Interactive effect of angiotensin II type 1 receptor (AGT1R) polymorphisms and plasma irbesartan concentration on antihypertensive therapeutic responses to irbesartan.

摘要

BACKGROUND: To investigate the interactive effect of plasma irbesartan concentration and angiotensin II type 1 receptor (AGT1R) gene polymorphisms on blood pressure (BP) response to irbesartan treatment. METHODS: This study included 1049 Chinese hypertensive patients who were treated with daily oral 150 mg irbesartan for 4 weeks. BP at predose and 28th day of treatment and trough plasma irbesartan concentration (on 28th day of treatment) were measured. Four AGT1R gene polymorphisms (rs2640539, rs1492097, rs388915, rs5186) were genotyped. Multiple linear regression models were used to assess interactive effect of plasma irbesartan concentration and gene polymorphisms on BP response, with adjustment for covariates. RESULTS: When stratified by genotypes, patients carrying allele C of single-neucleotide polymorphism (SNP) rs5186 showed positive association between irbesartan concentration and BP response [SBP: beta +/- SE=6.1 +/- 2.3 with false discovery rate (FDR) P=0.029; DBP: beta +/- SE=2.7 +/- 1.0 with FDR P=0.029], but this was not seen in patients with AA genotype. There was a significant interaction between plasma irbesartan concentration and SNP rs5186 on SBP response (interaction P=0.0335) and DBP response (interaction P=0.0190). There also were significant interactions between plasma irbesartan concentration and hap3, hap5 and hap6 (constructed by four genotyped SNPs) on SBP response (FDR P<0.001), but not on DBP response. CONCLUSION: Our data suggest that AGT1R gene polymorphisms and plasma concentration of irbesartan can act interactively to modulate individual response to antihypertensive therapy using irbesartan.