| Part I THE RELEVANT STUDY BETWEEN SINGLE NUCLEOTIDE POLYMERPHISMS AND SUSCEPTIBILITYAND RISK FACTOR OF ACUTE MYOCARDIALINFARCTIONBACKGROUND: Acute myocardial infarction(AMI), characterized bydangerous pathogenic conditions and high fatality,is a serious complicationand major cause of death of coronary heart disease(CHD). The prevalence of AMI tended to increase and its incidence showed younger trend. Recently, AMI has become one of the most dangerous diseases that seriously affected the quality of life of our citizens with an increasing burden of economy and medicine. With the development and adaptation of genetic sequencing technology, single nucleotide polymorphisms(SNPs) have been to a new generation of molecular genetic markers and have identified lots of genetic loci associated disease susceptibility. It has been well documented that SNPs in 9p21 was associated with AMI. The mutation and expression disorders of BRG1 gene and cyclin-dependent kinase inhibitor 2A/2B(CDKN2A/2B) gene can be affect proliferation and apoptosis of vascular cell,, and directly or indirectly, resulting in atherosclerosis. The proprotein convertase subtilisin/kexin type 9(PCSK9) genes increase the risk of AMI by affecting the abnormal metabolism of LDL. Moreover, the upregulation of chemokine(C-X-C motif) ligand 12(CXCL12) genes can promote CXCL12 migration and improve the ischemia anoxic myocardial cells subsequently. The association of BRG1 rs1122608, PCSK9 rs11206510, CDKN2A/2B rs4977574 and CXCL12 rs1746048 SNPs with AMI have been reported in the European and American populations. However, little was known about this association in Chinese population, especially in population from Guangxi province. Therefore, the understanding of the association of these loci with susceptibility and risk factors for AMI may help to know the genetic characteristics and further provide new approach to screen high-risk population and prevention for AMI.OBJECTIVE: The present study was undertaken to detect the associations of BRG1 rs1122608, PCSK9 rs11206510, CDKN2A/2B rs4977574, CXCL12 rs1746048 SNPs and gene-risk factors interactions with the susceptibility for AMI.METHOD: Totals of 600 cases of blood samples were obtained from patients with AMI(n = 300) and an equal number of blood samples from normal people(n=300) at the same period were collected as normal group. All of them were from Guangxi province. Genotyping of BRG1 rs1122608, PCSK9 rs11206510, CDKN2A/2B rs4977574, CXCL12 rs1746048 SNPs were performed using polymerase chain reaction and restriction fragment length polymorphism(PCR-RFLP). Information on medical history, dietary structure, lifestyle factors, height, weight, waist circumference, blood pressure, and family history were collected with standardized questionnaires. The two group were compared the difference of genotypic and allelic frequencies and explored the associations between the four SNPs and susceptibility for AMI. Non-conditional binary logistic regression analysis was performed to assess the relationship of risk factors such as sex, age, cigarette smoking, alcohol consumption, body mass index, lipid levels, and genotypes with AMI. After a Bonferroni correction, p < 0.0125 is considered to have significant differences.RESULTS1. Comparison of generalized features: the values of mean age(61.67 ± 10.43 vs 58.49 ± 10.54) and body mass index(BMI, 23.76 ± 3.11 vs 22.66 ± 3.15) were higher in AMI group than in normal group. The numbers(percentages) of subjects who smoked cigarettes and consuming alcohol were 144(48.00), 74(24.67%) in AMI group, 75(25.00%), 60(20.00%) in normal group, respectively. Both the numbers of subjects who smoked cigarettes and consuming alcohol were higher in AMI group than normal group(p < 0.001 for all). There was no significant difference in the sex structure between the two groups(p > 0.0125).2. Comparison of lipid levels: The levels of serum total cholesterol(TC) and low-density lipoprotein cholesterol(LDL-C) were 5.20 ± 0.95 mmol/L and 3.71 ± 0.92 mmol/L in AMI group; 4.97 ± 1.05 mmol/L and 2.89 ± 0.87 mmol/L in normal group; respectively. There was significant difference in the levels of serum TC and LDL-C. AMI group had higher levels of serum TC and LDL-C than normal normal group(P < 0.0125 for all). However, the serum high-density lipoprotein cholesterol(HDL-C) levels were lower in AMI group than in normal group(1.08 ± 0.26 mmol/L vs 1.36 ± 0.25 mmol/L, P < 0.001). There was no significant difference in the levels of serum triglyceride(TG)(p > 0.0125).3. Comparison of the genotypic and allelic frequencies:(1) BRG1 rs1122608 SNPs: The wild-type GG genotype and G allele frequency respectively was 23.67% and 48.67% in AMI group, lower than 82.67% and 89.83% of normal group; The frequencies of mutations GT, TT, GT + TT genotypes and T allele respectively were 50.00%, 26.33%, 76.33% and 51.33% in AMI group, higher than 14.33%, 3.00%, 17.33% and 10.17% of the normal population group in normal group. Significant differences in both genotypic and allelic frequencies between AMI and normal group were detected(P < 0.001 for all).