Journal of Human Hypertension (2014), 1–9 © 2014 Macmillan Publishers Limited All rights reserved 0950-9240/14 www.nature.com/jhh

REVIEW

An update on the pharmacogenetics of treating hypertension V Fontana1, MR Luizon2 and VC Sandrim3 Hypertension is a leading cause of cardiovascular mortality, but only one third of patients achieve blood pressure goals despite antihypertensive therapy. Genetic polymorphisms may partially account for the interindividual variability and abnormal response to antihypertensive drugs. Candidate gene and genome-wide approaches have identified common genetic variants associated with response to antihypertensive drugs. However, there is no currently available pharmacogenetic test to guide hypertension treatment in clinical practice. In this review, we aimed to summarize the recent findings on pharmacogenetics of the most commonly used antihypertensive drugs in clinical practice, including diuretics, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, beta-blockers and calcium channel blockers. Notably, only a small percentage of the genetic variability on response to antihypertensive drugs has been explained, and the vast majority of the genetic variants associated with antihypertensives efficacy and toxicity remains to be identified. Despite some genetic variants with evidence of association with the variable response related to these most commonly used antihypertensive drug classes, further replication is needed to confirm these associations in different populations. Further studies on epigenetics and regulatory pathways involved in the responsiveness to antihypertensive drugs might provide a deeper understanding of the physiology of hypertension, which may favor the identification of new targets for hypertension treatment and genetic predictors of antihypertensive response. Journal of Human Hypertension advance online publication, 28 August 2014; doi:10.1038/jhh.2014.76

INTRODUCTION Hypertension is a global burden and represents a leading cause of cardiovascular mortality worldwide. However, only one-third of hypertensive patients achieve blood pressure (BP) goal, despite several classes of antihypertensive drugs available.1 Prescription errors, non-adherence and adverse effects are among the causes of these alarming rates. Interindividual genetic variability is one of the reasons for abnormal response to antihypertensive drugs.2 Over the past two decades, an increasing number of studies have been focused on pharmacogenetics and pharmacogenomics. Pharmacogenetics is the study of the effect of genetic polymorphisms on drug response and adverse effects. Pharmacogenomics is a broader term used to describe all genes in the genome that may affect drug response. Although both terms are used interchangeably, pharmacogenetics will be use in this review. Single nucleotide polymorphisms (SNPs) are the most frequent variation in human genome, which are constituted by the presence of two or more different nucleotides (alleles) at the same position in the general population. Some alleles may affect the quantity or the function of the protein coded by the gene. Therefore, some alleles may be of functional relevance, as they may affect the amount and/or activity of the gene products in the cells, and may change the pharmacokinetics or the pharmacodynamics of the drug depending on the individual genotype. Pharmacogenetics promises to change the 'trial and error' approach to a personalized prescription approach based on the genetic profile of each individual, which may favor the selection of the 'right drug' and the most

favorable dose to maximize the drug benefit and reduce the incidence of adverse events.2 The major goal of antihypertensive treatment is the prevention of adverse cardiovascular outcomes largely attributed to blood pressure (BP) control. The pathophysiology of hypertension and BP control is quite heterogeneous at the molecular level and essential hypertension includes a broad set of mechanisms, suggesting that once the impaired mechanism is identified, the patient would be benefit from an individualized combination of drugs and dose. Thus, the identification of those mechanisms underlying hypertension could contribute to an individualized treatment, by favoring BP control and consequently reducing hypertension-related morbidity and mortality. The heritability of BP was estimated in 0.51 for systolic and 0.56 for diastolic.3 and extensive efforts have been propelling the identification of genetic variants associated with hypertension and BP traits. Currently, candidate gene studies, genome-wide linkage scans and association studies have discovered common genetic variants which explain less than 3% of the observed variance of the BP levels.4 Although the 1000 Genomes Project and the ENCODE Project have contributed to respectively annotate rare variants and likely causal variants.5 the complexity of the genome regulation and the heterogeneity of hypertension are some of the reasons for the slow progress in the knowledge on the genetics of hypertension and the pharmacogenetics of abnormal response to antihypertensive drugs. Therefore, the identification of genetic variants related to BP regulation may reveal new drug targets for the treatment of hypertension. Genetic association studies in

