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

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.

Reduced plasma levels of RGM-A predict stroke-associated pneumonia in patients with acute ischemic stroke: A prospective clinical study

“…The evaluation of RGM-A as an immunoregulatory protein has recently increased in translational medical research, especially with regard to peritonitis (21, 22) and acute lung injury (23,24). In our previous study, we found that the RGM-A level was reduced in atherosclerotic aortas and in macrophages isolated from plaques, suggesting that RGM-A has a potential protective effect in cerebrovascular atherosclerosis (20). Previous researchers have demonstrated that RGM-A is expressed in pathogenic Th17 cells in experimental autoimmune encephalomyelitis (18), and the binding of RGM-A to its receptor neogenin inhibits PMN migration and increases the attachment of CD4+ cells to intercellular adhesion molecule-1 to attenuate the inflammatory response (18,21,22).…”

“…To our knowledge, this study is the first to show that the plasma RGM-A level is decreased in patients with SAP. RGM-A is a promising target for the diagnosis and treatment of numerous diseases based on its versatility; it is involved in ischemic stroke (35), Parkinson's disease (36), autoimmune encephalomyelitis (18), multiple sclerosis (19), and cerebrovascular atherosclerosis (20). The evaluation of RGM-A as an immunoregulatory protein has recently increased in translational medical research, especially with regard to peritonitis (21, 22) and acute lung injury (23,24).…”

“…In other studies involving an acute lung injury model, the RGM-A receptor neogenin was strongly induced within injured pulmonary tissue, and the binding of RGM-A to its receptor inhibited leukocyte migration, decreasing the production of proinflammatory cytokines and promoting inflammation resolution in acute lung injury (23,24). Moreover, in our previous study, we found that RGM-A was involved in vascular inflammation and cerebrovascular atherosclerosis (20,25). RGM-A levels were reduced in atherosclerotic aortas and in macrophages isolated from plaques (20).…”

“…Moreover, in our previous study, we found that RGM-A was involved in vascular inflammation and cerebrovascular atherosclerosis (20,25). RGM-A levels were reduced in atherosclerotic aortas and in macrophages isolated from plaques (20).…”

“…It is the first molecule found to guide axons to their final location through a balance of chemoattractive or chemorepulsive signals in the developing nervous system (15)(16)(17). Recent evidence has identified RGM-A as a versatile immunoregulatory protein that is involved in a variety of inflammatory and immune diseases including autoimmune encephalomyelitis (18), multiple sclerosis (19), cerebrovascular atherosclerosis (20), peritonitis (21,22), and acute lung injury (23,24). RGM-A is strongly expressed in peripheral tissues, especially the surface of immune cells and tissues sensitive to infection, and it plays crucial roles in the regression of acute inflammation and tissue regeneration via its receptor neogenin (21,22).…”