多药物耐药基因多态性与缺血性脑卒中患者阿司匹林抵抗的相关性

Association of ABCB1 gene polymorphisms with aspirin resistance in patients with ischemic stroke

目的 探讨多药物耐药（ABCB1/MDR1）基因多态性与缺血性脑卒中患者阿司匹林抵抗（AR）的关系。方法 纳入2014年9月至2016年5月在青岛大学附属医院神经内科因脑梗死住院的患者300例，根据血栓弹力图（TEG）结果将其分为阿司匹林抵抗（AR）组和阿司匹林敏感（AS）组。采用聚合酶链反应–限制性片段长度多态性技术（PCR–RFLP）和直接测序方法对ABCB1基因C1236T、G2677T/A、C3435T 3位点进行基因多态性检测。结果 C1236T、G2677T/A、C3435T两两间分别存在连锁不平衡（D′＝0.8；r2＝0.9）。位点C3435T T的等位基因频率在AR组和AS组中分别为57.3%和43.1%，差异有统计学意义（χ2＝9.143，P＝0.002），且AR组中（CT＋TT）基因型高于AS组，差异亦有统计学意义（χ2＝4.369，P＝0.037）。而C1236T和G2677T/A等位基因频率及基因型分布在两组间差异均无统计学意义。对3位点所构建的单倍型进行分析，单倍体（C–T–T）的OR值为1.602 （χ2＝5.374，P＝0.02），单倍体（C–G–C）的OR值为0.495（χ2＝8.775，P＝0.003），单倍体（T–G–C）的OR值为3.010 （χ2＝5.846，P＝0.015），单倍体（T–T–T）的OR值为3.308（χ2＝4.650，P＝0.031）。结论 C3435T基因多态性与缺血性卒中患者AR有关。单倍体（C–T–T，T–G–C，T–T–T）亦与缺血性卒中患者AR发生有关。

Objective To investigate the relationship of single nucleotide polymorphisms of Multi-drug resistance （ABCB1/MDR1） gene with Aspirin resistance （AR） in patients with ischemic stroke.Methods Three hundred ischemic stroke patients from Department of Neurology, Affiliated Hospital of Qingdao University were collected from September 2014 to May 2016. According to the results of Thromboelastogram （TEG）, the patients were divided into aspirin resistance （AR） group and aspirin sensitive （AS） group. The genotypes of ABCB1 gene （C1236T, G2677T/A, C3435T） were detected by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） and direct sequencing.Result Linkage disequilibrium was found among the three loci （D′=0.8; r2=0.9）. The T allele frequency of C3435T in AR group and AS group was 57.3% and 43.1% respectively, and the difference was statistically significant （χ2=9.143, P=0.002）. The frequency of genotypes CT＋ TT in AR group was higher than AS group, and the difference was also significant （χ2=4.369, P=0.037）. But there was no difference in allele frequency and genotype distribution of C1236T and G2677T/A between the two groups.Haplotypes constituted by the three loci were analyzed, and the OR value of haplotype （C-T-T） was 1.602 （χ2=5.374, P=0.02）, the OR value of haplotype （C-G-C） was 0.495 （χ2=8.775, P=0.003）, the OR value of haplotype （T-G-C） was 3.010 （χ2=5.846, P=0.015）, while the OR value of haplotype （T-T-T） was 3.308 （χ2=4.650, P=0.031）.Conclusions The polymorphisms of C3435T in the ABCB1 gene have a relationship with AR in the patients with ischemic stroke. The haplotypes （C-T-T, T-G-C, T-T-T） are also related to the AR in the patients with ischemic stroke.