1 Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences, University of Campinas (Unicamp), Campinas, SP, Brazil; 2Institute of Biosciences, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil and 3Department of Pharmacology, Institute of Biosciences, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil. Correspondence: Dr VC Sandrim, Department of Pharmacology, Institute of Biosciences, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil. E-mail: [email protected] Received 31 January 2014; revised 24 June 2014; accepted 10 July 2014

An update on hypertension pharmacogenetics V Fontana et al

2 hypertension and blood pressure traits have been recently reviewed.6,7 While the majority of cases of hypertension are multifactorial and polygenic, a small subset of the hypertensive population is affected by monogenic disease. Linkage studies have identified rare polymorphisms in genes associated with monogenic hypertension, including: SCNN1 (sodium channel), CYP11 and CYP11B2 (enzymes involved in aldosterone synthesis), WNK1 and WNK4 (kinases that regulate ions transport in kidney cells), KCNJ5 (potassium channel), ENaC (epithelial Na++ channel) and NR3C2 (mineralocorticoid receptor).5 Liddle's syndrome is an example where the knowledge regarding the molecular mechanism of hypertension may favor treatment individualization based on the identification of the implicated genetic variants. This syndrome is a monogenic form of hypertension caused by a gain of function mutation in the ENaC and enhanced sodium absorption. The affected individuals did not respond to mineralocorticoid receptor blockers, but they showed significant improvement with amiloride, an ENaC blocker.8 Furthermore, the application of pharmacogenetics in drug development has increased in last decades. The inclusion of pharmacogenetics offers the potential of identify and exclude patients at risk for poor response or adverse events in early phases of clinical studies. An example of pharmacogenetics in drug development is the inclusion of a pharmacogenetic test to identify patients with abacavir hypersensitivity, which increased the sales and reduced the number of adverse events associated with abacavir.9 However, a recent review showed that pharmacogenetics is rarely used in clinical development (0.23% of studies registered in the clinicaltrials.gov database from 1999–2012), and that most studies have been conducted in academic institutions. The main challenges pointed out by the authors were the limited knowledge about the targets, genes and outcomes, limited familiarity with pharmacogenetics, high costs and regulatory and methodological issues.10 Therefore, the inclusion of pharmacogenetics in drug development may provide valuable information and its growing utilization is expected in the coming years. In spite of several efforts to understand the role of genetic variants associated with antihypertensive drugs response, there is no currently available pharmacogenetic test to guide hypertension treatment in clinical practice. The challenge in clinical implementation of a genetic-guided prescription is the lack of robust evidence about the impact of genetic variants on the improvement of antihypertensive response. First, the association results are frequently not replicated in populations from different ethnicities, races and geographic regions. It should be noted that these different populations must not be necessarily of a different racial/ethnic group. Most of the association findings in hypertension pharmacogenetics are not the functional variant, but likely a tagging SNP that may not replicate across different racial/ethnic groups. This would be due to the differential patterns of linkage disequilibrium, which could account for the non replication of the associated tagging SNPs. Second, specific guidelines on how to use genetic information to adjust drug regimens followed by extensive healthcare professionals training is warranted for the adoption of pharmacogenetics in clinical practice. The Pharmacogenomics Knowledge Base (PharmGKB) is a resource that compiles information of human genetic variation on drug responses to support personalized medicine projects.11 Moreover, PharmGKB and the Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health's Pharmacogenomics Research Network aim to provide peer-reviewed guidelines based on the quality of the evidence and the strength of the recommendation to facilitate the translation of pharmacogenomic findings to clinical decision.12 In this review, we aimed to summarize the recent findings on the pharmacogenetics of antihypertensive drugs, with a focus on the studies that meet the criteria stated in the next section. Journal of Human Hypertension (2014), 1 – 9

