To identify genes influencing blood pressure response to an angiotensin II receptor blocker, single nucleotide polymorphisms recognized by genome-wide association analysis of the response to candesartan were validated by reverse direction associations with the response to a thiazide diuretic, hydrochlorothiazide. AA genotype, the mean systolic BP/diastolic BP reactions to hydrochlorothiazide were 4.7/6.3 mmHg less for the GG than for the AA genotype (Number 2). While statistical significance of the opposite direction association with BP response to hydrochlorothiazide was maximal at rs7933335 in (1-sided markedly reduced statistical significance of the association of rs3758785 in with BP response to candesartan (2-sided rs3758785 genotype dependence of the odds ratios for good BP response and the imply systolic and diastolic blood pressure declines in response to each drug. Number 3 Chromosome 11q21 storyline of ideals for association of solitary nucleotide polymorphisms with blood pressure response to candesartan in White colored Americans. Table 3 Lead solitary nucleotide polymorphisms associated with good versus poor blood pressure response to candesartan and reverse direction association with blood pressure response to hydrochlorothiazide in White colored Americans Additional SNPs in the chromosome 11q21 region recognized in Whites also validated for same direction associations with BP response to candesartan in the African American sample (1-sided (rs3758786 and rs3758789); one was near (rs12270338); and two near (rs16924603 and rs16912567), of which rs16924603 was most significantly connected (1-sided region but not with SNPs in (please observe http://hyper.aha.journals.org, Number S4). Other lead SNPs found out and validated in Whites included rs11649420 in the gene encoding the -subunit (the odds of good BP response to hydrochlorothiazide was two-fold less than for the combined AA+AG group (please observe http://hyper.aha.journals.org, Number S5). The mean modified systolic BP/diastolic BP reactions to candesartan were 7.0/5.5 mmHg higher for the GG than for the AA+AG group, the imply systolic BP/diastolic BP responses to hydrochlorothiazide were 4.5/2.5 mmHg Ifosfamide IC50 less for the GG than for the AA genotype. Conversation We sought to identify SNPs associated with directionally reverse BP reactions to candesartan and hydrochlorothiazide because of their higher potential power in personalizing antihypertensive drug therapy than SNPs that only forecast response to a single drug or the same response to medicines from multiple classes. Pursuit of this objective was also motivated by Ifosfamide IC50 the knowledge that founded predictors of antihypertensive drug reactions have Ifosfamide IC50 directionally reverse associations with BP reactions to diuretics and inhibitors of the renin-angiotensin system.10, 11 These inverse relationships reflect the complementary effects of angiotensin-mediated arterial constriction and intra-arterial volume to keep up BP, which reciprocally oppose declines in BP when either system is inhibited.5 Accordingly, we hypothesized that alternative alleles of SNPs associated with BP response to candesartan may have directionally opposite associations with BP response to hydrochlorothiazide. Our analytical approach was also guided by the opposite direction associations of known predictors with BP reactions to candesartan and hydrochlorothiazide.6, 7 Since none of the large number of SNPs tested for associations with BP response to candesartan accomplished the cause Liddles syndrome, a rare familial form of low-renin, sodium-volume dependent hypertension that responds to diuretic therapy with amiloride.15 In contrast, treatment of low-renin, sodium-volume dependent Mouse monoclonal to BNP hypertension with inhibitors of the renin-angiotensin system has been associated with opposite-direction pressor responses.16 We have previously reported that SNPs (rs5723 and rs5729) in strong linkage disequilibrium with the lead SNP, rs11649420 (SNPs were among those most strongly associated with BP response to candesartan had reverse direction associations with BP response to hydrochlorothiazide is consistent with the counterregulatory effect of renal sodium reabsorption to keep up intra-arterial volume and oppose the decrease in Ifosfamide IC50 BP following inhibition of the renin-angiotensin system with candesartan.18 Only three previous studies possess reported polymorphisms in candidate genes to forecast BP responses to ARBs.19C21 In the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial, 49 adults with stage ICII hypertension were treated with the irbesartan for three months and 74 SNPs were genotyped in 25 genes encoding regulators of volume, vasoconstriction, and drug rate of metabolism.22 The SNPs found to be associated with BP response were in the genes encoding aldosterone synthase20, 23 (polymorphism (?344 C/T) with BP response to candesartan20 and the same polymorphism (*1/*2/*3) with BP response to losartan.21 However, the alleles associated with higher BP.