| Objective: To study the polymorphism of CYP3A4&5?POR?PXR?and CACNA1C&D on efficacy of amlodipine in the treatment of mild and moderate essential hypertension in Han Population of Northeast Sichuan.Methods: The study was performed on the people in Han Population of Northeast Sichuan,who were diagnosed mild and moderate essential hypertension according to the ?2010 China Hypertension Prevention And Treatment Guidelines?.Efficacy evaluations according to the?Cardiovascular drug Clinical Research Guidelines?.A newly-developed technology named improved Multiplex Ligation Detection Reaction,iMLDR,which used to detect target genes and SNPs.SPSS19.0 ? Haploview ? SHEsis and MDR(Multifactor Dimensionality Reduction)were used to analysis results.Results: 1.The efficient of amlodipine was70.1%,the cases for significant efficient was 32(22.2%),efficient was69(57.9%)and inefficient was 43(29.9%).The side-effects morbidity rate: Ankle Edema(2.78%),Dizziness(0.69%),Facial Blushing(2.08%),Cardiopalmus(3.47%).2.After adjustment of confounding factors including age?gender?BMI? smoking?drinking?BUN?UA?LDL?DM?CHD and so on,we found that the Genotype of CYP3A5*3 6986A>G AA vs.(GA+GG)was associated with SBP reduction(10.80±10.19 mmHg,22.74±15.31 mmHg,B=-10.093,P=0.015,respectively),and there was no significant relation with DBP reduction(6.27±8.03 mmHg,8.53±9.99 mmHg,P=0.715).CYP3A4 82266C>T,PXRSNPs 44477T>C?63396C>T?7635A>G?69789A>G and 24381G>T have no significant relation with BP reduction(P>0.05),POR A503V(rs1057868),CACNA1 C rs1051375G>A and CACNA1 D rs312481G>A?rs3774426C>T have no significant relation with BP reduction(P>0.05)?3.By SHEsis we discovered haplotypes C-T-T-G-A and T-G-T-A-A,which were both being found in PXR SNPS(44477T>C?63396C>T?69789A>G?7635A>G?24381G>T).Haplotype C-T-T-G-A in ?SBP control group was significant below than the case group(OR=2.894,95%CI=1.266-6.617,P<0.05);Haplotype T-G-T-A-A in ?DBP control group was significant higher the case group(OR=0.415,95%CI=0.172-0.998,P<0.05).4.PXR SNPs 44477T>Cand 24381 G>T are in complete linkage disequilibrium(D?=1,r2=1),the frequency of PXR 44477C/24381 T was 24.7%?5.By MDR we discovered between CYP3A4 82266C>T;CYP3A5 6986A>G;POR A503V;PXR 44477T>C ? 63396C>T ? 69789A>G ?7635A>G ? 24381G>T;CACNA1C rs1051375G>A;CACNA1D rs312481G>A?rs3774426C>T didn't have interaction(P>0.05),and between CYP3A4 82266C>T;CYP3A5 6986A>G;POR A503V;PXR 44477T>C?63396C>T?69789A>G?7635A>G?24381G>T;CACNA1C rs1051375G>A;CACNA1D rs312481G>A?rs3774426C>T and gender?BMI?family history?diabetes?smoking?drinking?cholesterol?triglyceride?LDL didn't have interaction(P>0.05)?Conclusion: 1.The efficient of amlodipine was70.1%.The side-effects morbidity rate was 9.03%.2.CYP3A5*3 6986A>G is associated with efficacy of amlodipine,AA genotype carriers with a significant higher SBP reduction than GA+GG genotype carriers.3.Patients with the haplotype T-G-T-A-A of PXR will be hypo-reponsiveness to amlodipine;while with the haplotype C-T-T-G-A of PXR have a significant efficacy on amlodipine.4.PXR SNPs 44477T>C(rs1523130)and 24381 G>T(rs1523127)are in complete linkage disequilibrium(D?=1,r2=1),the frequency of PXR 44477C/24381 T was 75.3%?5.CYP3A4 82266C>T,PXR SNPs 44477T>C?63396C>T?7635A>G?69789A>G and 24381G>T have on efficacy of amlodipine,POR A503 V,CACNA1C rs1051375G>A and CACNA1 D rs312481G>A?rs3774426C>T have no efficacy of amlodipine. |
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