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Pharmacogenomics of hypertension: a genome?wide, placebo?controlled cross?over study, using four classes of antihypertensive drugs.

ABSTRACT: BACKGROUND:Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment. METHODS AND RESULTS:We conducted a genome-wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study is a double-blind, placebo-controlled cross-over study where each subject received amlodipine, bisoprolol,hydrochlorothiazide, and losartan, each as a monotherapy, in a randomized order. Replication analyses were performed in 4 studies with patients of European ancestry (PEAR Study, N=386; GERA I and II Studies, N=196 and N=198; SOPHIA Study, N=372). We identified 3 single-nucleotide polymorphisms within the ACY3 gene that showed associations with bisoprolol response reaching genome-wide significance (P<5x10(-8))however, this could not be replicated in the PEAR Study using atenolol. In addition, 39 single-nucleotide polymorphisms showed P values of 10(-5) to 10(-7). The 20 top-associated single-nucleotide polymorphisms were different for each antihypertensive drug. None of these top single-nucleotide polymorphisms co-localized with the panel of >40 genes identified in genome-wide association studies of hypertension. Replication analyses of GENRES results provided suggestive evidence for a missense variant (rs3814995) in the NPHS1 (nephrin) gene influencing losartan response, and for 2 variants influencing hydrochlorothiazide response, located within or close to the ALDH1A3 (rs3825926) and CLIC5 (rs321329) genes. CONCLUSIONS:These data provide some evidence for a link between biology of the glomerular protein nephrin and antihypertensive action of angiotensin receptor antagonists and encourage additional studies on aldehyde dehydrogenase–mediated reactions in antihypertensive drug action.

SUBMITTER: Hiltunen TP

PROVIDER: S-EPMC4330076 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Pharmacogenomics of hypertension: a genome‐wide, placebo‐controlled cross‐over study, using four classes of antihypertensive drugs.

Hiltunen Timo P TP Donner Kati M KM Sarin Antti-Pekka AP Saarela Janna J Ripatti Samuli S Chapman Arlene B AB Gums John G JG Gong Yan Y Cooper-DeHoff Rhonda M RM Frau Francesca F Glorioso Valeria V Zaninello Roberta R Salvi Erika E Glorioso Nicola N Boerwinkle Eric E Turner Stephen T ST Johnson Julie A JA Kontula Kimmo K KK

Journal of the American Heart Association 20150126 1

<h4>Background</h4>Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment.<h4>Methods and results</h4>We conducted a genome-wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study is a double-blind, placebo-controlled cross-over study where each subject received amlod ...[more]

PMID: 25622599

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Project description:BackgroundMedication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs.MethodsBalanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t½) (primary outcome), maximum concentration (Cmax), Cmax first time (Tmax), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or to Tmax of overt drug (AUCOverttmax), and Cmax/AUCI were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range.ResultsFifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUCT, AUCI, Cmax, AUCOverttmax, and Cmax/AUCI were within the bioequivalence range, except for ibuprofen Cmax (76.66-98.99), ibuprofen Cmax/AUCI (77.19-98.39), and ibuprofen (45.32-91.62) and paracetamol (51.45-98.96) AUCOverttmax. Out of the 126 individual covert/overt ratios, 2.0-16.7% were outside the +25% range for AUCT, 2.0-4.2% for AUCI, 25.0-44.9% for Cmax, 67.3-76.7% for AUCOverttmax, and 45.8-71.4% for Tmax.ConclusionsThis study couldn't confirm that awareness of drug ingestion modulates its bioavailability. However, it demonstrates the trivial effect of blinding in bioequivalence studies and the extent of bio-variability that would be expected when comparing a drug product to itself.Trial registrationClinicalTrials.gov identifier: NCT01501747 (registered Dec 26, 2011).

Project description:We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10-8 ). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10-4 , Beta = 3.09, diastolic BP response P = 5 × 10-3 , Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients' subgroup (P = 2.35 × 10-4 , odds ratio = 1.57, 95% confidence interval = 1.23-1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.

