锌指同源框3基因多态性与不同亚型缺血性卒中结局的特异性关联研究

doi:10.3969/j.issn.1673-5765.2021.11.004

摘要/Abstract

摘要： 目的分析中国卒中人群中锌指同源框3（zinc finger homeobox 3，ZFHX3）基因单核苷酸变异（single nucleotide variant，SNV）位点对卒中结局的影响。方法本研究基于全国多中心前瞻性中国国家卒中登记研究Ⅲ，连续纳入2015年8月-2018年3月首次发生急性缺血性卒中或TIA的患者，收集人口学信息、病史和卒中结局等相关临床资料。卒中结局包括随访1年内卒中复发（缺血性卒中或出血性卒中）、联合血管事件（卒中、心肌梗死及血管性死亡事件）及不良功能结局（mRS＞2分）。采用竞争性等位基因特异性PCR技术对3个SNV位点（rs7193343、 rs879324、rs12932445）进行基因分型。对于研究过程中的计量资料和计数资料，分别采用线性回归或逻辑回归进行关联分析；对于卒中结局，分别采用Cox或逻辑回归进行关联分析。结果最终纳入7674例患者，平均年龄61.7±11.5岁，其中女性2438例（31.77%）。关联分析结果显示，处于高度连锁不平衡状态（相关系数R 2=0.88）的rs879324和rs12932445位点与心房颤动、入院时NIHSS评分及卒中亚型有关联。在不同卒中亚型中，3个SNV位点均与1年联合血管事件相关，在校正年龄、性别及心房颤动协变量后关联性仍然显著。在心源性栓塞型卒中患者中，rs7193343位点的T等位基因与卒中复发、联合血管事件的发生有关联（校正HR 1.92，95%CI 1.21～3.05；校正HR 1.95，95%CI 1.26～3.01）；rs879324位点的A等位基因和rs12932445位点的C等位基因与联合血管事件有关联（校正HR 1.58，95%CI 1.10～2.27；校正HR 1.66，95%CI 1.16～2.38）。在原因未明型卒中患者中，rs7193343位点的T等位基因与卒中复发和联合血管事件的发生有关联（校正HR 1.34，95%CI 1.09～1.64；校正HR 1.36，95%CI 1.11～1.66）。校正相关因素后未发现3个SNV位点与不良功能结局之间存在关联。结论 ZFHX3基因上的变异位点与特定卒中亚型的卒中复发及联合血管事件的发生风险存在关联，但未发现与不良功能结局有关。

文章导读： 本研究分析了ZFHX3基因上3个SNV位点（rs7193343、rs879324和rs12932445）与卒中结局及卒中相关危险因素之间的关联，首次发现了此3个SNV位点与卒中复发和联合血管事件的关联性，且该关联具有卒中亚型特异性特点。

关键词: 锌指同源框3基因; 卒中结局; 卒中遗传学; 关联分析

Abstract: Objective To investigate the association between single nucleotide variants (SNVs) of zinc finger homeobox 3 (ZFHX3) and post-stroke outcomes in different stroke subtypes. Methods This study was based on the data of the Third China National Stroke Registry (CNSR- Ⅲ), a national multicenter prospective cohort study, which enrolled participants with firstever acute ischemic stroke or TIA from August 2015 to March 2018. Demographic information, diseases history and follow-up outcomes were collected. The outcomes included recurrent stroke and composite vascular events (stroke, myocardial infarction and vascular death) within 1-year

follow-up, and poor functional outcome (mRS>2) at 1 year. Three SNVs (rs7193343, rs879324,

rs12932445) were genotyped using competitive allele-specific PCR technique. For quantitative and qualitative data were analyzed using linear and logistic regression. Cox regression or logistic regression was used to determine the association between ZFHX3 gene polymorphisms and poststroke outcome. Results A total of 7674 eligible participants were included, with a mean age of 61.7±11.5 years old and 2438 females (31.77%). The SNVs rs879324 and rs12932445 (in high linkage disequilibrium, R 2=0.88) were associated with atrial fibrillation (AF), NIHSS at admission and stroke subtype. Three SNVs were all associated with 1-year composite vascular events in different stroke subtypes, even after adjusting for age, gender and AF. In cardioembolic stroke, T allele in rs7193343 was associated with recurrent stroke and composite vascular events within 1 year (aHR 1.92, 95%CI 1.21-3.05; aHR 1.95, 95%CI 1.26-3.01), A allele in rs879324 and C allele in rs12932445 were associated with composite vascular events within 1 year (aHR 1.58, 95%CI 1.10-2.27; aHR 1.66, 95%CI 1.16-2.38, respectively). In stroke of undemonstrated etiology, T allele in rs7193343 was associated with recurrent stroke and composite vascular events within 1 year (aHR 1.34, 95%CI 1.09-1.64; aHR 1.36, 95%CI 1.11-1.66). None of the 3 SNVs were found to be associated with poor functional outcome after adjusting for the confounding factors. Conclusions ZFHX3 variants were associated with recurrent stroke and composite vascular events within 1 year after onset in specific stroke subtypes, but not associated with poor functional outcome.

Key words: Zinc finger homeobox 3 gene; Stroke outcome; Stroke genetics; Association analysis

程丝, 许喆, 左颖婷, 刘阳, 王安心, 石延枫, 李昊, 王拥军. 锌指同源框3基因多态性与不同亚型缺血性卒中结局的特异性关联研究[J]. 中国卒中杂志, 2021, 16(11): 1102-1109.

CHENG Si, XU Zhe, ZUO Ying-Ting, LIU Yang, WANG An-Xin, SHI Yan-Feng, LI Hao, WANG Yong-Jun. Association between Zinc Finger Homeobox 3 Gene Polymorphism and Outcomes in Different Ischemic StrokeSubtypes[J]. Chinese Journal of Stroke, 2021, 16(11): 1102-1109.

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