DataSheet1_Deciphering the causal association and underlying transcriptional mechanisms between telomere length and abdominal aortic aneurysm.xlsx

BackgroundThe purpose of this study is to investigate the causal effect and potential mechanisms between telomere length and abdominal aortic aneurysm (AAA).
MethodsSummary statistics of telomere length and AAA were derived from IEU open genome-wide association studies and FinnGen R9, respectively. Bi-directional Mendelian randomization (MR) analysis was conducted to reveal the causal relationship between AAA and telomere length. Three transcriptome datasets were retrieved from the Gene Expression Omnibus database and telomere related genes was down-loaded from TelNet. The overlapping genes of AAA related differentially expressed genes (DEGs), module genes, and telomere related genes were used for further investigation. Telomere related diagnostic biomarkers of AAA were selected with machine learning algorisms and validated in datasets and murine AAA model. The correlation between biomarkers and immune infiltration landscape was established.
ResultsTelomere length was found to have a suggestive negative associations with AAA [IVW, OR 95%CI = 0.558 (0.317-0.701), P < 0.0001], while AAA showed no suggestive effect on telomere length [IVW, OR 95%CI = 0.997 (0.990-1.004), P = 0.4061]. A total of 40 genes was considered as telomere related DEGs of AAA. PLCH2, PRKCQ, and SMG1 were selected as biomarkers after multiple algorithms and validation. Immune infiltration analysis and single cell mRNA analysis revealed that PLCH2 and PRKCQ were mainly expressed on T cells, while SMG1 predominantly expressed on T cells, B cells, and monocytes. Murine AAA model experiments further validated the elevated expression of biomarkers.
ConclusionWe found a suggestive effect of telomere length on AAA and revealed the potential biomarkers and immune mechanism of telomere length on AAA. This may shed new light for diagnosis and therapeutics on AAA

**研究背景**：本研究旨在探讨端粒长度与腹主动脉瘤（abdominal aortic aneurysm, AAA）之间的因果关联及其潜在作用机制。
**研究方法**：本研究的端粒长度与腹主动脉瘤的汇总统计量分别取自IEU开放全基因组关联研究数据库与FinnGen R9队列。采用双向孟德尔随机化（Mendelian randomization, MR）分析，以阐明二者之间的因果关联。从基因表达综合（Gene Expression Omnibus, GEO）数据库中检索得到3组转录组数据集，并从TelNet数据库下载端粒相关基因。将腹主动脉瘤相关差异表达基因（differentially expressed genes, DEGs）、模块基因与端粒相关基因的交集基因用于后续分析。通过机器学习算法筛选出腹主动脉瘤的端粒相关诊断生物标志物，并在数据集与小鼠腹主动脉瘤模型中进行验证。此外，本研究还构建了生物标志物与免疫浸润图谱之间的关联。
**研究结果**：研究发现端粒长度与腹主动脉瘤存在提示性负相关[逆方差加权（inverse variance weighting, IVW），比值比（odds ratio, OR）95%置信区间（confidence interval, CI）=0.558（0.317~0.701），P<0.0001]；而腹主动脉瘤对端粒长度无明显影响[IVW，OR 95%CI=0.997（0.990~1.004），P=0.4061]。共计40个基因被认定为腹主动脉瘤相关的端粒相关差异表达基因。经多种算法筛选与验证后，PLCH2、PRKCQ及SMG1被选为生物标志物。免疫浸润分析与单细胞mRNA测序分析显示，PLCH2与PRKCQ主要表达于T细胞，而SMG1主要表达于T细胞、B细胞与单核细胞。小鼠腹主动脉瘤模型实验进一步验证了这些生物标志物的表达上调。
**研究结论**：本研究证实端粒长度对腹主动脉瘤存在提示性影响，并阐明了端粒长度影响腹主动脉瘤的潜在生物标志物与免疫机制。该研究可为腹主动脉瘤的诊断与治疗提供新的研究思路。