Abstract
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.
Highlights
Atherosclerosis (AS), a common pathogenesis associated with intracerebral or extracerebral artery stenosis, can cause a series of ischemic cerebrovascular events in people
We evaluated whether functional single-nucleotide polymorphism (SNP) in the Repulsive guidance molecule a (RGMa) promoter were associated with AS burden in the cerebral arteries of patients with acute ischemic cerebrovascular accident
We compared the genetic frequency between the enrolled patients and the Han population in Southern China (CHS), a population of age and sex matched healthy subjects published by the 1,000 Genome project
Summary
Atherosclerosis (AS), a common pathogenesis associated with intracerebral or extracerebral artery stenosis, can cause a series of ischemic cerebrovascular events in people. Previous studies have shown that the neural guidance protein (NGP), a type of pluripotent molecule, affects neural guidance, cell apoptosis, and inflammatory regulation in various disease processes, and influences AS development [1]. One well-studied NGP, netrin-1, is secreted by macrophages in plaques and exerts a pro-atherogenic effect by prohibiting macrophage emigration from vessel walls [3, 4]. It seems paradoxical that netrin-1, which is expressed by endothelial cells, can prevent AS by inhibiting inflammatory cytokine secretion and monocyte recruitment [5]. Semaphorin 3E (Sema3E), a critical NGP in inflammation, is highly upregulated in macrophages from late-stage AS plaques [6]. Sema3E inhibits macrophage emigration in a Plexin D1-dependent manner, which hampers the elimination of AS-related inflammation [7]. It is believed that NGP exerts diverse functions in AS progression depending on its temporospatial distribution
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