Association Study Of The Single Nucleotide Polymorphisms In 6 Chromosomal Regions With The Susceptibility To Coronary Artery Disease

Background: Coronary artery disease(CAD)is a heart disease characterized by myocardial ischemia or myocardial necrosis caused by coronary artery stenosis or obstruction,also known as ischemic heart disease.As a common chronic disease that seriously endangers global health,CAD has a high morbidity and mortality rate.In China,CAD is the leading cause of death.The pathogenesis of CAD is not yet fully understood.It is currently certain that CAD is a complex polygene genetic disease whose causes include environmental factors,genetic factors,and the interaction between them.In recent years,the global genome-wide association study(GWAS)of cardiovascular disease,especially CAD and other complex diseases,has developed rapidly.A series of related genes or loci of CAD have been found,which pushed human genome research to a new stage.Based on the results of GWAS research related to CAD at home and abroad in recent years,the rs413582,rs693758,rs9349379,rs1004467,rs17115149,rs12413409,rs3519,rs1169310,rs9899364 and rs428253 in the chromosomal regions of the 1,6,10,12,17 and 19 were elected in this study.A case-control study was conducted to investigate the association of loci located in the above chromosomal regions with CAD susceptibility and severity.Part I Association study of the single nucleotide polymorphisms in 6 chromosomal regions with the susceptibility to coronary artery diseaseObjective: To investigate the frequency distribution of rs413582,rs693758,rs9349379,rs1004467,rs17115149,rs12413409,rs3519,rs1169310,rs9899364 and rs428253 single nucleotide polymorphisms(SNPs)and their alleles in the Han population of CAD and the controls in Chongqing in the six chromosomal regions which were reported by GWAS,explore the relationship between gene polymorphism and susceptibility to CAD in these SNPs,so as to provide a new target and basis for early screening and prevention and treatment of high risk population of CAD.Method :(1)A total of 928 patients with CAD criteria were selected as the CAD group in the Chongqing area.928 cases of non-CAD population in the same period were selected as control group(2)The genomic DNA of peripheral blood cells was extracted by Tiangen DP318 DNA centrifugal column kit,rs413582,rs693758,rs9349379,rs1004467,rs17115149,rs12413409,rs3519,rs1169310,rs9899364 and rs428253 genotypes were conducted using the Sequenom Mass Array system.(3)The basic characteristics of the study population and the association between the frequency distribution of genotypes and allele in each group and CAD were analyzed by software SPSS20.0Result:(1)Compared with the TT genotype,the CC genotype of rs413582 could reduce the risk of CAD,early onset CAD and CAD in female(CAD: OR = 0.696,95% CI: 0.496-0.975;early onset CAD: OR = 0.480,95% CI: 0.245-0.942;CAD in female: OR = 0.624,95% CI: 0.395-0.988).The CT genotype of rs413582 was associated with the decreased risk of CAD and CAD in male(CAD: OR = 0.785,95% CI: 0.627-0.982;CAD in male: OR = 0.682,95% CI: 0.493-0.943).The C allele of rs413582 was statistically correlated with the reduced risk of CAD,early onset CAD,old onset CAD,CAD in male and female(p <0.05).(2)The A allele of rs9349379 might decrease the risk of CAD and CAD in female compared to the G allele(CAD: OR = 0.853,95% CI: 0.738-0.986;CAD in female: OR = 0.802,95% CI: 0.652-0.986).(3)The frequency of AG genotype in rs9899364 was statistically different between the CAD group and the control group(p= 0.036).Allelic analysis showed that A allele had protective effect on CAD,old onset CAD and CAD in female(CAD: OR = 0.855,95% CI: 0.750-0.975;old onset CAD: OR = 0.830,95% CI: 0.707-0.974;CAD in female: OR = 0.828,95% CI: 0.689-0.995).(4)Genetic model analysis showed that wild type homozygotes of rs413582(p = 0.014)and rs9899364(p = 0.038)were risk factors for CAD in the dominant model.Conclusion:(1)Rs413582 was related to the susceptibility to CAD.(2)The A allele of s9349379 could reduce the risk of CAD and CAD in female.(3)The AG genotype of rs9899364 had an association with the susceptibility to CAD,and the A allele of rs9899364 had decreased of CAD,old onset CAD and CAD in female.Part II Association study of the single nucleotide polymorphisms in 6 chromosomal regions with the severity of coronary artery diseaseObjective: A total of 400 patients undergone coronary angiography(CAG)were selected from patients diagnosed with CAD.SNPs and CAD severity were analyzed to investigate the effect of gene polymorphism on CAD severity.Method:(1)Among the six hospitals in Chongqing,400 patients who were diagnosed with CAD and had undergone CAG treatment or examination were selected as the case group.Participants who participated in a physical examination in the six hospitals at the same period were selected as the control group.(2)CAG angiography was performed by two or more experienced cardiologists,and the Gensini scores were counted using the Gensini score system.Results:(1)Compared with the TT genotype,the CT genotype of rs413582 could reduce the risk of right coronary artery(RCA)and left anterior descending artery(LAD)lesions(RCA: OR = 0.559,95% CI: 0.362-0.861;LAD: OR = 0.578,95% CI: 0.409-0.819);The risk of LAD disease in AG genotype carriers of rs9349379 was 0.63 times lower than that of GG genotype carriers(OR = 0.630,95% CI: 0.446-0.889);The genotype of rs9899364 was statistically correlated with the reduction of RCA,LAD and left circumflex(LCX)lesions(RCA: OR = 0.550,95% CI: 0.359-0.842;LAD: OR = 0.586,95 % CI: 0.409-0.839;LCX: OR = 0.531,95% CI: 0.327-0.863),and the risk of RCA stenosis was lower in AA genotype with rs9899364 than in GG genotype(OR = 0.350,95% CI: 0.185-0.665).(2)The genotype frequencies of rs413582,rs9349379 and rs9899364 were statistically significant(p = 0.041,0.022 and 0.036,respectively)in the 2-vessel disease(VD)group and the control group.The genotype of rs9899364 was also associated with 1VD(p = 0.023).(3)The G allele frequency of rs9349379 was positively correlated with the Gensini score levels,and the corresponding Gensini score was also increased(ptrend = 0.026)as the frequency increased.Conclusion:(1)Rs413582,rs9349379 and rs9899364 heterozygous genotypes were associated with CAD lesions in Chinese Han population;(2)Rs413582,rs9349379 and rs9899364 gene polymorphisms are associated with 2 vascular lesions in CAD;(3)Allele dosage of rs9349379 may affect the severity of CAD.