Bai Zihao, An Jia, Han Jingru, Zhang Yuxi, Wang Hao, Yang Zhaocong, Mo Xuming
Nanjing Children's Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Nanjing 210008, China; Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou 510182, China.
Int J Biol Macromol. 2025 Jun;316(Pt 1):144380. doi: 10.1016/j.ijbiomac.2025.144380. Epub 2025 May 21.
Aortic aneurysm (AA) is a genetic cardiovascular disease marked by progressive weakening and dilation of the aortic wall, often resulting in high mortality if untreated. Early diagnosis and prevention remain challenging. This study integrated genome-wide association studies (GWAS), proteome-wide Mendelian randomization (PW-MR), and single-cell RNA sequencing data from large-scale cohorts (FinnGen, deCODE Genetics, and UK Biobank Pharma Proteomics Project) to identify new biomarkers and therapeutic targets for AA. Analyzing genetic data from 8125 AA patients and 381,977 controls, we identified four significant loci (ADAMTS8, PLCE1, NOC3L, and SPSB1). PW-MR highlighted numerous plasma proteins, with interleukin-6 receptor (IL6R) showing strong association and colocalization in both deCODE and UK Biobank Pharma Proteomics Project (UKB-PPP) datasets. Multi-trait colocalization analysis supports IL6R's role, suggesting that drugs targeting IL6R, such as tocilizumab, may benefit AA treatment, though potential side effects warrant consideration. Single-cell analysis indicated that macrophages are crucial in AA progression, particularly through the IL6R-mediated inflammatory response. These findings emphasize IL6R as a potential target for early intervention and AA prevention. By integrating genetic associations, proteomic evidence, and single-cell insights, this study offers new strategies for identifying biomarkers, understanding disease mechanisms, and developing targeted therapies for aortic aneurysm.
主动脉瘤（AA）是一种遗传性心血管疾病，其特征是主动脉壁逐渐变薄和扩张，如果不进行治疗，通常会导致高死亡率。早期诊断和预防仍然具有挑战性。本研究整合了全基因组关联研究（GWAS）、全蛋白质组孟德尔随机化（PW-MR）以及来自大规模队列（芬兰基因研究、解码遗传学和英国生物银行药物蛋白质组学项目）的单细胞RNA测序数据，以确定主动脉瘤的新生物标志物和治疗靶点。通过分析8125例主动脉瘤患者和381977例对照的遗传数据，我们确定了四个显著位点（ADAMTS8、PLCE1、NOC3L和SPSB1）。PW-MR突出了许多血浆蛋白，白细胞介素-6受体（IL6R）在解码遗传学和英国生物银行药物蛋白质组学项目（UKB-PPP）数据集中均显示出强烈的关联和共定位。多性状共定位分析支持IL6R的作用，表明靶向IL6R的药物，如托珠单抗，可能对主动脉瘤治疗有益，尽管潜在的副作用值得考虑。单细胞分析表明，巨噬细胞在主动脉瘤进展中至关重要，特别是通过IL6R介导的炎症反应。这些发现强调IL6R作为早期干预和主动脉瘤预防的潜在靶点。通过整合遗传关联、蛋白质组学证据和单细胞见解，本研究为识别生物标志物、理解疾病机制以及开发主动脉瘤的靶向治疗提供了新策略。
