CRP基因rs3093068位点多态性与缺血性卒中危险因素及卒中结局的相关性研究

doi:10.3969/j.issn.1673-5765.2022.03.004 Association of CRP Gene rs3093068 Polymorphism

摘要/Abstract

摘要：

目的探索CRP基因rs3093068位点多态性与缺血性卒中相关危险因素和卒中结局的相关性。

方法本研究基于中国国家卒中登记Ⅲ（China national stroke registry-Ⅲ，CNSR-Ⅲ）队列中的遗传亚组数据库，连续纳入2015年8月-2018年3月首次发生缺血性卒中或TIA的患者，收集人口学信息、病史、 hs-CRP、LDL-C和卒中结局等相关临床资料。使用竞争性等位基因特异性PCR（kompetitive allele-specific PCR，KASP）技术检测rs3093068位点的基因型分布，采用ANOVA、Kruskal-Wallis、χ 2检验或Fisher确切概率法分析不同基因型携带者已知危险因素的差异，采用logistic回归模型分析不同遗传模型下该位点基因多态性与1年随访卒中复发、联合血管事件以及不良功能结局（mRS≥3分）的相关性，并对卒中亚型进行分层分析。

结果共纳入7773例符合入组和排除标准的患者，其中GG基因型5334例（68.62%），GC基因型2196例（28.25%），CC基因型243例（3.13%）。rs3093068位点GG、GC、CC基因型患者的hs-CRP中位水平分别为1.53（0.75～4.07）mg/L、2.04（1.00～5.14）mg/L、2.75（1.30～6.62）mg/L，不同基因型患者血液hs-CRP水平差异有统计学意义（P <0.001）。在校正年龄、性别、入院NIHSS和联合血管事件后， logistic回归分析显示该位点在加性和隐性模型下CC基因型与病因未明型卒中患者的不良功能结局相关（校正OR 2.19，95%CI 1.01～4.41；校正OR 2.29，95%CI 1.06～4.57）；未发现该位点与其他危险因素及其他卒中亚型结局的相关性。

结论 CRP基因rs3093068位点CC基因型与患者的hs-CRP水平升高相关，并且与病因未明型缺血性卒中患者不良功能结局相关。

文章导读： 本研究系统分析了CRP基因rs3093068位点与卒中结局及危险因素的相关性，发现该位点与病因未明型卒中的不良功能结局之间存在相关性。

关键词: C反应蛋白; rs3093068; 位点多态性; 危险因素; 卒中结局; 关联分析

Abstract: Objective To investigate the relationship between rs3093068 polymorphism in CRP gene and ischemic stroke related risk factors and stroke outcome. Methods This study enrolled the consecutive patients with first-ever ischemic stroke or TIA from the genetic subgroup database of China national stroke registry-Ⅲ (CNSR-Ⅲ) from August 2015 to March 2018. The kompetitive allele-specific PCR technique was used to detect rs3093068 genotype. Differences in stroke related risk factors among carriers of different genotypes were analyzed by ANOVA, Kruskal-Wallis, chi-square or Fisher test. Logistic regression model was used to determine the association between rs3093068 polymorphism and 1-year outcomes of ischemic stroke under different genetic models. The 1-year outcomes included stroke recurrence, composite

vascular events and poor functional outcome (mRS≥3). Different stroke subtypes were analyzed.

Results A total of 7773 eligible patients were included in the final analysis, including 5334 (68.62%) with GG genotype, 2196 (28.25%) with GC genotype and 243 (3.13%) with CC genotype. The median levels of hs-CRP in patients with GG, GC and CC genotypes at rs3093068 genetic locus were 1.53 (0.75-4.07) mg/L, 2.04 (1.00-5.14) mg/L and 2.75 (1.30-6.62) mg/L, respectively. There was a statistical difference in the level of hs-CRP among patients with different genotypes (P <0.001). After adjusting for age, gender, admission NIHSS and composite vascular events, multivariate logistic regression analysis showed that the CC genotype under dominant and recessive models were associated with poor functional outcome of patients with stroke of other etiology (aOR 2.19, 95%CI 1.01-4.41; aOR 2.29, 95%CI 1.06-4.57). The association between CC genotype of rs3093068 and other stoke risk factors and outcomes of other subtype stroke were not found. Conclusions The CC genotype of rs3093068 in CRP gene was associated with higher hs-CRP level and poor functional outcome of stroke of other etiology.

Key words: C-reactive protein; rs3093068; Polymorphism; Risk factor; Stroke outcome; Association analysis

石延枫, 程丝, 许喆, 刘阳, 李昊, 王拥军. CRP基因rs3093068位点多态性与缺血性卒中危险因素及卒中结局的相关性研究[J]. 中国卒中杂志, 2022, 17(03): 236-243.

SHI Yanfeng, CHENG Si, XU Zhe, LIU Yang, LI Hao, WANG Yongjun. Association of CRP Gene rs3093068 Polymorphism with Ischemic Stroke Risk Factors and Stroke Outcome[J]. Chinese Journal of Stroke, 2022, 17(03): 236-243.

