Association Between ENOS Glu298A Polymorphism And Risk Of ISR In Patients Underwent PCI

Background:Percutaneous coronary intervention(PCI)is one of the main treatments for coronary heart disease at present,but there is still a certain incidence of in-stent restenosis(ISR)after PCI,and the effect of ISR is not ideal,which affects the prognosis of patients.The pathological mechanisms of ISR include delayed reendothelialization and vascular smooth muscle cell proliferation,which involve multiple factors,in which genetic factors may play an important role.The aim of this study was to investigate the relationship between rs1799983(Glu298Asp,G298A)polymorphism of endothelial nitric oxide synthase gene(eNOS gene)and in-stent restenosis.Methods:(1)Patients who underwent coronary angiography(CAG)or PCI at the same time in Xiangya Hospital of Central South University and the first affiliated Hospital of Zhengzhou University were selected for retrospective analysis.All the patients were successfully implanted with drug-coated stents(DES)in the past and were rehospitalized for coronary angiography about 10 months after PCI.According to the results of CAG after admission,restenosis was defined as 50% or more of stenosis.The patients were divided into in-stent restenosis group(n = 159)and non-stent restenosis group(n = 355).DNA was extracted from peripheral blood of all patients and genotypes of Glu298 Asp polymorphisms of eNOS gene were determined by sequencing.SPSS17.0 software was used for statistical analysis,Additive model,Dominant model and Recessive model were established for analysis,and Logistic regression model was used to detect the relationship between Glu298 Asp and ISR risk.At the same time,according to diabetes subgroup,stent implantation subgroup and statins type,the difference of ISR outcome between Asp298 allele carriers and patients with wild homozygous(GG)in ISR group and non-ISR group was compared.(2)The genotype distribution data of this case-control study were meta-analyzed with the data of previous literature on Glu298 Asp polymorphism and ISR susceptibility.According to PRISMA guidelines,6 articles were selected from Pubmed and Web of Science to extract qualified data from the literature.Five genetic models(Dominant model,Recessive model,Homozygote model,Heterozygote model and Allele model)were analyzed by STATA16 software,and subgroup analysis was performed according to race and stent type.Publication bias was evaluated by Begg test and Egger test,and the stability of the results was evaluated by sensitivity analysis.Result:(1)A case-control study included 159 patients with ISR and 355controls(non-ISR).The analysis of clinical data showed that history of diabetes,hyperglycosylated hemoglobin level,drinking history,coronary multi-vessel lesion and the number of stents implanted were risk factors for ISR.The genotype distribution of eNOS Glu298 Asp polymorphism was in accordance with Hardy-Weinberg balance in both cases and controls.The Asp298 allele frequency of Glu298 Asp polymorphism in non-ISR group(13%)was significantly higher than that in ISR group(8%).The genotype frequencies of Glu298 Asp GG,GT and TT in ISR group were 84%,16% and 0%,respectively.The non-ISR group was 77%,21% and 2%,respectively.After adjusting for potential confounding factors,compared with GG homozygote(wild type genotype),the risk of ISR in patients with eNOS Glu298 Asp polymorphism Asp298 allele was significantly reduced(P=0.03,OR=0.54,95%CI: 0.31-0.96).Stratified analysis showed that patients with Asp298 allele(GT+TT)were less susceptible to ISR when more than 3 stents were implanted and non-Atrovastatin was used to reduce blood lipid levels(stent number more than 3: P=0.02,OR=0.35,95%CI: 0.14-0.88;non-Atrovastatin:P=0.03,OR=0.38,95%CI: 0.16-0.91).(2)A total of 6 articles were included in the meta-analysis,combined with our case-control study data,including 428 cases and 1110 controls.Analysis of five genetic models showed that there was no significant association between Glu298 Asp polymorphism of eNOS gene and susceptibility to ISR after PCI(Dominant model: P=0.08,OR=1.58,95%CI: 0.94-2.66;Recessive model: P=0.77,OR=0.92,95%CI: 0.50-1.67;Homozygote model:P=0.78,OR=1.09,95%CI: 0.59-2.02;Heterozygote model: P=0.06,OR=1.64,95%CI: 0.98-2.73 and Allele model: P=0.15,OR=1.36,95%CI:0.89-2.08).In ethnic subgroup analysis,it was found that Glu298 Asp polymorphism was significantly associated with increased risk of ISR in dominant model,heterozygote model and allele model in Caucasian population(GT+TT vs GG: P<0.01,OR=1.77,95%CI: 1.20-2.62;GT vs GG: P<0.01,OR=1.84,95%CT: 1.22-2.78;T vs G: P=0.01,OR=1.46,95%CI: 1.08-1.97).Subgroup analysis based on stent type showed that dominant model,heterozygote model and allele model suggested that Glu298 Asp polymorphism was significantly associated with increased risk of ISR in patients with BMS(GT+TT vs GG: P < 0.01,OR=2.42,95%CI: 1.52-3.84;GT vs GG: P<0.01,OR=2.54,95%CT: 1.56-4.13;T vs G:P<0.01,OR=1.78,95%CI: 1.26-2.52).Conclusion:1)The carrying of eNOS Glu298 Asp polymorphism Asp298 allele can reduce the risk of ISR after DES implantation in Chinese population.2)meta-analysis showed that Glu298 Asp polymorphism in the whole population was not related to the risk of ISR after PCI,but could increase the risk of ISR in Caucasians and after BMS implantation.