Table_1_Common Polymorphisms in the RGMa Promoter Are Associated With Cerebrovascular Atherosclerosis Burden in Chinese Han Patients With Acute Ischemic Cerebrovascular Accident.DOCX

Repulsive guidance molecule a (RGMa) plays a vital role in the progression of numerous inflammatory diseases. However, whether it participates in atherosclerosis development is not known. Here, we explored the influence of RGMa in atherogenesis by investigating whether an association exists between functional polymorphisms in the RGMa promoter and cerebrovascular atherosclerosis burden (CAB) in Chinese Han patients diagnosed with acute ischemic cerebrovascular accident. To this end, we conducted a genetic association study on 201 patients with prior diagnoses of acute ischemic stroke or transient ischemic attack recruited from our hospital. After admission, we conducted three targeted single-nucleotide polymorphisms (SNPs) genotyping and evaluated CAB by computed tomography angiography. We used logistic regression modeling to analyze genetic associations. Functional polymorphism analysis indicated an independent association between the rs725458 T allele and increased CAB in patients with acute ischemic cerebrovascular accident [adjusted odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.01–2.74, P = 0.046]. In contrast, an association between the rs4778099 AA genotype and decreased CAB (adjusted OR = 0.10, 95% CI = 0.01–0.77, P = 0.027) was found. Our Gene Expression Omnibus analysis revealed lower RGMa levels in the atherosclerotic aortas and in the macrophages isolated from plaques than that in the normal aortas and macrophages from normal tissue, respectively. In conclusion, the relationship between RGMa and cerebrovascular atherosclerosis suggests that RGMa has a potential vasoprotective effect. The two identified functional SNPs (rs725458 and rs4778099) we identified in the RGMa promoter are associated with CAB in patients diagnosed with acute ischemic cerebrovascular accident. These findings offer a promising research direction for RGMa-related translational studies on atherosclerosis.

排斥性导向分子a（Repulsive guidance molecule a, RGMa）在多种炎症性疾病的进展中发挥关键作用。然而，其是否参与动脉粥样硬化的发生发展尚不清楚。本研究旨在明确RGMa在动脉粥样硬化发生中的作用，为此我们分析了中国汉族急性缺血性脑血管病患者体内，RGMa启动子区功能多态性与脑血管动脉粥样硬化负荷（cerebrovascular atherosclerosis burden, CAB）之间是否存在关联。为此，我们纳入本院收治的201例既往确诊急性缺血性脑卒中或短暂性脑缺血发作的患者，开展了一项遗传关联研究。入院后，我们对3个目标单核苷酸多态性（single-nucleotide polymorphisms, SNPs）进行了基因分型，并通过计算机断层血管造影术评估了CAB。我们采用logistic回归模型分析遗传关联。功能多态性分析显示，急性缺血性脑血管病患者中rs725458位点T等位基因与CAB升高存在独立关联[校正后比值比（odds ratio, OR）=1.66，95%置信区间（confidence interval, CI）=1.01~2.74，P=0.046]。与之相反，本研究发现rs4778099位点AA基因型与CAB降低存在关联[校正后OR=0.10，95%CI=0.01~0.77，P=0.027]。本研究通过基因表达综合数据库（Gene Expression Omnibus, GEO）分析发现，动脉粥样硬化主动脉及斑块分离的巨噬细胞中RGMa的表达水平，分别低于正常主动脉及正常组织来源的巨噬细胞。综上，RGMa与脑血管动脉粥样硬化的关联提示RGMa可能具有潜在的血管保护作用。本研究在RGMa启动子区鉴定出的2个功能多态性位点（rs725458与rs4778099），与急性缺血性脑血管病患者的CAB存在显著关联。上述研究结果为RGMa相关的动脉粥样硬化转化研究提供了极具潜力的研究方向。