Effects Of CACNA1C Polymorphisms And BMI On The Efficacy Of Low-dose Amlodipine In The Treatment Of Essential Hypertension

BackgroundL-type calcium channel blockers (CCBs), amlodipine, are widely used to treat hypertension. A number of trials including CHIEF and VALUE, have demonstrated that amlodipine effectively lower blood pressure at the rate of62-78%, but one third of patients have not achieved the control of blood pressure. Recent studies indicate that the role of genetic differences between individuals appears to be a key factor to explain the variable drug efficacy. Recent studies showed that single nucleotide polymorphisms (SNPs) of L-type calcium channel alpha subunit1C gene (CACNA1C) might be associated with efficacy of dihydropyridine(DHP) CCBs(dCCBs). The interaction between gene polymorphism and environmental factors may contribute to the patient’s variable response to antihypertensive drugs. Epidemiological data and studies show that BMI is associated with blood pressure level of individuals, and it might be associated with sensitivity to the antihypertensive effects dCCBs.ObjectiveTo study the effects of single nucleotide polymorphisms (SNPs) of L-type calcium channel alpha subunit1C gene (CACNA1C) and SNP-by-BMI interaction on efficacy of low-dose amlodipine in the treatment of hypertension.MethodsA pharmacogenetic analysis was performed on181Chinese subjects with essential hypertension who were treated with low-dose amlodipine based antihypertensive drugs. Subjects were obtained from the Chinese Hypertension Intervention Efficacy study (CHIEF) and another amlodipine involved ambulatory blood pressure assessing trial. Seven SNPs (rs1051375, rs2238032, rs7311382, rs2239050, rs2239127, rs2239128, rs2239129) in CACNA1C were chosen for genotypic analysis using direct sequencing method. Multiple linear regression was used to perform association analysis between genetic polymorphisms and efficacy of amlodipine. And ordinal logistic regression was used to perform analysis of SNP-by-BMI interactions, as well as genotype-by-genotype interactions. ResultsAfter adjustments of the influence of confounding factors including basic blood pressure, age, gender, smoking, uric acid, triglyceride and drug, both BMI and genotypes of rs2238032(GG vs. GT+TT) were associated with systolic BP reduction after treatments(4.0±11.6mmHg vs.19.9q14.1mmHg, B=-0.622, P=0.041; B=-11.186, P=0.049, respectively), individuals with normal BMI had a higher SBP reduction than individuals with abnormal BMI, and rs2238032(GG vs. GT+TT) also was related to diastolic BP reduction(1.2±4.5mmHg vs.10.0±8.9mmHg, B=-12.276, P=0.001). SNPs rs2239050, rs7311382, rs2239127, rs2239128, rs2239129, rs1051375showed a difference in BP reduction over genotypes respectively(P>0.05). Multi-factor analysis of variance showed a significant interaction effect between BMI and genotype of rs2238032on efficacy of amlodipine(P=0.043). The carriers of the genotype TT with a normal BMI<25kg/m2)and the carriers of allele G with a abnormal BMI(≥25kg/m2) had a better treatment response(SBP) to amlodipine. And ordinal logistic regression showed a similar trend in interaction effects between BMI and genotype GT of rs2238032on efficacy of amlodipine (B=0.212, P=0.066), the carriers of the genotype GT who had a higher BMI seams to receive a better drug response (SBP).ConclusionSNPs rs2238032in CACNA1C and BMI are associated with efficacy of amodipine in the treatment of essential hypertension. BMI and polymorphisms of rs2238032T>G may have an interaction effect on efficacy (systolic BP reduction after treatments) of amodipine. Our data provide new evidence to phramacogenomics of dCCBs in Chinese patients, and might provide practical guidance in the clinic for selecting a CCB for treatment of hypertension. It is valuable for verification of the association of these polymorphisms with the effects of amlodipine in a larger sample of Chinese patients with hypertention.