(2) CDKN2A/2B rs4977574 SNPs: The wild-type AA genotype and A allele frequency respectively was 38.00% and 60.67% in AMI group, higher than 16.33% and 44.67% of normal group; The frequencies of mutations AG, GG, AG + GG genotypes and G allele respectively were 45.33%, 16.67%, 62.00% and 39.33% in AMI group, lower than 56.67%, 27.00%, 83.67% and 55.33 of the normal population group in normal group. There were significant differences in both genotypic and allelic frequencies between AMI and normal group(P < 0.001 for all).(3) PCSK9 rs11206510 SNPs: The wild-type TT genotype and T allele frequency respectively was 79.67% and 87.83% in AMI group, lower than 87.34% and 93.50% of normal group; The frequencies of mutations TC, CC genotypes and C allele respectively were 16.33%, 4.00% and 12.17% in AMI group, higher than 12.33%, 0.33% and 6.50% in normal group. There were significant differences in both genotypic and allelic frequencies between AMI and normal group(P < 0.0125 for all).(4) CXCL12 rs1746048 SNPs: There were no significant difference in genotypic and allelic frequencies between AMI and normal group was detected(P > 0.0125 for all).4. Risk factors: Non-conditional binary logistic regression analysis showed that Diabetes, rs1122608, high blood pressure, age and smoking were associated with risk of AMI, and the OR values were 69.214, 16.038, 9.080, 4.775 and 4.674 respectively; But HDL-C and rs4977574 were negative correlation with the risk of AMI with the OR value of 0.052 and 0.468 respectively; There were significant differences about the risk between AMI group and normal group(P < 0.001 for all). However, no significant differences in the correlations of sex, BMI, TC, TG, alcohol, rs11206510, rs1746048 and LDL-c with the risk of AMI between the two groups(P > 0.0125 for all).CONCLUSION:1. The genotypic and allelic frequencies of BRG1 rs1122608 SNPs were significantly different between AMI group and normal group. The mutant GT, TT, GT + TT genotypes were positively correlated with the risk of AMI. The T allele carriers had higher risk of AMI morbidity.2. The genotypic and allelic frequencies of CDKN2A/2B rs4977574 SNPs were significantly different between AMI group and normal group. The mutant AG, GG, AG + GG genotypes were associated with reduced susceptibility of AMI and the G allele was a protective gene for AMI.3. Significant differences were detected in the genotypic and allelic frequencies of PCSK9 rs11206510 SNPs between AMI group and normal group. The mutant TC, CC, TC+ CC genotypes were positively correlated with the risk of AMI. The C allele carriers had higher risk of AMI morbidity.4. There were no differences of genotypic and allelic frequencies in CXCL12 rs1746048 SNPs between the two groups.5. Diabetes, rs1122608, high blood pressure, age and smoking were associated with risk of AMI while HDL-C and rs4977574 were negatively correlated with risk of AMI.Part II THE RELEVANT STUDY BETWEEN SINGLE NUCLE-OTIDE POLYMERPHISMS AND CLINICAL CHARA-CTERISTICS OF ACUTE MYOCARDIALINFARCTIONBACKGROUND: Acute myocardial infarction(AMI) was a serious disease associated with high mortality. It is the key that early rapid diagnosis and timely thrombolysis or percutaneous coronary intervention(PCI) therapy for treatment of AMI effectively. The companion for the management of ST segment elevation acute myocardial infarction was put forward by European Society of Cardiology in 2012. The companion suggested that the patients should be given thrombolytic therapy in 30 minutes or PCI in 90 minutes for which can significantly reduce the mortality and improve prognosis. Recently, along with the development and application of genome-wide association study(GWAS), the international hapmap project, and high-throughput SNPs classification technology, more and more studies have focused on molecular genetics of AMI and put major concentration in screening of susceptibility genes. However, little was known about the association between susceptive SNPs and clinical features of AMI. It has reported that BRG1 rs1122608, PCSK9 rs11206510, CXCL12 rs1746048, and