Mark Colin Gissler, Johannes Neumann, Linlin Guo, Patrick Malcolm Siegel, Timoteo Marchini, Hauke Horstmann, Sophie Hansen, Hanna Wolf, Virgina K Haacke, Debora Ehrhardt, Juana Dominguez, Daniela Stallmann, Ana Sophia Burkard, Xiaowei Li, Xin Gu, Ingo Hilgendorf, Thorsten Kessler, Panagiotis Antiochos, Holger Winkels, Lucas Bacmeister, Nils A Sörensen, Paul M Haller, Betül Toprak, Jonas Lehmacher, Andreas Zirlik, Constantin von Zur Mühlen, Raphael Twerenbold, Dirk Westermann, Diana Lindner, Dennis Wolf
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引用次数: 0
Abstract
Background and aims: The co-stimulatory signaling dyad of CD40 and CD40L is a potent inducer of cardiovascular inflammation and vulnerability of atherosclerotic plaques. A cytosine-to-thymidine transition (-1C > T) in the Kozak sequence of the CD40 gene (rs1883832) lowers CD40 protein expression. Here, we interrogate whether this CD40 gene variant correlates with recurrent cardiovascular events after acute coronary syndromes.
Methods: The Biomarkers in Acute Cardiac Care (BACC) cohort prospectively enrolled patients presenting to the emergency department with acute chest pain and suspected myocardial infarction. Genotype status (homozygous C/C or T/T, heterozygous: C/T) was determined by a TaqMan assay in 1298 patients with either confirmation of or ruled out acute myocardial infarction (AMI). The CD40 genotype-adjusted risk for major adverse cardiovascular events (MACE) during a median follow-up time of 5.2 years was studied by multivariate Cox regression.
Results: Relative abundances of the genotypes among all participants were 55.8% for C/C, 37.1% for C/T, and 7.2% for T/T. None of the genotype variants was associated with diabetes, hypertension, hyperlipoproteinemia, or a history of coronary artery disease (CAD). T/T carriers showed a strong trend towards an increased sex- and age-adjusted risk for AMI at admission (OR 1.58, 95% CI 0.95-2.64, p = 0.078) in logistic regression analysis. MACE occurred more often in patients with the T/T genotype (HR 1.46, 95% CI 1.01-2.11, p = 0.046) compared to C/T (HR 0.96, 95% CI 0.77-1.19, p = 0.70) and C/C (HR 0.94, 95% CI 0.76-1.16, p = 0.54) carriers. This effect was independent of age, sex, diabetes mellitus, hyperlipoproteinemia, arterial hypertension, smoking status and left ventricular ejection fraction in multivariable regression.
Conclusions: Our data indicate that - unexpectedly - the T/T genotype of rs1883832 is associated with an enhanced risk for myocardial infarction and subsequent MACE. As this SNP impedes effective CD40 translation, our findings suggest a potentially protective role of CD40 in high-risk patients.
背景和目的：CD40和CD40L的共刺激信号二极体是心血管炎症和动脉粥样硬化斑块易感性的有效诱导剂。CD40基因（rs1883832）的Kozak序列中的胞嘧啶-胸苷转换（-1C > T）降低CD40蛋白的表达。在这里，我们询问CD40基因变异是否与急性冠状动脉综合征后复发性心血管事件相关。方法：急性心脏护理中的生物标志物（BACC）队列前瞻性地纳入了因急性胸痛和疑似心肌梗死而就诊于急诊室的患者。在1298例确诊或排除急性心肌梗死（AMI）的患者中，通过TaqMan测定基因型状态（纯合子C/C或T/T，杂合子C/T）。在中位随访时间5.2年期间，通过多因素Cox回归研究CD40基因型调整的主要不良心血管事件（MACE）风险。结果：C/C基因型相对丰度为55.8%，C/T基因型为37.1%，T/T基因型为7.2%。所有基因型变异均与糖尿病、高血压、高脂蛋白血症或冠状动脉疾病（CAD）史无关。logistic回归分析显示，T/T携带者入院时发生AMI的性别和年龄调整风险明显增加（OR 1.58, 95% CI 0.95-2.64, p = 0.078）。与C/T （HR 0.96, 95% CI 0.77-1.19, p = 0.70）和C/C （HR 0.94, 95% CI 0.76-1.16, p = 0.54）携带者相比，T/T基因型患者MACE发生率更高（HR 1.46, 95% CI 1.01-2.11, p = 0.046）。在多变量回归中，该效应与年龄、性别、糖尿病、高脂血症、动脉高血压、吸烟状况和左心室射血分数无关。结论：我们的数据表明，出乎意料的是，rs1883832的T/T基因型与心肌梗死和随后的MACE风险增加有关。由于这种SNP阻碍了CD40的有效翻译，我们的研究结果表明CD40在高危患者中具有潜在的保护作用。
期刊介绍：
Atherosclerosis has an open access mirror journal Atherosclerosis: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review.
Atherosclerosis brings together, from all sources, papers concerned with investigation on atherosclerosis, its risk factors and clinical manifestations. Atherosclerosis covers basic and translational, clinical and population research approaches to arterial and vascular biology and disease, as well as their risk factors including: disturbances of lipid and lipoprotein metabolism, diabetes and hypertension, thrombosis, and inflammation. The Editors are interested in original or review papers dealing with the pathogenesis, environmental, genetic and epigenetic basis, diagnosis or treatment of atherosclerosis and related diseases as well as their risk factors.
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