Li Ao, Feng ZiAn, Fu ShiHao, Ma ZhenXiao, Zhang HaiYang, Zhao ZhiWei
Department of Cardiovascular Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China(Anhui Provincial Hospital), Anhui, Hefei 230001, China.
Graduate School, University of Science and Technology of China, Anhui, Hefei 230001, China.
Int J Cardiol Heart Vasc. 2024 Oct 15;55:101530. doi: 10.1016/j.ijcha.2024.101530. eCollection 2024 Dec.
There exists a robust correlation between the infiltration of immune cells and the pathogenesis of aortic dissection (AD). Moreover, blood metabolites serve as immunomodulatory agents within the organism, influencing the immune system's response and potentially playing a role in the development of AD. Nevertheless, the intricate genetic causal nexus between specific immune cells, blood metabolites, and AD remains partially elucidated.
This study aims to elucidate the causal relationships between specific immune cell types and the risk of developing AD, mediated by blood metabolites, using Mendelian Randomization (MR) methods.
We undertook a comprehensive investigation of 731 immune cell types through the analysis of published genome-wide association studies (GWAS). Our methodology hinged on the application of two-sample Mendelian randomization (MR) and mediator MR analyses, prioritizing blood metabolites as potential intermediary factors and AD as the principal outcome of interest. The primary statistical method employed was inverse variance-weighted estimation, complemented by a variety of sensitivity analyses to reinforce our conclusions. The entirety of our statistical analyses was executed on the R software platform.
Our analyses elucidated that three immune cell types exhibited a positive correlation with the incidence of AD, whereas two immune cell types were inversely associated with AD risk. Significantly, our mediation Mendelian randomization (MR) findings identified Benzoate as a pivotal mediator in the influence of CD19 on IgD - CD38br cells on AD, with a mediation proportion of 5.38 %. Additionally, N-acetylproline was determined to mediate the effect of CD24 on IgD- CD38- cells on AD, accounting for a mediation proportion of 13.70 %. Furthermore, Carnitine C5:1 was found to mediate the effect of CD28 on secreting T regulatory (Treg) cells on AD, with a mediation proportion of 17.80 %.
These findings offer a nuanced understanding of the pathophysiological mechanisms underlying AD, thereby advancing the precision medicine paradigm in the clinical management of AD.Abbreviations: AD: aortic dissection; AA: aortic aneurysm; GWAS: genome-wide association study; MR: Mendelian randomization; TSMR: two-step Mendelian randomization; Treg: secreting T regulatory cell; VSMC: vascular smooth muscle cell; MMP: matrix metalloproteinase; ROS: reactive oxygen species; IV: instrumental variable; SNP: single-nucleotide polymorphism; IVW: inverse variance weighted; LDSC: linkage disequilibrium score regression; OR: odds ratio; CI: confidence interval; LD: linkage disequilibrium; AC: absolute cell; MFI: median fluorescence intensity; MP: morphological parameter; RC: relative cell; CLSA: Canadian Longitudinal Study of Aging; Lp(a): Lipoprotein a; OxPL: oxidised phospholipid; NMDAR: N-methyl-d-aspartate glutamate receptor; STROBE-MR: Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization.
免疫细胞浸润与主动脉夹层（AD）的发病机制之间存在密切关联。此外，血液代谢产物作为生物体内的免疫调节因子，影响免疫系统的反应，并可能在AD的发生发展中发挥作用。然而，特定免疫细胞、血液代谢产物与AD之间复杂的遗传因果关系仍部分未明。
本研究旨在使用孟德尔随机化（MR）方法阐明特定免疫细胞类型与AD发生风险之间由血液代谢产物介导的因果关系。
我们通过分析已发表的全基因组关联研究（GWAS），对731种免疫细胞类型进行了全面研究。我们的方法基于两样本孟德尔随机化（MR）和中介MR分析的应用，将血液代谢产物作为潜在的中介因素，将AD作为主要关注结果。采用的主要统计方法是逆方差加权估计，并辅以多种敏感性分析以强化我们的结论。我们所有的统计分析均在R软件平台上进行。
我们的分析表明，三种免疫细胞类型与AD的发生率呈正相关，而两种免疫细胞类型与AD风险呈负相关。值得注意的是，我们的中介孟德尔随机化（MR）研究结果确定苯甲酸是CD19对IgD - CD38br细胞影响AD的关键中介，中介比例为5.38%。此外，已确定N - 乙酰脯氨酸介导CD24对IgD - CD38 - 细胞影响AD的作用，中介比例为13.70%。此外，发现肉碱C5:1介导CD28对分泌性调节性T细胞（Treg）影响AD的作用，中介比例为17.80%。
这些发现为AD潜在的病理生理机制提供了细致入微的理解，从而推动了AD临床管理中的精准医学模式。缩写：AD：主动脉夹层；AA：主动脉瘤；GWAS：全基因组关联研究；MR：孟德尔随机化；TSMR：两步孟德尔随机化；Treg：分泌性调节性T细胞；VSMC：血管平滑肌细胞；MMP：基质金属蛋白酶；ROS：活性氧；IV：工具变量；SNP：单核苷酸多态性；IVW：逆方差加权；LDSC：连锁不平衡评分回归；OR：比值比；CI：置信区间；LD：连锁不平衡；AC：绝对细胞；MFI：中位荧光强度；MP：形态学参数；RC：相对细胞；CLSA：加拿大衰老纵向研究；Lp(a)：脂蛋白a；OxPL：氧化磷脂；NMDAR：N - 甲基 - D - 天冬氨酸谷氨酸受体；STROBE - MR：使用孟德尔随机化加强流行病学观察性研究报告。
