Association Of MicroRNA-Related Polymorphisms With Clinical Features And Prognosis Of Patients With Coronary Artery Disease

Part I Association of micro RNA-related polymorphisms with clinical characteristics of patients with coronary artery diseaseObjectiveA large number of studies have shown that mi RNA-related polymorphisms are not only associated with the susceptibility of complex diseases, but also affect the clinical features of patients, such as blood lipids. This study aimed to investigate association between 6 mi RNA-related polymorphisms(mi R-149 rs71428439, mi R-146 a rs2910164, mi R-499 rs3746444, mi R-423 rs6505162, mi R-4513 rs2168518, and FABP2 rs11724758) and clinical features of patients with coronary artery disease(CAD).Methods: Six mi RNA-related polymorphisms(mi R-149 rs71428439, mi R-146 a rs2910164, mi R-499 rs3746444, mi R-423 rs6505162, mi R-4513 rs2168518, and FABP2 rs11724758) were genotyped using ligase detection reaction-PCR in 1004 patients with coronary artery disease. We further evaluated the relationship between six mi RNA-related SNPs and clinical features of patients with coronary artery disease.Results: Since FABP2 rs11724758 deviated from Hardy-Weinberg equilibrium(p < 0.05), it was excluded from further analysis. mi R-4513 rs2168518 was associated with blood pressure, triglycerides, total cholesterol, and fasting glucose levels, and risk of diabetes mellitus(p < 0.05). mi R-499 rs3746444 and mi R-423 rs6505162 were associated with blood pressure and HDL levels, respectively(p < 0.05). Conclusion: mi R-4513 rs2168518, mi R-499 rs3746444 and mi R-423 rs6505162 were associated with clinical features of patients with coronary artery disease, such as blood pressure, blood lipids, fasting glucose levels, and risk of diabetes mellitus.Part II Influence of micro RNA-related polymorphisms on clinical outcomes in coronary artery diseaseObjective: Genetic variants in micro RNA(mi RNA) genes may affect their function, which result in various diseases and affect the prognosis of patients. This study aimed to examine the effect of mi RNA-related polymorphisms on prognosis in 1004 patients with coronary artery disease(CAD).Methods: This study is a prospective follow-up study of patients with coronary artery disease. A total of 1004 patients with angiographic coronary artery disease were recruited between 2007 and 2012. The primary endpoint of the study was the first major cardiovascular event [myocardial infarction(MI), heart failure, stroke, recanalization, coronary artery bypass grafting, resuscitated cardiac arrest, and cardiovascular death]. Second endpoint was all-cause mortality. By 2013, a total of 244(24.3%) major cardiovascular events occurred in 1004 patients with coronary artery disease. The average follow-up period was 4.86 years. Survival analysis was performed using Kaplan-Meier method and log-rank test. Cox proportional hazard model were carried out to evaluate the effect of mi RNA SNPs on the survival time of patients with coronary artery disease.Results: Survival analysis showed that mi R-499 rs3746444 and mi R-4513 rs2168518 were associated with even-free survival(EFS). The GG genotype of mi R-499 rs3746444 was associated with shorter EFS under codominant [adjusted hazard ratio(HR) = 1.913, 95%CI: 1.162-3.152, p = 0.011] and recessive models(adjusted HR = 1.954, 95%CI: 1.197-3.192, p = 007). mi R-4513 rs2168518 showed an effect on the primary endpoint under codominant(CT vs TT, adjusted HR = 1.345, 95%CI: 1.022-1.770, p = 0.034; TT vs CC, adjusted HR = 1.714, 95%CI: 1.077-2.729, p = 0.023), dominant(adjusted HR = 1.401, 95%CI: 1.079-1.819, p = 0.011) and additive models(adjusted HR = 1.323, 95%CI: 1.084-1.615, p = 0.006). In addition, mi R-4513 rs2168518 was associated with shorter overall survival time(dominant model, adjusted HR = 2.349, 95%CI: 1.483-3.721, p < 0.001; recessive model, adjusted HR = 2.101, 95%CI: 1.063-4.152, p = 0.033; additive model, adjusted HR = 1.879, 95%CI: 1.360-2.959, p < 0.001). The GG genotype of mi R-149 rs71428439 was related to worse prognosis of patients with coronary disease(adjusted HR = 1.821, 95%CI: 1.008-3.290, p = 0.047).Conclusion:mi R-4513 rs2168518, mi R-499 rs3746444 and mi R-149 rs71428439 might be potential biomarkers for the clinical prognosis of CAD.Part III serum expression of micro RNAs in patients with coronary artery diseaseObjective Micro RNA(mi RNA) is a type of small non-coding RNA molecules that function as important gene expression regulators by targeting messenger RNAs by post-transcriptional endonucleolytic cleavage or translational inhibition. mi RNAs play vital roles in pathogenesis of complex diseases, such as coronary artery disease(CAD). This study aimed to investigate serum levels of mi RNA in patients with coronary artery disease.Subjects and Methods Quantitative reverse transcriptase PCR(q RT-PCR) was carried out to detect the serum levels of precursor and mature mi RNAs(mi R-149, mi R-146 a, mi R-499, mi R-4513, and mi R-423) in 86 patients with coronary artery disease, and 86 controls.Results: Serum pre-mi R-146 a and pre-mi R-499 were dysregulated in patients with coronary artery disease compared with controls(p < 0.05). Pre-mi R-146 a was upregulated(fold change = 2.75, p = 0.025), but pre-mi R-499 was downregulated(fold change = 2.14, p = 0.031) in patients with coronary artery disease. We found no differences in serum expression of pre-mi R-149, pre-mi R-4513 and pre-mi R-423 between patients with coronary artery disease and controls(p > 0.05). In addition, serum mi R-146 a was upregulated(fold change = 1.96, p = 0.039), but pre-mi R-499 was downregulated(fold change = 2.02, p = 0.042) in patients with coronary artery disease compared with controls.Conclusions: Serum pre-mi R-146 a, pre-mi R-499, mi R-146 a, and mi R-499 were aberrantly expressed in patients with coronary artery disease, indicated that pre-mi R-146 a, pre-mi R-499, mi R-146 a, and mi R-499 may be potential biomarkers for coronary artery disease.