PHARMACOGENETICS OF ANTIHYPERTENSIVE DRUGS Adverse cardiovascular outcomes and BP reduction by the use of the available antihypertensive drugs are largely characterized by interindividual variability, for which the underlying causes are not completely elucidated and few consistent predictors have been identified.13 Pharmacogenetic studies aim to identify genetic predictors of drug response and adverse effects to be applied in clinical practice before starting the treatment. Differences in drug response among individuals can be explained by the amount of the drug that reaches its receptor (pharmacokinetics) or by differences in response triggered by drug-receptor interactions (pharmacodynamics). Genetic variants affecting absorption, distribution, metabolism and elimination may alter pharmacokinetics and, therefore, drug response and toxicity. Furthermore, genetic variants that impair drug-receptor interactions or subsequent intracellular signals may change pharmacodynamics and drug efficacy. In the present review, we summarize recent findings from studies on the pharmacogenetics of the most commonly used antihypertensive drugs in clinical practice, including diuretics, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, beta-blockers and calcium channel blockers. We first searched for the level of evidence for genetic variants associated with response to these antihypertensive drugs classes, accordingly to the PharmGKB annotation.9 For diuretics, a moderate level of evidence (Level 2B) was found and indicates that ‘the association must be replicated but there may be some studies that do not show statistical significance, and/or the effect size may be small’.9 Notably, a low level of evidence (Level 3) was found for most of the other antihypertensive drugs classes, which means that ‘annotation for a variant-drug combination based on a single significant (not yet replicated) or annotation for a variantdrug combination evaluated in multiple studies but lacking clear evidence of an association’.9 However, we did not include only SNPs and genes that have information in the PharmGKB annotation system. In this review, we included only studies that showed no deviations for Hardy-Weinberg equilibrium and met at least one of the following criteria: 1) passed the significance level in the study, 2) replicated in an independent population, 3) showed functional evidence for the genetic variants or 4) the gene implicated is within a cardiovascular or drug metabolism pathway. The reviewed studies are summarized in the Table 1, according to the antihypertensive drug classes. DIURETICS Thiazide diuretics are the most common drug used in the treatment of hypertension, and the majority of pharmacogenetic studies of diuretics have focused on hydrochlorothiazide (HCTZ). A moderate evidence of an association (Level 2B) was showed between HCTZ response and SNPs in or near the genes YEATS4 (YEATS domain containing 4), PRKCA (protein kinase C, alpha) and NEDD4L (neural precursor cell expressed, developmentally downregulated 4-like). A genome-wide association study (GWAS) that evaluated diastolic BP response to HCTZ in blacks identified a region of chromosome 12q associated with HCTZ response (P = 2.369 × 10 − 7). The haplotype analysis identified the SNPs near YEATS4, LYZ and FRS2 on chromosome 12q associated with HCTZ response. The ATC haplotype (formed by the combination of alleles for the SNPs rs317689, rs315135 and rs7297610, respectively) was more frequent among black good responder (P = 0.0002), whereas the ACT and ATT were more frequent among black poor responders (P = 0.0018 and 0.0219, respectively). The SNP rs7297610 had the most significant individual value (P = 0.00036), and it was suggested to contribute with most of the observed association. These findings were replicated in an independent population of 291 blacks and 294 white subjects, suggesting the region YEATS4 and LYZ is associated with DBP © 2014 Macmillan Publishers Limited

