| Background:KCNH2potassium channels have an integral role in regulating the excitability of smooth muscle cells. Some pathways driven by angiotensin Ⅱ, nitric oxide and adrenergic receptors blocker are involved in modulating the properties of KCNH2potassium channels,and the mutation Y652A (1956,C>T;2690,A>C) can attenuate the sensitivity of the targeting substances.And these pathways are closely related to blood pressure regulation. While,TRIB3is a pseudokinase binding to and inhibiting Akt activation that signaling by insulin. The studies show that TRIB3could be a potential regulator in blood presure contral, and mRNA levels of TRIB3were conspicuously increased by valsartan exposure or by TRIB3(251,A>G) mutation. RGS2is GTP-ase targeting to Gaq-protein-coupled receptor, a key modulator in BP regulating progress; RGS2(-395, G>C) mutation result in increased RGS2mRNA expression. These studies suggest that KCNH2IRIB3and RGS2genetic polymorphisms may have an influence on antihypertensive drug therapy. Thus, our study aimed to confirm that the polymorphisms affect the BP response to antihypertensive drug therapy in Chinese population with essential hypertension.Methods:To evaluate the interactions between KCNH2genetic polymorphisms and individual blood pressure response to antihypertensive drugs,386subjects with essential hypertension (EH) were studied. Genotype for the gene was determined by PCR-RFLP. Heart rate and BP were measured every two weeks for the duration of antihypertensive therapy. In evaluating the interactions between KCNH2genetic polymorphisms and drug response to blood pressure, multivariable ANOVA analysis and stratification analysis followed by Bonferroni correction were performed.Results:1. There were statistically significant interactions between KCNH2(1956, C>T) polymorphism and DBP change (P=0.010), MAP change (P=0.014) on azelnidipine or nitrendipine therapy patients at the end of6weeks. We found that the KCNH2(1956,C>T) polymorphism was associated with the hypotensive effects of a,(3-ADR blockers of DBP change at the end of4and6weeks’ treatment in an age-and gender-dependent manner (P=0.007and0.019, respectively). Similar results were also observed for changes in MAP at the end of4and6weeks (P-values were0.035and0.078, respectively). While patients who received imidapril, candesartan and irbesartan therapy, no significant difference in drug response among KCNH2(1956,C>T) genotype was observed.2. The DBP and MAP change from baseline between TRIB3(251, A>G) AA and AG/GG genotype carriers have significant difference after imidapril medication at the end of6weeks(P=0.016and0.030,respectively). While, this genotype difference to azelnidipine and nitrendipine treatment groups also have profound influence on DBP (P=0.048)change from baseline at the end of2weeks, MAP(P=0.007) and DBP (P=0.034) changes from baseline at the end of4weeks. Stratified Analysis found that TRIB3(251, A>G) genetic polymorphism is genotype-age(Age≤50y v.s Age>50y) dependent related to heart rate and SBP change after α,β-ADR blocker treatment at the end of4weeks(interaction P-value were0.003and0.019,respectively).3. Between RGS2(-395,C>G) CC and CG/GG genotype carriers group, a significant in SBP(p=0.008) change at the end of2weeks, pulse pressure(0.006) and MAP(0.022) change were observed after patients on candesartan or irbesartan therapy. In addition, a significant difference also be observed, which were RGS2(-395,C>G) genotype-age(Age<55y v.s Age>55y) specific associated with HR,SBP and MAP changes with α,β-ADR blocker treatment at the end of4weeks(interaction P-value were0.004,0.008and0.012,respectively).Conclusion:We have reported for the first time that KCNH2(1956, C>T),TRIB3(251,A>G) and RGS2(-395,C>T) polymorphisms are associated with the responsiveness of antihypertensive drugs therapy, and may serve as a useful biomarker for individualized therapy for certain antihypertensive drugs. |
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