CDKN2A/2B rs4977574 SNPs were correlated with susceptibility of AMI in European and American populations. However, there were hardly any previous studies pre-sented the direct relationship between these SNPs and susceptibility of AMI in humans. The discovery of the correlation between rs1122608, rs4977574, rs11206510, and rs1746048 SNPs by genotyping and AMI(typical symptoms, early diagnosis, serious complications, and infarction location) may help to develop better early diagnosis and treatment.OBJECTIVE: The present study was undertaken to detect the correlations between BRG1 rs1122608, CDKN2A/2B rs4977574, PCSK9 rs11206510, and CXCL12 rs1746048 SNPs and clinical features of AMI, and to further investigate the association of these SNPs with typical symptoms, early diagnosis, serious complications, and infarction location of AMI.METHODS: Genotyping have been performed in 300 cases of AMI patients formerly and then the 300 cases were regrouped.(1) They were divided into two groups according to typical symptoms: typical symptoms group(n = 78) and atypical symptoms group(n = 222);(2) They were divided into four subgroups according to diagnosis time(DT): DT ≤ 2h group(n = 40), 2h < DT ≤ 6h group(n = 119), 6h < DT ≤ 12 h group(n = 116), and DT > 12 h group(n = 25);(3) They were divided into six subgroups according to infarction location: extensive anterior wall group(n = 141), inferior wall group(n = 97), anteroseptal wall group(n = 18), side wall group(n = 7), right ventricular group(n = 13), and muti-vessel lesion group(n = 24);(4) They were divided into two subgroups according to serious complications: no serious complications group(n = 275) and serious complications group(n = 25). Comparison of the genotypic and allelic frequencies of BRG1 rs1122608, CDKN2A/2B rs4977574, PCSK9 rs11206510, and CXCL12 rs1746048 SNPs were performed among the subgroups. After a Bonferroni correction, p < 0.0125 is considered to have significant differences.RESULTS1. SNPs and the diagnosis time: There were significant differences in the genotypic frequencies of rs1122608 and rs4977574 SNPs among the subgroups(P < 0.001 for each) while no differences in the genotypic and allelic frequencies of rs11206510 and rs1746048 SNPs among the subgroups(P > 0.0125 for each). The frequency of GT genotypes of rs1122608 SNPs was the highest in DT ≤ 2h group(52.50%), higher than those of the others groups(P < 0.001). The frequency of AG genotypes of rs4977574 SNPs was the highest in 2h < DT ≤ 6h(68.91%) higher than those of the others groups(P < 0.001).2. SNPs and serious complications: The frequencies of CT genotypes of CXCL12 rs1746048 SNPs was the highest in serious complications group(68.00%), higher than those of the others groups(P < 0.0125); The frequencies of CT + TT genotype and T allele of CXCL12 rs1746048 SNPs respectively was 72.00% and 38.00% of serious complications group, higher than 42.82% and 21.27% of no serious complications group(P < 0.0125 for each). There were no significant differences in the genotypic and allelic frequencies of DKN2A/2B rs4977574, BRG1rs1122608 and PCSK9 rs11206510 between the two groups(P > 0.0125 for all).3. No significant differences were detected in the genotypic and allelic frequencies of the four SNPs between the two subgroups according to typical symptoms, and among the six subgroups according to infarction location(P > 0.0125 for all).CONCLUSIONS1. The GT + TT genotypes of BRG1 rs1122608 SNP and AG + GG genotypes of CDKN2A/2B rs4977574 SNP were positively correlated with the early diagnosis(DT ≤ 6h) of AMI.2. There was a positive correlation between CT + TT genotype and T allele of CXCL12 rs1746048 SNPs and AMI associated with severe complications.3. There were no evidences to support a correction of BRG1 rs1122608, CDKN2A/2B rs4977574, PCSK9 rs11206510 and CXCL12 rs1746048 SNPs with typical symptoms and infarction location; respectively.Part III GENE-ENVIRONMENT INTERACTION EFFECT ONACUTE MYOCARDIAL INFARCTIONBACKGROUND: It is a complicated process for acute myocardial infarction(AMI) to occur. With the rapid development and widespread application of molecular biology technology and the smooth implementation of human genome project, many diseases were found that modulated by genetic and environmental factors. It is shown that individuals carry disease susceptibility genes may not suffer from illness, but occur until its exposure to certain environment. Therefore, identification of the gene-environment interaction involved in AMI could provide a clue to search for the risk of 22 exposure and thereby new therapeutic or preventive