Effect of Smoking Status and Genetic Risk Factors on Restenosis and Efficacy of Clopidogrel After de Novo Percutaneous Coronary Intervention

Overview

Restenosis occurs for many different reasons. Over the years, many predictive clinical, biological, genetic, epigenetic, lesion-related, and procedural risk factors for restenosis have been identified. Smoking is one of most important factors, however the results were contradictory. And the genetic factors of restenosis have been studied mostly in European populations. Based on literature review, study of candidate genes for restenosis in Chinese population was insufficient. With due attention to this matter mentioned above, the investigators aim to preliminary explore genetic variation and smoking effect on clinical restenosis in patients diagnosed with after percutaneous coronary intervention in the Chinese population, with correlation analysis of factors and gene-set analysis of biological pathways related to restenosis and platelet approach were widely used in this study.

The design of the study was retrospective study using secondary data from medical records of coronary heart disease patients who taking antiplatelet drugs and had genetic test at Peking University First Hospital. These patients were enrolled in a previous study, which was approved by the ethics committee of Peking University First Hospital (NO. 2013 \[634\]). The study investigated the association between genetic polymorphism and clopidogrel pharmacodynamics and drug adverse effect, and enrolled total 168 patients. The primary endpoints clinical restenosis, defined as unplaned revascularization including arget vessel revascularization (TVR) or target lesion revascularization (TLR) , either by repeated percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). The platelet function was assessed using VerifyNow® P2Y12 (VN-P2Y12) assay (Accumetrics, San Diego, California, USA). To analysis the association of SNP with unplaned revascularization and PRU, the investigators investigated pathways related to known platelet reaction (platelet production, platelet apoptosis, platelet activity, antiplatelet, platelet resistance, platelet adhesion, and etc.) and restenosis-related processes (inflammation, vascular function, proliferation and transcription) from the KEGG, BioCarta and Gene Cards . The genetic statistical analyses were performed using the set-based test of PLINK v1.07 adjusted by smoking statues. During the set-based test of PLINK the joint effect of all genetic variation, fulfilling the test constraints, within the set of genes of pathway of interest is evaluated. First a single SNP analysis of all SNPs within the pathway set was performed, SNPs with the lowest p-value in the single SNP analysis were selected. This analysis was repeated 10,000 times in simulated datasets, subsequently, a mean SNP statistic was calculated from the single SNP statistics of a maximum amount of independent SNP with a p-value \<0.01 SNPs are considered independent when the LD expressed in R2 is lower than 0.5. Analysis of gene mutation distribution conforms to the genetic equilibrium law of Hardy-Weinberg by chi-square test, P \<0.05 is considered possible deviations of population distribution. The investigators use the result of 30 month as a replication, SNPs both significant in 18 month and 30 month were reported in the study.