0
/ / 推荐

导出引用管理器 EndNote|Ris|BibTeX

链接本文: http://www.chinastroke.org.cn/CN/10.3969/j.issn.1673-5765.2022.03.004 Association of CRP Gene rs3093068 Polymorphism

http://www.chinastroke.org.cn/CN/Y2022/V17/I03/236

参考文献

[1] WU Y，POTEMPA L A，EL KEBIR D，et al. C-reactive protein and inflammation：conformational changes affect function[J]. Biol Chem，2015，396（11）：1181-1197.
[2] KASAPIS C，THOMPSON P D. The effects of physical activity on serum C-reactive protein and inflammatory markers：a systematic review[J]. J Am Coll Cardiol，2005，45（10）：1563-1569.
[3] CLEARFIELD M B. C-reactive protein：a new risk assessment tool for cardiovascular disease[J]. J Am Osteopath Assoc，2005，105（9）：409-416.
[4] VANGILDER R L，DAVIDOV D M，STINEHART K R，et al. C-reactive protein and long-term ischemic stroke prognosis[J]. J Clin Neurosci，2014，21（4）：547-553.
[5] DI NAPOLI M，PAPA F，BOCOLA V. C-reactive protein in ischemic stroke：an independent prognostic factor[J]. Stroke，2001，32（4）：917-924.
[6] LADENVALL C，JOOD K，BLOMSTRAND C，et al. Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype[J]. Stroke，2006，37（8）：2018-2023.
[7] KUHLENBAEUMER G，HUGE A，BERGER K，et al. Genetic variants in the C-reactive protein gene are associated with microangiopathic ischemic stroke[J]. Cerebrovasc Dis，2010，30（5）：476-482.
[8] WILLIAMS S R，HSU F C，KEENE K L，et al. Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke[J]. Neurology，2016，86（4）：351-359.
[9] DAS S，ROY S，KAUL S，et al. CRP gene（1059G>C）polymorphism and its plasma levels in ischemic stroke and hemorrhagic stroke in a south Indian population[J]. Inflammation，2014，37（5）：1683-1688.
[10] WANG Y J，JING J，MENG X，et al. The third China national st roke regist ry（CNSR-Ⅲ）for patients with acute ischaemic stroke or transient ischaemic attack：design，rationale and baseline patient characteristics[J]. Stroke Vasc Neurol，2019，4（3）：158-164.
[11] CHENG S，XU Z，LIU Y，et al. Whole genome sequencing of 10K patients with acute ischaemic stroke or transient ischaemic at tack：design，methods and baseline patient characteristics[J]. Stroke Vasc Neurol，2021，6（2）：291-297.
[12] AY H，BENNER T，ARSAVA E M，et a l. A computerized algorithm for etiologic classification of ischemic stroke：the causative classification of stroke system [J]. Stroke，2007，38（11）：2979-2984.
[13] PARSONS B L，MCKINZIE P B，HEFLICH R H. Allele-specific competitive blocker-PCR detection of rare base substitution[M/OL]//KEOHAVONG P，GRANT S G. Molecular toxicology protocols. Methods in molecular biology™. Totowa：Humana Press，2005：235-245[2021-12-12]. https://doi.org/10.1385/1-59259-840-4：235.

[14] AROUCA A B ，MEIRHAEGH E A ， DALLONGEVILLE J，et al. Interplay between the Mediterranean diet and C-reactive protein genetic polymorphisms towards inflammation in adolescents[J]. Clin Nutr，2020，39（6）：1919-1926.
[15] WANG L，LI Y X，WANG C Y，et al. C-reactive protein，infection，and outcome after acute ischemic stroke：a registry and systematic review[J]. Curr Neurovasc Res，2019，16（5）：405-415.
[16] ZHANG X G，XUE J，YANG W H，et al . Inflammatory markers as independent predictors for stroke outcomes[J/OL]. Brain Behav，2021，11（1）：e01922[2021-12-12]. https://doi.org/10.1002/brb3.1922.
[17] WANG G Y，JING J，LI J J，et al. Association of elevated hs-CRP and multiple infarctions with outcomes of minor stroke or TIA：subgroup analysis of CHANCE randomised clinical trial[J]. Stroke Vasc Neurol，2021，6（1）：80-86.
[18] KIRZINGER B，STROUX A，RACKOLL T，et al. Elevated serum inflammatory markers in subacute stroke are associated with clinical outcome but not modified by aerobic fitness training：results of the randomized controlled PHYS-STROKE trial[J/OL]. Front Neurol，2021，12：713018[2021-12-12]. https://doi.org/10.3389/fneur.2021.713018.

[19] BLANCO-COLIO L M，MÉNDEZ-BARBERO N，PELLO LÁZARO A M，et al. MCP-1 predicts recurrent cardiovascular events in patients with persistent inflammation[J]. J Clin Med，2021，10（5）：1137.
[20] COVENEY S，MURPHY S，BELTON O，et al. Inflammatory cytokines，high-sensitivity C-reactive protein，and risk of one-year vascular events，death， and poor functional outcome after stroke and transient ischemic attack[J]. Int J Stroke，2022，17（2）：163-171.
[21] DEN HERTOG H M，VAN DEN HERIK E G，DIPPEL D W，et al. Variation in the C-reactive protein gene is associated with serum levels of CRP in patients with acute ischemic stroke[J]. Cerebrovasc Dis，2010，29（4）：372-375.
[22] REITZ C，BERGER K，DE MAAT M P，et al. CRP gene haplotypes，serum CRP，and cerebral smallvessel disease：the Rotterdam scan study and the MEMO study[J]. Stroke，2007，38（8）：2356-2359.
[23] RIDKER P M，PARE G，PARKER A，et al. Loci related to metabolic-syndrome pathways including LEPR，HNF1A IL6R，and GCKR associate with plasma C-reactive protein：the women's genome health study[J]. Am J Hum Genet，2008，82（5）：1185-1192.