Study On Risk Factors Of Coronary Artery Disease And Inflammation Genetic Variants Associated With The Prognosis Of Coronary Artery Disease

Background:Coronary artery disease (coronary artery disease, CAD) is the leading cause of the diseases related death in the 21st century. In China, the morbidity and mortality of CAD had been increasing since 1990s and it becomes one of the public health problems. CAD is a complex disease which results from the interplay of genetic and environmental factors. Genetic factors play the important roles in the occurrence and development of CAD.Studies on the pathogenesis of CAD found that Interleukin-1 (IL-1) family play an important role in vascular inflammation. IL-1B cytokine might regulate endothelial cell procoagulant activity and alter the functions of vascular endothelium, which would affects the formation of atherosclerosis. IL1f7, as aninhibition of the production of inflammatory cytokines and activation on the macrophages, plays a protective effect on atherosclerosis-related diseases. IL-3 is a major component of the immune system, which plays a key role in regulating various mature cell growth, differentiation and gene expression. IL-18 plays an important role in the process of immune regulation, anti-infection, antitumor and chronic inflammatory diseases. It can affect the occurrence and development of atherosclerotic plaque and is highly expressed in the atherosclerotic plaques, and it is also shown that the higher level of IL-18 is associated with the instability of the plaque.Single nucleotide polymorphism (SNP) variant is the most common human genetic variation. Variants in inflammation genes could result in the change of inflammation-related protein complexes, and finally affect the inflammatory response. Previous studies showed that IL-1 cytokine involved in the pathogenesis of atherosclerosis and aneurysm formation, and the SNPs in IL-1 gene are associated with atherosclerosis. IL1B rs16944 TT genotype is associated with the release of cytokines and severe inflammation response. The polymorphisms in IL3 rs2073506 G>A、IL18 rs360719 A>G、IL18R rs13015714 G>T and IL18RAP rs917997 C>T are associated with the occurrence and development of various diseases. Previous studies found that the IL-1, IL-3 and IL-18 could participate in the inflammatory response, but the association between the gene polymorphisms and coronary artery disease was little considered. A case-control study and a follow-up study are carried out to explore the associations between the risk factors of CAD, polymorphisms in IL-1, IL-3 and IL-18 genes and major adverse cardiovascular events of CAD patients.Objectives:1、To analyze the association between risk factors and CAD and the interaction among risk factors in a case-control study.2、To explore the relationship between ILIA rs 1800587 C>T, IL1B rs 16944 G>A, IL1f7 rs3811047 G>A, IL3 rs40401 C>T, IL3 rs2073506 G>A, IL18 rs360719 A>G, IL18R rs13015714 G>T, IL18RAP rs917997 C>T polymorphisms and major adverse cardiovascular events and the interaction between genetic variation and environmental factors.Methods:1.The case-control study:1741 CAD patients and 799 non-CAD controls were collected from the cardiology department of Zhongda Hospital Affiliated to Southeast University. All of the subjects were diagnosed by coronary angiography and conducted an epidemiological survey on physical examination, medical history and biochemistry test.2.The follow-up study:1013 CAD patients were followed up for 5-8 years and collected the information on the major adverse cardiovascular events 711 patients obtained both the outcomes and the blood samples. Using SNPscan TM method, ILIA rs1800587 C>T, ILIB rs16944 G>A, IL1f7 rs3811047 G>A, IL3 rs40401 C>T, IL3 rs2073506 G>A, IL18 rs360719 A>G, IL18R rs13015714 G>T, IL18RAP rs917997 C>T SNPs of these patients were detected.3、Data analysis:We established the dataset using Epidata (V3.2). Statistical methods include frequency distribution and the median descriptive analysis, t test, Chi-square test, multivariate Logistic regression, log-rank test, multivariate Cox regression, Crossover analysis. All the data were analyzed in SPSS21.0 software.Results:1、A total of 1741 patients with coronary artery disease (CAD) and 799 control people with negative CAG were enrolled in our case-control study. There were significant differences between patients group and control group in demographic characteristics (such as gender, age, BMI, hypertension, diabetes mellitus, smoking, drinking, working intensity, usual frequency of physical exercise), and clinical biochemical indicators (such as fasting blood-glucose (FBG), apolipoprotein A (apo A), lipoprotein a, total cholesterol (TC), low density lipoprotein (LDL), low density lipoprotein (HDL), left ventricular ejection fraction (LVEF) measured by ultrasound cardiogram after admission to hospotial) (P< 0.05).Compared with the control group, univariate logistic regression showed that male, older than 60, BMI≥ 24 (kg/m2), history of high blood pressure and diabetes, smoking, high lipoprotein a, high levels of triglycerides were associated with the increased risk of CAD. Higher levels of apo A and HDL-C were associated with 27% and 42% reduced risks of CAD respectively (Adjusted OR=0.63,95%CI:0.52-0.77; Adjusted OR=0.58,95%CI:0.48-0.70), and apo A and HDL-C were considered as protective factors of CAD. Multivariate logistic regression analysis showed that age, hypertension and diabetes, smoking are risk factors of CAD, and there are interactions between age and high blood pressure,age and diabetes, smoking and high blood pressure in coronary artery disease.2、IL3 rs2073506 G>A gene polymorphism was associated with the major adverse cardiovascular events(MACEs) of CAD. Compared with the IL3 rs2073506 GG genotype, the patients with GA genotype had a 35% increased risk of MACEs (HR=1.35,95%CI: 1.08-1.68). In the dominant model, compared with the IL3 rs2073506 GG genotype, the patients with GA/AA genotypes had a 32% increased risk of MACEs (HR=1.32,95%CI: 1.07-1.65). Multivariate COX regression analysis found that the diabetic patients had a 46% increased risk of MACEs compared with non-diabetic people (HR=1.46,95%CI:1.14-1.87). Patients with high levels of CRP had a 157% increased risk of MACEs (HR=2.57,95%CI: 2.00-3.30). Patients with 3 or more coronary lesions had a 38% increased risk of MACEs (HR=1.38,95%CI:1.05-1.81). There is positive interaction between IL3 rs2073506 G>A genovariation and diabetes.IL3 rs2073506 genetic variation with diabetes,5% MACEs of coronary artery disease was attributable to the interaction of two risk factors.Conclusion:1、T Diabetes, hypertension, smoking were associated with the increased risk of CAD. There are positive interactions between age and high blood pressure, age and diabetes, high blood pressure and smoking on the occurance of CAD.2、IL3 rs2073506 G>A polymorphism were associated with the increased risk of MACEs of CAD patients, and there was a positive interaction between IL3 rs2073506 G>A genovariation and diabetes on MACEs.