Project description:UnlabelledTreatment of hypertension in hemodialysis (HD) patients is characterised by lack of evidence for both the blood pressure (BP) target goal and the recommended drug class to use. Telmisartan, an Angiotensin receptor blocker (ARB) that is metabolised in the liver and not excreted via HD extracorporeal circuit might be particularly suitable for HD patients. We designed and conducted a randomised, placebo-controlled, double-blind and cross-over trial for treatment of dialysis-associated hypertension with telmisartan 80 mg once daily or placebo on top of standard antihypertensive treatment excluding other Renin-Angiotensin-System (RAS) blockers. In 29 patients after randomization we analysed BP after a treatment period of 8 weeks, while 13 started with telmisartan and 16 with placebo; after 8 weeks 11 continued with telmisartan and 12 with placebo after cross-over, respectively. Patients exhibited a significant reduction of systolic pre-HD BP from 141.9±21.8 before to 131.3±17.3 mmHg after the first treatment period with telmisartan or placebo. However, no average significant influence of telmisartan was observed compared to placebo. The latter may be due to a large inter-individual variability of BP responses reaching from a 40 mmHg decrease under placebo to 40 mmHg increase under telmisartan. Antihypertensive co-medication was changed for clinical reasons in 7 out of 21 patients with no significant difference between telmisartan and placebo groups. Our starting hypothesis, that telmisartan on top of standard therapy lowers systolic office BP in HD patients could not be confirmed. In conclusion, this small trial indicates that testing antihypertensive drug efficacy in HD patients is challenging due to complicated standardization of concomitant medication and other confounding factors, e.g. volume status, salt load and neurohormonal activation, that influence BP control in HD patients.Trial registrationClinicaltrialsregister.eu 2005-005021-60.

Project description:Background The implementation of genotyping for anti-hypertensive drugs in clinical practice remains a challenge. We conducted this study to analyze the distribution of polymorphisms of antihypertensive drug-related genes in Changsha County in China and compare the clinical effectiveness of genotype-guided and clinical experience-guided antihypertensive therapy in hypertensive individuals. Methods A total of 9,933 essential hypertensive participants from Changsha County were consecutively enrolled in our study, and 7 genetic polymorphic loci (CYP2D6*10, ADRB1, CYP2C9*3, AGTR1, ACE, CYP3A5*3 and NPPA) were detected by a polymerase chain reaction (PCR)-fluorescence probe. From an available sample of 660 hypertensive participants, 495 cases were randomly identified by genotype-guided therapy and 165 cases by clinical experience-guided therapy. We performed 24-hour ambulatory blood pressure (BP) monitoring on each of these cases, pre- and post-intervention. Results In the enrolled 9,933 cases, the mutation frequencies of CYP2C9*3, ADRB1(1165G>C), AGTR1(1166A>C), CYP2D6*10, ACE(I/D), CYP3A5*3 and NPPA(2238T>C) were 4.41%, 74.60%, 5.55%, 57.08%, 30.94%, 69.03% and 1.19%, respectively. In both genotype-guided and clinical experience-guided groups, the comparisons of intra-group pre-and post-treatments showed significant decreases in diastolic blood pressure (DBP) (P<0.01) and significant increases in the control rate of BP (47.1% vs. 38.6% and 37.5% vs. 33.9%, P<0.05) in response to adjusted antihypertensive agents. Correspondingly, the extent of the reduction of systolic blood pressure (SBP; 3.52±11.72 vs. 0.92±9.14 mmHg), the extent of the increase in the rate of BP control (8.5% vs. 3.6%) and the percentage rate of decrease of grades 2 and 3 hypertensive individuals were more significant in the genotype-guided group than that in the clinical experience-guided group (P<0.01). Conclusions While prescribing anti-hypertensive drugs, appropriate dosage and type adjustments should be made according to the gene mutation frequency and individual circumstances. Pharmacogenomics-guided personalized treatment of hypertensive patients is likely to be a more effective strategy, especially in those with significantly elevated SBP.

Dataset Information

Pharmacogenomics of hypertension: a genome?wide, placebo?controlled cross?over study, using four classes of antihypertensive drugs.

Publications

Pharmacogenomics of hypertension: a genome‐wide, placebo‐controlled cross‐over study, using four classes of antihypertensive drugs.

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