| Background:Stroke has become the leading cause of adult death in China.Ischemic stroke approximately accounted for 80% of all stroke.Statin is a main medication for secondary prevention of ischemic stroke.Previous studies have shown that individual variations of response to statin were mainly due to activity of transporters and metabolic enzymes.Statin transporters included: 1.organic anion-transporting polypeptides 1B1(OATP1B1),encoded by solute carrier organic anion transporter family member 1B1(SLCO1B1),mainly located outside the basement membrane of liver cells and transported statin from portal vein to liver;2.The superfamily of ATP-binding cassette(ABC)transporters of which the member ABCG2 was mainly responsible for the excretion of statin metabolites from hepatocytes into bile.Atorvastatin was mainly metabolized by cytochrome P450 3A4(CYP3A4)and CYP3A5.Rosuvastatin was mainly excreated by prototype,and it was not affected by CYP3A4 and CYP3A5.Current studies have shown that common variants within CYP3A4,CYP3A5,SLCO1B1 and ABCG2 were associated with changerd statin pharmacokinetics,lipid lowering response and statin-related adverse effect.However,to our knowledge,the association of common variants within CYP3A4,CYP3A5,SLCO1B1 and ABCG2 and prognosis of ischemic stroke has not been reported.Objectives:This study assessed statin treatment in patients hospitalized with acute ischemic stroke in a Han Chinese population in Henan Province.By analyzing factors associated with statin compliance of secondary prevention,and investigating associations of common variants within CYP3A4,CYP3A5,SLCO1B1 and ABCG2 with prognosis of acute ischemic stroke in a Han Chinese population in Henan Province,the present study aimed to provide evidence for individualized treatment for secondary prevention of ischemic stroke.Methods:1.Establishment of ischemic stroke registration database and biobank.From January 2014 to December 2016,consecutive patients hospitalized with acute ischemic stroke within 3 days after onset in neurological wards of the first affiliated hospital of Zhengzhou university were enrolled,with written informed consent.All patients were Han Chinese residing in Henan Province.Clinical data were recorded into ischemic stroke database by trained residents in the department of neurology.Peripheral venous blood samples were collected by ethylene diamine tetraacetic acid(EDTA)anticoagulant tube from patients on fasting condition in the next morning.Genomic DNA was extracted by extraction kit and put into ischemic stroke biological sample database.Patients were regularly followed up by telephone or outpatient appointments by residents independently from registration at 3 month,6month and 1 year after index stroke onset.Information on medication,biochemical examination,major vascular events and death during the follow-up period were recorded.The modified Rankin scale(mRS)was used to evaluate the prognosis of patients at follow-up.The good prognosis was defined as mRS ≤ 1,while poor prognosis as mRS ≥ 2.2.Study on current status of statin treatment in patients hospitalized with acute ischemic stroke and adherence on secondary prevention.Retrospectively analyze statin therapy in patients hospitalized with acute ischemic stroke in the ischemic stroke database.Statin adherence was evaluated by proportion of days covered(PDC).PDC ≥ 80% was defined as fully adherent,while PDC < 80% as not fully adherent.Multiple logistic regression analysis was performed to analyze the factors associated with the statin adherence at 1 year.3.Study on association of common variants within SLCO1B1 and ABCG2 with acute ischemic stroke prognosis in a Han Chinese population in Henan province: DNA samples were selected from ischemic stroke biological sample database.The variants,SLCO1B1 521T>C,SLCO1B1 388A>G,ABCG2 34G>A and ABCG2 421C>A were genotyped by improved multiple ligase detection reaction(iMLDR)platform.Binary logistic regression analysis were used to assess association of SLCO1B1 521T>C,SLCO1B1 388A>G,ABCG2 34G>A and ABCG2 421C>A with 1-year poor outcome,with adjusted odds ratio(OR)and 95% confidence interval(CI).The hwe.chisq function in the genetics package in the R computing environment was used to calculate whether the population genotype distribution conforms to the Hardy-Weinberg equilibrium.Generalized multifactor dimensionality reduction method was performed to analyze gene-gene interaction.4.Study on association of common variants within CYP3A4 and CYP3A5 with acute ischemic stroke prognosis in a Han Chinese population in Henan province: DNA samples were from ischemic stroke biological sample database.CYP3A4*1G and CYP3A5*3 were genotyped by improved iMLDR platform.Binary logistic regression analysis were used to assess association of CYP3A4*1G and CYP3A5*3 with 1-year poor outcome,adjusted odds ratio(OR)and 95% confidence interval(CI).The hwe.chisq function in the genetics package in the R computing environment was used to calculate whether the population genotype distribution conforms to the Hardy-Weinberg equilibrium.Generalized multifactor dimensionality reduction method was performed to analyze gene-gene interaction.Results:1.Study on current status of statin treatment in patients hospitalized with acute ischemic stroke and adherence on secondary prevention.Total of 795 patients were enrolled with an average age of 59.19(12.17)years old,and 544 patients(68.4%)were male.During hospitalization,624(78.5%)patients received high-intensity statin therapy(atorvastatin 40mg-80mg/d or rosuvastatin 20mg/d)and 171(21.5%)patients received moderate-intensity statin therapy(atorvastatin 10-20mg/d or rosuvastatin 5-10mg/ d).Total of 731 patients had completed the 1-year follow-up,and 646(88.4%)patients were fully adherent to statin.2.Study on association of common variants within SLCO1B1 and ABCG2 with acute ischemic stroke prognosis in a Han Chinese population in Henan province: Total of 622 patients with acute ischemic stroke were enrolled,with an average age of 63.71(11.62)years old and 433 males(69.3%).At 1-year follow-up,449 patients developed good outcome(mRS ≤ 1),while 173 patients had poor outcome(mRS ≥ 2).Binary logistic regression analysis showed that ABCG2 34 GA genotype(co-dominant model,OR = 0.55;95% CI,0.36-0.85;P = 0.007)and GA+AA genotypes(dominant model,OR = 0.65,95%CI,0.44-0.98,P = 0.039)were associated with good prognosis at 1-year follow-up after adjustment of conventional factors.No association of ABCG2 421C>A,SLCO1B1 521T>C and SLCO1B1 388A>G with 1-year prognosis of acute ischemic stroke was identified.3.Study on association of common variants within CYP3A4 and CYP3A5 with acute ischemic stroke prognosis in a Han Chinese population in Henan province: Total of 433 patients with acute ischemic stroke were included for statistical analysis,with an average age of 62.34(11.03)years old and 302 males(69.7%).Binary Logistic regression analysis showed that CYP3A4*1G/*1G genotype were associated with 1-year poor prognosis of acute ischemic stroke under co-dominant model(OR = 2.92,95%CI,1.07-7.98,P = 0.037)and recessive model(recessive model,OR = 3.37;95% CI,1.26 – 9.04;P = 0.016).No association between CYP3A5*3 and 1-year prognosis of acute ischemic stroke in the studied population was identified.Conclusions:1.In the Han Chinese population from Henan province,78.5% of patients with acute ischemic stroke received high-intensity statin treatment during hospitalization.For patients who had completed 1-year follow-up,88.4% of the patients were fully adherent to statin.2.The ABCG2 34 G>A may be associated with 1-year good prognosis of acute ischemic stroke in the Han Chinese population in Henan Province.3.The CYP3A4*1G may be associated with 1-year poor prognosis of acute ischemic stroke in the Han Chinese population in Henan Province. |
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