Chromosome 9p21 And Abca1 Gene Polymorphisms And Ischemic Cardiovascular And Cerebrovascular Disease Relationship

Part â…  ASSOCIATION OF9p21GENETIC POLYMORPHISMS AND CORONARY HEART DISEASE AND ISCHEMIC STROKE[Background] Coronary heart disease and ischemic stroke are two complex disorders with strong genetic background. Previous genome-wide association studies indicated that a particular region in chromosomes9showed evidence of linkage with coronary heart disease and ischemic stroke, but the associations need to be confirmed by replication studies in different ethnic groups.[Objective] The aim of the present paper was to explore the susceptibility functional variants of coronary heart disease and ischemic stroke in this region by genotyping of several single nucleotide polymorphisms (SNPs) in case-control DNA samples. This study also detected the gene-environment interaction between SNPs in9p21and traditional risk factors of coronary heart disease and ischemic stroke.[Method] Three SNPs of rs1333040, rs1333042and rs4977574were selected from public SNP data by haploview4.2. Genotyping of the SNPs were performed in1675subjects of Han nationality including565patients with coronary artery disease,569patients with ischemic stroke and541normal controls.[Results] The genotype distribution of rs1333040, rs4977574and rs1333042in patients with coronary heart disease and control group was significant difference (P=0.035,0.006and0.021; respectively). The significance remained for rs4977574after the Bonferroni correction (P=0.018).All of the three SNPs showed a significant association with coronary heart disease susceptibility in different genetic models after adjusted traditional risk factors, coronary heart disease risk was significantly associated with rs1333040under dominant genetic model (OR=1.79,95%CI=1.12-2.88) and codominant genetic model (TT vs. CC:OR=1.84,95%CI=1.13-3.01); in analysis of rs4977574and coronary heart disease, OR was1.27(95%CI=1.06-1.53) under additive genetic model and1.52(95%CI=1.11-2.07) under dominant genetic model; OR was1.64(95%CI=1.14-2.37) when GG vs. AA and1.44(95%CI=1.04-2.02) when AG vs. AA under codominant genetic model, in single SNP analysis of rs1333042, OR was1.27(95%CI=1.04-1.56) under additive genetic model; OR was1.83(95%CI=1.16-2.89) under dominant genetic model; rs1333042G allele was also associated with higher susceptibility to cornary artery disease under codomiant genetic model (GG vs. AA:OR=1.92,95%CI=1.20-3.08; AG vs. AA:OR=1.73,95%CI=1.06-2.80). Further stratified analysis revealed that, compared with the AA widetype homozygous, the risk effects of the rs1333042and rs4977574were more evident in males, age older than60year, BMI more than24, non-smokers and non-hypertension subgroups. The SNP rs4977574showed weakly significant interaction with age (P=0.022).The genotype distribution of rs4977574in patients with ischemic stroke and the control group showed significant difference (P=0.015), and the significance remained after the Bonferroni correction (P=0.045). Ischemic stroke risk was also significantly associated with rs4977574SNP, OR was1.27(95%CI=1.06-1.52) under additive genetic model,1.51(95%CI=1.12-2.03) under dominant genetic model, under codominant model, OR was1.63(95%CI=1.14-2.33) when GG vs. AA and1.44(95%CI=1.05-1.98) when AG vs. AA.In stratified analysis, the risk association with the GG genotype was stronger in the individuals who were males, over60years old, BMI more than24and not smoking. But there was no significant interaction between rs4977574and these risk factors.[Conclusion] The SNPs of rs1333040, rs1333042and rs4977574on chromosome9p21are significantly associated with coronary heart disease in the Guangxi Han population, but only SNP rs4977574is associated with ischemic stroke. Part â…¡ ASSOCIATION OF ABCA1GENETIC POLYMORPHISMS AND CORONARY HEART DISEASE AND ISCHEMIC STROKE[Background] ATP-binding cassette transporter Al (ABCA1) plays a key role in high density lipoprotein (HDL) forming and the regulation of lipid levels in serum. It may contribute to atherosclerosis, coronary heart disease and ischemic stroke. But the evidence is reluctant in different ethnic groups.[Objective] To investigate the distribution of rs2066715SNP in the exon17and rs2740483SNP in the promoter region of ATP binding cassette transporter (ABCA1) gene in the Guangxi Han population and the association with serum lipid levels, further investigate the possible association with coronary heart disease and ischemic stroke.[Method] Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method was used to determine the genotypes of the two SNPs in the ABCA1gene among646healthy Han population recruited randomly. The frequencies of diverse genotypes and their association with serum lipid levels were evaluated by ANOVA and then followed multiple Linear Logistic regression. The two SNPs were further evaluated in565patients with coronary heart disease,569patients with ischemic stroke and541control subjects as described in Part â… [Results] The prevalence of the ABCA1alleles and genotypes in these groups were in Hardy-Weinberg equilibrium law. The A allele carriers of rs2066715had lower serum HDL-C levels compared with the A allele non-carriers (P=0.023and0.029; respectively). In case-control study, similar finding was obtained in the control group (P=0.002and P=0.004), but only the rs2740483SNP showed protective effect on coronary heart disease (P=0.034). OR was0.43(95%CI=0.22-0.83) when CC vs. GG under codominant genetic model and OR=0.46(95%CI=0.24-0.89) under recessive genetic model.Ischemic stroke risk was also significantly associated with rs2740483SNP. The statistical significance was found in all the genetic models, especially under codominant genetic model, dominant model and recessive model.In stratified analysis, the protective association of the GC/CC genotype was strong in individuals who were BMI more than24in the two case-control studies, but only weak interaction between rs2740483and BMI was found in predicting ischemic stroke risk.[Conclusion] The SNP of ABCA1rs2740483is significantly associated with coronary heart disease and ischemic stroke in the Guangxi Han population, but only SNP of rs2066715is weakly associated with serum lipid profiles in healthy subjects.Part â…¢ GENE-GENE INTERACTIONS BETWEEN9p21AND ABCA1AND CORONARY HEART DISEASE AND ISCHEMIC STROKE [Background] In Part â…  and Part â…¡, we found several SNPs in9p21and ABCA1may contribute to susceptibility of coronary heart disease and ischemic stroke. But it is not known whether there are interactions between these SNPs to influence coronary heart disease and ischemic stroke.[Objective] The aim of this study was to search for possible gene-gene interactions among the SNPs studied in Part â…  and Part â…¡ in predicting coronary heart disease and ischemic stroke.[Method] The gene-gene interaction was evaluated by multifactor dimensionality reduction analysis, Then the best models were replicated in Logistic regression models.[Results] The MDR gene-gene interaction analysis indicated that two SNPs of rs1333040and rs1333042were the best interaction model for predicting risk of coronary heart disease and ischemic stroke, and four SNPs of rs1333040, rs1333042, rs2066715and rs2740483were the best model for predicting risk of coronary heart disease. Logistic regression analysis can successfully replicate the possible association.[Conclusion] These results suggest that gene-gene interaction of9p21may play a role in the etiology of coronary heart disease and ischemic stroke.