关键词: 卒中, 动脉粥样硬化, 年龄组, CYP2C19基因, 基因多态性, 细胞色素P450, 血小板计数, 氯吡格雷, 预后

Abstract: Background　As a classic platelet aggregation inhibitor，clopidogrel has been widely used in secondary prevention and treatment of patients with ischemic stroke. However，some patients with clopidogrel treatment still have ischemic stroke，which might be attributed to CYP2C19 gene polymorphisms，but it remains controversial whether CYP2C19 gene polymorphisms are independently associated with increased risk of stroke in different age groups of patients. Objective　To explore the correlation between CYP2C19 polymorphisms and clinical outcomes in different age groups of patients with minor stroke caused by large-artery atherosclerosis（LAA）. Methods　A total of 479 inpatients with minor stroke due to LAA（169 cases≤60 years old，and 310 cases>60 years old） and one-year oral administration of clopidogrel were selected from Department of Neurology，the First Affiliated Hospital of Soochow University from April 2015 to April 2018. Baseline data were collected，including age，gender，NIHSS score，blood glucose，high-density lipoprotein（HDL），low-density lipoprotein（LDL），total cholesterol（TC），triacylglycerol（TG），white blood cell count，prevalence of diabetes，hypertension，CYP2C19 LOF alleles，smoking，and drinking. Recurrence of stroke or death within three months after stroke was obtained during follow-up. One-year clinical outcome was evaluated using the Modified Rankin Scale（mRS）（mRS score ≤2 indicating good outcome，and mRS score >2 indicating poor outcome）. The homogeneity test was used to analyze the heterogeneity of the results in different age groups. Multivariate Logistic regression was used to analyze the potential predictors of outcome in different age groups. Results　In patients aged ≤60 years old，significant differences in average NIHSS score，blood glucose，LDL，and white blood cell count，as well as prevalence of diabetes，hypertension，CYP2C19 LOF，smoking between good and poor outcome cases（P<0.05）. In patients aged>60 years，there were statistically significant differences in gender ratio，average blood glucose，HDL，LDL，and TG，as well as prevalence of diabetes，and hypertension between good and poor outcome cases（P<0.05）. Breslow-Day test found that there was an interaction effect between age and correlation of CYP2C19 LOF allele carriage with clinical outcome （χ2=6.352，P=0.012）. Tarone test also demonstrated that there was an interaction effect between age and correlation of CYP2C19 LOF allele carriage and clinical outcome（χ2=6.351，P=0.012）. The size of the interaction effect analyzed using binary Logistic regression showed that the difference in the size of the interaction effect was statistically significant〔P=0.013，OR=3.63，95%CI（1.31，10.07）〕. In addition，there was no heterogeneity in the correlation between CYP2C19 LOF alleles and stroke recurrence or death 3 months after stroke in patients of different age groups（P>0.05）. CYP2C19 LOF allele carriers had higher rate of stroke recurrence or death within 3 months after stroke than non-carriers（P=0.023）. Multivariate Logistic regression analysis showed that in patients ≤60 years old，CYP2C19 LOF alleles carriage，hypertension，diabetes，smoking，and elevated LDL may be independent predictors of clinical outcome（P<0.05）. Among those aged >60 years old，hypertension，diabetes，drinking，male，elevated blood glucose and HDL may be independent predictors of clinical outcome（P<0.05）. After controlling for confounding factors，such as CYP2C19 LOF alleles，hypertension，diabetes，smoking，drinking，gender，NIHSS score，blood glucose，TC，TG，LDL，HDL，and white blood cell count，it is still not certain whether CYP2C19 LOF was the independent predictor of stroke recurrence or death three months after stroke（P>0.05）. Conclusion　The correlation between CYP2C19 polymorphisms and long-term clinical outcome might be stronger in younger patients with minor stroke due to LAA treated with clopidogrel.

Key words: Stroke, Atherosclerosis, Age groups, CYP2C19 genetic, Genetic polymorphism, Cytochrome P450, Platelet count, Clopidogrel, Prognosis