ABO基因通过NPC1L1调控胆固醇代谢及血脂水平在缺血性卒中的作用及机制研究

非O血型和ABO基因作为心血管事件发生的危险因素备受关注，但其与缺血性卒中的关系和机制尚不明确。基于中国国家卒中登记研究-III，申请人研究发现7674例患者ABO基因位点rs505922与大动脉粥样硬化性卒中亚型强相关，该位点与O血型决定位点连锁，非O基因型患者脂代谢相关蛋白显著上调；ABO基因在人小肠上皮表达，敲低ABO引起肠上皮细胞胆固醇吸收下降、胆固醇转运蛋白NPC1L1含量改变。因此，我们推测ABO基因通过影响NPC1L1介导的胆固醇吸收过程调控血脂代谢，增加缺血性卒中风险。本项目将1）明确ABO基因与缺血性卒中亚型的关系，2）明确ABO基因影响肠上皮细胞胆固醇代谢机制，及其与NPC1L1的关系，3）探索通过依折麦布干预NPC1L1降低非O血型人群胆固醇吸收减少卒中风险的可能性。该研究有助于揭示ABO在缺血性卒中的功能和机制，为ABO血型/基因型指导卒中预防和治疗提供实验依据。

Non-O blood types and ABO gene which acted as risk factors for cardiovascular events have attracted much attention, but the relationship and mechanism between them and ischemic stroke are still unclear. Based on the third China National Stroke Registry-III (CNSR-III), the applicant has found that rs505922 in ABO gene was strongly associated with the stroke subtype of large-artery atherosclerosis in 7674 patients, this locus was linked to the O blood type determining locus, and the related proteins in lipid metabolism were significantly up-regulated in patients with non-O genotype. The ABO gene was expressed in the human small intestinal epithelium. Knockdown of ABO caused a decrease in the absorption of cholesterol in intestinal epithelial cells and changes in the content of the intestinal sterol transporter NPC1L1. Therefore, we hypothesize that ABO gene can regulate lipid metabolism and increase the risk of ischemic stroke by affecting the cholesterol absorption process mediated by NPC1L1. This project will 1) clarify the relationship between ABO gene and ischemic stroke subtypes, 2) identify the mechanism of ABO gene affecting cholesterol metabolism in intestinal epithelial cells, and its relationship with NPC1L1, 3) explore the use of ezetimibe to interfere with NPC1L1 to reduce cholesterol absorption and stroke risk in non-O blood group population. This study will help to reveal the function and mechanism of ABO in ischemic stroke, and provide experimental evidence for ABO blood group/genotype to guide the prevention and treatment of stroke.