Background:Individual variability in the therapeutic response to an antihypertensive drug could have agenetic basis.We investigated whether the αlA-adrenergic receptor(alA-AR) Arg347 Cys,angiotensin II type 1 receptor(AT1 R),potassium inwardly rectifying channel,subfamily J,member 11(KCNJ11) I337 V,and kininogen(KNG1) Ilel97 Met gene polymorphisms are associated with the blood pressure(BP) therapeutic response to irbesartan and whether the association couldbe altered by the plasma irbesartan level.Methods:A total of 1049 hypertensive subjects were treated with a daily oral dose of 150 mg irbesartan.Baseline BP was measured before the first dose.On the 28 th day,after 27 consecutive days of treatment andan overnight fast,BPs and blood samples were obtained before the morning dose(0 hours) and 6 hours after the morning dose was taken.Plasma irbesartan concentrations were measured by use of HPLC-fluorescence.All gene polymorphisms were determined using high-throughput TaqMan technology.Results:1) Relative to noncarriers,alA-AR Cys347 allelic carriers had a significantly greater diastolic blood pressure(DBP) response at 0 hours(7.5±8.4 mm Hg versus 5.5±8.4 mm Hg;P=0.016) and at 6 hours(16.2±9.1 mm Hg versus 14.2±8.9 mm Hg,P=0.025).When subjects were stratified into subgroups with high or low plasma irbesartan concentrations,Cys347 allelic carriers in the high-concentration group,relative to noncarriers,had a more pronounced DBP response at 0 hours(adjusted[p±SE],3.0±1.0 mm Hg;P=0.004) and at 6 hours(3.0±1.2 mm Hg;P=0.014),and the same was true for the SBP response at 0 hours(5.6±2.1 mm Hg;P=0.006) and at 6 hours(4.7±2.0 mm Hg;P=0.021).In contrast,in the low-concentration group,there was no significant association between DBP or SBP responses and Arg347 Cys genotypes at 0 hours and 6 hours.2) When stratified by genotypes,patients carrying allele C of AT1 R rs5186 showed positive association between irbesartan concentration and BP response[SBP:p±SE=6.1±2.3 with false discovery rate(FDR) P=0.029;DBP:β±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 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 rs2640539,rsl492097,rs388915,and rs5186 four genotyped SNPs) on SBP response(FDR P< 0.001),but not on DBP response.3) In nonsmokers,relative to the GG genotype,subjects with the KCNJ11 homozygous AA genotype had a significantly higher therapeutic response to irbesartan(adjusted β±SE:4.7 ±1.9 mm Hg,P = 0.015).In smokers,the subjects with the homozygous AA genotype had a significantly lower therapeutic response to irbesartan(adjusted p± SE:-5.6 ± 2.5 mm Hg,P = 0.026).A multivariate linear regression model confirmed that there was a significant interactive effect between the KCNJ11 gene and smoking on irbesartan treatment(interaction P = 0.001).4) A further test for a multiplicative interaction between the KNG1 Ile197 Met polymorphism and gender in association with ln-plasma irbesartan concentrations in a multiple linear regression model was also significant(P for interaction =0.033).Conclusion:Our data suggest that the α1 A-AR,AT1 R gene polymorphisms and plasma concentration of irbesartan can act interactively to modulate individual response to irbesartan antihypertensive therapy.The interactive effect of the KCNJ111337 V,KNG1 Ilel97 Met genotypes and environmental factors may also influence the antihypertensive effects of irbesartan,which indicates a consideration for future individualized antihypertensive drug treatment by precision medicine.