福建汉族脑梗死患者氯吡格雷抵抗的影响因素及与CYP2C19基因多态性的关系

Influencing factors of clopidogrel resistance and the relationship with CYP2C19 gene polymorphisms in patients with cerebral infarction in Fujian Han population

目的探讨影响福建汉族脑梗死患者氯吡格雷抵抗的发生率、相关危险因素、与CYP2C19基因多态性的关系及其对白细胞介素6(IL-6)的影响。方法前瞻性纳入福建汉族脑梗死恢复期(≥3个月)患者102例。入院后给予氯吡格雷75 mg/d,于用药后第8天,采用血栓弹力图检测血小板聚集抑制率,其中≥40%为氯吡格雷敏感组,<40%为氯吡格雷抵抗组。采用聚合酶链反应-限制性片段长度多态性方法检测CYP2C19*2和*3位点的基因型;酶联免疫吸附法检测治疗前后的血清IL-6水平。结果 102例患者中,氯吡格雷抵抗组27例,氯吡格雷抵抗发生率为26.5%。(1)氯吡格雷抵抗组低密度脂蛋白胆固醇(LDL-C)水平高于氯吡格雷敏感组[分别为(3.6±0.9)、(3.2±0.8)mmol/L,P<0.05];而性别、高血压病、糖尿病、总胆固醇、三酰甘油及高密度脂蛋白胆固醇的差异均无统计学意义(P均>0.05)。(2)两组患者的CYP2C19*2和CYP2C19*3位点等位基因频率和基因型总体分布不一致(P<0.01)。氯吡格雷抵抗组的*1等位基因频率和*1/*1基因型频率明显低于氯吡格雷敏感组(分别为40.7%对比80.0%,18.5%对比61.3%,均P<0.01),而*2等位基因频率和*2/*2基因型频率明显高于氯吡格雷敏感组(分别为53.7%对比18.7%,29.6%对比1.3%,P均<0.01)。(3)治疗后氯吡格雷抵抗组IL-6浓度明显高于氯吡格雷敏感组[(18.4±1.8)ng/L对比(12.9±1.8)ng/L,P<0.01]。与治疗前比较,氯吡格雷抵抗组血清IL-6水平下降(5.1±2.6)ng/L,低于氯吡格雷敏感组的(10.3±2.7)ng/L,P<0.01。结论福建汉族脑梗死患者氯吡格雷抵抗发生率较高。氯吡格雷抵抗不仅与CYP2C19的突变型基因相关,而且与LDL-C增高有关。氯吡格雷抵抗削弱了药物的抗炎作用。

Objective To investigate the incidence and the related risk factors for clopidogrel resistance and the relationship with CYP2C19 gene polymorphisms and the effect on interleukin-6 （IL-6） in patients with cerebral infarction in Fujian Han population. Methods A total 102 patients with cerebral infarction in recovery period （ I〉 3 months） in Fujian Han population were enrolled prospectively. Clopidogrel 75 mg/d were given after admission. At day 8 after administration, thrombelastogram was used to detect the platelet aggregation inhibition rate （/〉40% was clopidogrel sensitive group and 〈 40% was clopidogrel resistance group）. Polymerase chain reaction-restriction fragment length polymorphism was used to detect CYP2C19＊ 2 and CYP2C19 ＊ 3 alleles. Enzyme linked immunosorbent assay was used to detectserum IL-6 level before and after treatment. Results Of the 102 patients, 27 were in the clopidogrel resistance group, and the incidence was 26.5%. （ 1 ） The level of low density lipoprotein cholesterol （LDL-C） of the clopidogrel resistance group was higher than that of the clopidogrel sensitive group （3.6± 0.9 vs. 3.2 ± 0. 8 mmol/L; P 〈 0. 05 ）. There were no significant differences in sex, hypertension, diabetes,total cholesterol, glycerin trimyristate, and high density lipoprotein cholesterol （all P 〈 0.05 ）. （2） The CYP2C19＊ 2 and CYP2C19＊ 3 allele frequencies and the genotype overall distribution were inconsistent in patients of both groups （P 〈0.01 ）. The ＊ 1 allele and ＊ 1/＊ 1 genotype frequencies of the clopidogrel resistance group were significant lower than those of the clopidogrel sensitive group （40.7% vs. 80.0% ,P 〈0.01 ;1.3% vs. 18.5% ,P 〈0.01） ,and the ＊ 2 allele and ＊ 2/＊ 2 genotype frequencies were significantly higher than those of the clopidogrel sensitive group （53.7% vs. 18.7% , P 〈 0.01 and 1.3 % vs. 29.6 % , P 〈 0.01 ）. （3） After treatment, the serum IL-6 level of the clopidogrel resistance group was significantly higher than that of the clopidogrel sensitive group [ （ 18.4 ± 1.8 ） vs. （12.9 ±1.8） ng/L,P 〈 0.01 ]. Compared with before treatment, the serum IL-6 level of the clopidogrel resistance group decreased （ 5. 1± 2.6 ） ng,/L, and it was lower than （ 10. 3± 2.7 ） ng/L of the clopidogrel sensitive group,P 〈 0.01. Conclusion The incidence of clopidogrel resistance is higher in patients with cerebral infarction in Fujian Hart population. Clopidogrel resistance is not only associated with the mutation genotype of CYP2C19, but also associated with the increased LDL-C. Clopidogrel resistance weakened the anti-inflammatory effects of drugs.