Association Study Between Polymorphisms Of Clopidogrel Metabolism Related Genes And Clopidogrel Resistance In Chinese Population

Objective: We studied the correlation between clopidogrel resistance of Chinese population and gene polymorphism to increase gene data related to clopidogrel resistance in Chinese population and discover new SNP associated with clopidogrel resistance,providing more theoretical basis for individualized drug use of clopidogrel and accurate treatment for patients with coronary heart disease.Methods: 331 cases of clopidogrel resistance and 437 controls without the occurrence of clopidogrel resistance whose age and gender matched were using to conduct this case-control study.We collected the clinical information and whole blood sample to extract genomic DNA.30 function SNPs or susceptibility SNPs of ABCB1,CYP2C19,CYP3A4,PON1,CES1,CES2,ITGB3 gene was selected.These SNPs was detected using Sequenom Mass Array genotyping technology for each research object.SPSS22.0,HaploView,SHEsis and MDR software were used in correlation analysis,hierarchical analysis,haplotype analysis,regression analysis and interaction analysis of clopidogrel resistance.Results: Distribution of ABCB1 gene rs1045642 AA genotype(p=0.001,OR=2.023,95%CI=1.321-3.09)and A allele(p=0.002,OR=1.395,95%CI=1.133-1.719),PON1 gene rs662 TT genotype(p=0.002,OR=2.133,95%CI=1.309-3.476)and T allele(p=0.002,OR=1.407,95%CI=1.136-1.743),CES2 gene rs8192925 GA genotype(p=0.006,OR=1.549,95%CI=1.131-2.121),ITGB3 gene rs7208055 CA+AA genotype(p=0.009,OR=0.661,95%CI=0.485-0.900)and A allele(p=0.005,OR=0.678,95%CI=,0.517-0.891)and rs5919 CC genotype(p=0.005,OR=2.740,95%CI=1.328-5.650)has a statistically significant difference between the two groups.Stratified analysis showed that rs2317676 GG genotype in the population over the age of 60(p=0.005)and female(p=0.003),BMI?24kg/m2(p=0.003)group has statistical difference between control group and CR group,rs757158 CC genotype in people with abnormal platelet(p=0.013)has statistical difference between control group and CR group,rs854572 CG genotype of normal human platelet(p=0.009)and GG genotype in women with abnormal platelet(p=0.006)have significant difference between control group and CR group.A C haplotype of rs1045642,rs2032582 in ABCB1 gene(p=0.005,OR=1.836,95%CI=1.200-2.808),A G haplotype(p=0.045,OR=1.621,95%CI=1.007-2.610),G A haplotypes(p=0.038,OR=1.266,95%CI=,1.013-1.583)and G G haplotype(p=0.004,OR=0.728,95%CI=0.587-0.902)of rs4986893,rs4244285 in CYP2C19 gene,A G A G haplotype(p=0.006,OR=0.315,95%CI=0.133-0.746),A G C C haplotype(p=0.004,OR=1.476,95%CI=1.129-1.929)of rs2317385,rs3809861,rs55827077,rs7208055 in ITGB3 gene,C G haplotype of(p=0.019,OR=1.356,95%CI=1.050-1.751)rs5919,rs15908,A G haplotype(p=0.002,OR=1.583,95%CI=1.184-2.116)of rs4642,rs2317676 between the control group and CR group have significant difference.The rs1045642,rs662,rs8192925,rs4986893 and rs4244285 are the risk factors of CR in Logistic regression analysis.MDR analysis showed that rs1045642,rs4244285,rs662 and rs8192925 have interaction(p=0.011-0.012).Conclusion: The rs1045642 in ABCB1 gene,rs662 and rs854572 in PON1 gene,rs8192925 in CES2 gene,rs7208055,rs5919 and rs2317676 in ITGB3 gene have significant correlation with clopidogrel resistance.Haplotypes of rs1045642-rs2032582 A C,rs4986893-rs4244285 G A,G A,G G,rs2317385-rs3809861-rs7208055-rs55827077 A G A G,A G C C,rs5919-rs15908 C G,rs4642-rs2317676 G A have a significant correlation with clopidogrel resistance,rs1045642,rs662,rs8192925,rs4986893 and rs4244285 are risk factors for CR,rs1045642,rs4244285,rs662,rs8192925 have interaction.