Genetic predisposition to ischaemic stroke by RAGE and HMGB1 gene variants in Chinese Han population.

You Li,Mengxu Wang,Guoda Ma,Linfa Chen,Bin Zhao,Jing Zhu,Keshen Li,Shengnan Li,Weidong Hu,Hua Tao,Xuefeng Gu

doi:10.18632/oncotarget.22112

Abstract

Emerging evidence suggests that the multiligand receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 protein (HMGB1) contribute to the pathophysiology of ischaemic stroke (IS). The present study aimed to investigate the association of RAGE and HMGB1 variants with the risk of IS. A total of 1,034 patients and 1,015 age- and sex-matched healthy controls were genotyped to detect five genetic variants of the RAGE gene and four genetic variants of the HMGB1 gene using the Multiplex SNaPshot assay. We found that the rs2070600 variant of RAGE was associated with an increased risk of IS (OR = 1.19, 95% CI: 1.02-1.38, P = 0.043), whereas the rs2249825 variant of HMGB1 was associated with a decreased risk of IS (OR = 0.83, 95% CI: 0.71-0.98, P = 0.041). Further stratification by IS subtypes revealed that the presence of the TT genotype of the RAGE rs2070600 variant confers a higher risk of the large artery atherosclerosis subtype of IS (P = 0.036). Moreover, patients with the variant T allele of the RAGE rs2070600 variant presented with reduced serum soluble RAGE production. Patients carrying the variant G allele of the HMGB1 rs2249825 variant exhibited significantly lower infarct volumes than those with the major CC genotype. These clues may help in the development of optimal personalized therapeutic approaches for IS patients.

Highlights

Stroke is the leading cause of death and disability in China and other parts of the world [1]
We found that the rs2070600 variant of receptor for advanced glycation end products (RAGE) was associated with an increased risk of ischaemic stroke (IS) (OR = 1.19, 95% confidence interval (CI): 1.02-1.38, P = 0.043), whereas the rs2249825 variant of high mobility group box 1 protein (HMGB1) was associated with a decreased risk of IS (OR = 0.83, 95% CI: 0.71-0.98, P = 0.041)
The homocysteine (HCY) levels tended to be higher in the IS patients than in controls, whereas high-density lipoprotein (HDL) levels were lower at admission in the IS patients

Summary

Introduction

Stroke is the leading cause of death and disability in China and other parts of the world [1]. The multiligand receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, can interact with a broad range of ligands, including advanced glycation end products, high mobility group box-1 protein (HMGB1), S100/calgranulins and β-amyloid peptide [5]. HMGB1 is a nuclear protein with cytokine-type functions upon its extracellular release that are mediated by the activation of signalling pathways www.impactjournals.com/oncotarget coupled to toll-like receptors (TLRs), including TLR4 and TLR2, both of which are involved in inflammatory responses [6,7,8]. The binding of RAGE to its ligands triggers the activation of reactive oxygen species, nuclear factor kappa-B, mitogen-activated protein kinase and protein kinase C; the up-regulation of leucocyte adhesion molecules; and the production of proinflammatory cytokines and angiogenic factors [9], all of which are responsible for the development and progression of IS. The soluble form of RAGE (sRAGE) can potentially bind to an AGE ligand, thereby acting as a decoy and preventing the adverse effects of RAGE signalling [10]

Methods

Results

Conclusion