methods for AMI.OBJECTIVE: Our objectives were to identify the polymorphisms of BRG1 rs1122608, CDKN2A/2B rs11206510, PCSK9 rs4977574 and CXCL12 rs1746048 and interactions between those polymorphisms and environmental factors, smoking and alcohol consumption on AMI and provide the help to prevent the onset of AMI.METHODS: Logistic regression was used to assess the interaction between the 4 SNPs of BRG1 rs1122608, CDKN2A/2B rs11206510, PCSK9 rs4977574, CXCL12 rs1746048 and BMI, smoking and alcohol consumption on AMI. After a Bonferroni correction, p < 0.007 is considered to be significant differences.RESULTS1. Interaction between BRG1 rs1122608 and BMI, smoking or alcohol consumption: There were interactions between the subjects with T allele and smoking or alcohol consumption(P < 0.001 for each). The subjects of smoking < 20 cigarettes/day or smoking≥ 20 cigarettes/day and with T allele were 899.4% or 588.5% increase in risk for AMI. The subjects of alcohol consumption < 250 g/day or alcohol consumption ≥ 250 g/day and with T allele were 1166.7% or 3000% increase in risk for AMI. There was no interaction between the subjects with T allele and BMI(P > 0.007). The subjects of alcohol consumption ≥ 250 g/day and with GG genotype was 24545% increase in risk for AMI(P < 0.007). and no interaction among GG genotype and subjects of BMI and smoking in risk for AMI(P > 0.007 for all).2. Interaction between CDKN2A/2B rs4977574 and BMI, smoking or alcohol consumption: There were interaction between the subjects with GG genotype and BMI(P < 0.001). The subjects of BMI ≥ 24 Kg/m2 and with GG genotype was 247.5% increase in risk for AMI. There were interaction between the subjects with three kinds of genotypes and smoking(P < 0.007 for all). The subjects of smoking < 20 cigarettes/day and smoking ≥ 20 cigarettes/day and 23with AA, AG or GG genotypes were 3150% and 3200%, 755.5% and 393.7% or 2717.6 and 2550% increase in risk for AMI. The subjects of alcohol consumption < 250 g/day and alcohol consumption ≥ 250 g/day and with AG or GG genotypes were 914.2% and 2613.3% or 1531.9% and 2785.7% increase in risk for AMI(P < 0.007 for all).3. Interaction between PCSK9 rs11206510 and BMI, smoking or alcohol consumption: There were interactions between the subjects with TT genotype and smoking or alcohol consumption(P < 0.001 for all). The subjects of smoking < 20 cigarettes/day or smoking ≥ 20 cigarettes/day and with TT genotype were 1276.5% or 946.3% increase in risk for AMI. The subjects of alcohol consumption < 250 g/day or alcohol consumption ≥ 250 g/day and with TT genotypes were 962.8% and 1469.2% increase in risk for AMI, but no interaction between the subjects with TT genotype and BMI(P > 0.007). There were no interactions among T allele and subjects of BMI, smoking or alcohol consumption in risk for AMI(P > 0.007 for all).4. Interaction between CXCL12 rs1746048 and BMI, smoking or alcohol consumption: There were interactions between the subjects with CC genotype and smoking or alcohol consumption(P < 0.01 for all). The subjects of smoking < 20 cigarettes/day or smoking ≥ 20 cigarettes/day and with TT genotype were 1076.2% or 840% increase in risk for AMI. The subjects of alcohol consumption < 250 g/day or alcohol consumption ≥ 250 g/day and with TT genotypes were 1421.1% and 2400% increase in risk for AMI, but no interaction between the subjects with CC genotype and BMI(P > 0.07). In addition, there were interactions between the subjects with T allele and smoking or alcohol consumption(P < 0.001 for all). The subjects of smoking < 20 cigarettes/day or smoking ≥ 20 cigarettes/day and with T allele were 1375.7% or 958.9% increase in risk for AMI. The subjects of alcohol consumption < 250 g/day or alcohol consumption ≥ 250 g/day and with T allele were 750% or 1800% increase in risk for AMI, but no interaction between the subjects with T allele and BMI(P > 0.007).CONCLUSIONS1. The interaction between T allele of the BRG1 rs1122608 and smoking or alcohol; rs1122608 CC genotype and alcohol would increase the risk of exposure of AMI.2. The interactions between GG genotype of the CDKN2A/2B rs11206510 and BMI, smoking or alcohol; between AG genotype and smoking or alcohol; between AG genotype and smoking; would up the risk of exposure of AMI.3. The interaction between TT genotype of the PCSK9 rs4977574 and smoking or alcohol would increase the risk of exposure of AMI.4. The interaction between CC genotype and T allele of the CXCL12 rs1746048 and smoking or alcohol would increase the risk of exposure of AMI. |
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