MI and PBC-MI. In HL-1 cardiomyocytes, hypoxia increased Acad10, Sh2b3, and Tmem116 expression over time. In single-cell datasets, SH2B3 showed prominent expression in plaque macrophages, endothelial cells, and cardiac resident macrophages.
CONCLUSIONS
Specific ADs and MI share an immunogenetic architecture involving immune and vascular pathways. These findings prioritize pleiotropic loci, candidate genes, and immune-cell contexts that warrant further mechanistic investigation.
Chung-Chih Liao, W. Hu, Shun-Fa Yang et al.· Atherosclerosis· 0 citations
Cervical cancer remains the fourth most common malignancy among women worldwide, and patients with advanced-stage disease continue to experience poor clinical outcomes despite the availability of targeted therapies. In this study, we investigated the epigenetic role of endothelial cell-specific molecule 1 (ESM1), a soluble proteoglycan, and established an oncogene whose regulatory mechanisms in cervical cancer remain largely unexplored. The epigenetic mechanisms underlying tumor progression remain incompletely understood. Here, we identify ESM1 as a critical epigenetic regulator of cervical cancer malignancy. Integrative analyses of public datasets and clinical specimens revealed that marked ESM1 overexpression correlated with adverse patient prognosis. Functional loss- and gain-of-function studies have demonstrated that ESM1 is essential for maintaining proliferative, clonogenic, migratory, and invasive phenotypes in cervical cancer cells. Transcriptomic profiling revealed that inhibitor of DNA binding 3 (ID3) is a direct downstream tumor suppressor repressed by ESM1. Mechanistically, ESM1 selectively upregulates DNA methyltransferase 3 A (DNMT3A) to induce promoter hypermethylation and transcriptional silencing of ID3. Pharmacological demethylation reactivates ID3 expression and attenuates metastatic capacity. In vivo xenograft and experimental metastasis models validated that ESM1 depletion significantly impaired tumor growth and lung metastasis while increasing ID3 expression. These findings identify the ESM1/DNMT3A/ID3 axis as a novel epigenetic driver of cervical cancer and a potential therapeutic target.
Chen-Lin Yu, Chia-Liang Lin, Hsiang-Lin Lee et al.· Cell Death Discovery· 0 citations
Background: Interleukin-31 receptor alpha (IL31RA) has been implicated in cancer progression and tumor cell migration, but its genetic associations across cancers remain unclear. This study aimed to examine IL31RA polymorphisms in relation to lymph node involvement in oral cavity squamous cell carcinoma (OCSCC). Methods: In this case-control study, 2845 participants were enrolled, including 1352 patients with OCSCC and 1493 cancer-free controls. Associations between IL31RA SNPs and OCSCC susceptibility and clinicopathological characteristics were evaluated. Functional analyses, including cell migration assays, together with bioinformatic database analyses, were performed to investigate the biological significance of IL31RA and genotype–expression correlations. Logistic regression and other appropriate statistical methods were used to assess these associations. Results: IL31RA polymorphisms did not significantly influence OCSCC development. However, subsite-specific analysis revealed that gingival cancer patients with minor alleles at rs6876491 and rs10055201 had significantly higher lymph node involvement rates than wild-type carriers. IL31RA rs6876491 was also an independent predictor of lymph node involvement in gingival cancer after adjusting for clinical characteristics, with adjusted odds ratios of 2.172 (95% Confidence Interval: 1.095–4.310). Bioinformatic databases also showed that minor genotypes correlated with increased IL31RA expression. Patients with higher IL31RA expression tended to have poorer survival in head and neck squamous cell carcinoma (HNSCC) based on TCGA public database analyses (p = 0.053). Moreover, functional studies confirmed that IL31RA overexpression enhanced cellular migration (p < 0.05), while knockdown suppressed migratory capacity (p < 0.05). Conclusions: IL31RA polymorphisms may be associated with an increased propensity for lymph node involvement, particularly in gingival cancer, suggesting that IL31RA may have potential clinical relevance in OCSCC progression.
Hsueh-Ju Lu, Chiao-Wen Lin, C. Chuang et al.· Oncology Research· 0 citations