Diuretics Randomized trial/ GWAS

Randomized trial/ Candidate-gene study

Randomized and Prospective studies/ GWAS

Randomized trial/ Candidate-gene study

Randomized trial/ Candidate-gene study

Randomized trial/ Candidate-gene study

rs317689 rs315135 rs7297610

rs16960228

rs4149601

rs4149601 rs292449

rs1458038 rs3184504 rs4551053

YEATS4

PRKCA

NEDDL4

NEDDL4

FGF5 SH2B3 EBF1

Study type

Chr 12q15 region (rs317689, rs315135, and rs7297610)

Polymorphism or genomic region

YEATS4

Nearest Gene

© 2014 Macmillan Publishers Limited 428 whites

767 PEAR participants 1345 INVEST participants (269 cases)

5152 NORDIL Caucasian participants

228 PEAR 196 GERA 420 NORDIL 206 GENRES participants

746 Caucasian and African-American PEAR participants

195 white 194 blacks

Study subjects

Haplotype constructed from 3 SNPs (rs317689, rs315135, and rs7297610) was associated with DBP in black GERA participants. ATC haplotype (rs317689, rs315135 and rs7297610, respectively) was more frequent among black good responder (P = 0.0002), whereas the ACT and ATT were more frequent among black poor responders (P = 0.0018 and 0.0219, respectively). These findings were replicated in 291 black subjects and in 294 white subjects.14 ATT Haplotype constructed from 3 SNPs was more frequent in PEAR AfricanAmerican poor responders than good responders to HCTZ. These associations were not observed in Caucasians. In African-Americans, CC homozygotes for rs7297610 had greater BP responses to HCTZ than T-carrriers.15 The combined meta-analysis of the four studies for rs16960228 reached genomewide significance. A-allele carriers showed greater BP responses to HCTZ than the GG homozygotes and higher expression of PRKCA in white individuals.16 Among patients treated with β-blockers or thiazide diuretics in monotherapy, the G-allele was associated with greater SBP reduction after six months and a better cardiovascular outcomes in hypertensive subjects from NORDIL study.17 Increasing copies of the GC (rs4149601rs292449 haplotype) were associated with greater BP response to HCTZ in white PEAR participants, but not in African-Americans. Also, an increased risk for adverse cardiovascular outcomes was found in AG heterozygous for rs4149601 whites not treated with HCTZ in INVEST participants.18 The genetic score composed of the three BP-lowering alleles (C,C and G, for rs1458038, rs3184504 and rs4551053, respectively) was associated with greater home BP response to HCTZ monotherapy in PEAR participants, explaining 4.3% for SBP response and 5.3% for DBP.19

Results

Summary of the pharmacogenetics/genomics studies in hypertension by antihypertensive drug classes

Antihypertensive classes

Table 1.

P = 0.0006 for SBP and P = 0.0003 for DBP

P = 0.0006 for SBP P = 0.006 for DBP OR = 10.65 (1.18−96.25), P = 0.022 for adverse outcome

P = 0.047 for change in SBP using additive model RR = 0.52 (0.36−0.74), Po0.0001 for primary event G carriers vs AA homozygous

Meta-analysis P value = 3.3 × 10 − 8

P = 0.01 for haplotype analysis P = 0.0275 and P = 0.0196 (for SBP and DBP reduction, respectively) for single SNP analysis

nominal P = 2.39 × 10 − 7 for GWAS

P value/OR/HR

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Polymorphism or genomic region

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Beta-blockers

GRK4

rs11064426 (A3882C) rs2301339 (G5249A) rs5443 (C825T) rs2960306 (R65L) rs1024323 (A142V) rs1801058 (A486V)

340 whites

222 whites and 146 blacks from PEAR

Randomized trial/ Candidate-gene study

233 whites and 150 blacks

40 whites, AfricanAmericans and Hispanics

116 non-declared race/ethnicity

198 whites 193 blacks

279 Chinese

1447 Chinese

Study subjects

Prospective study/ Candidate-gene study

Randomized trial/ Candidate-gene study

rs1458038 rs871606 rs2932538 rs1799945

FGF5 CHIC2 MOV10 HFE

GNB3

Prospective study/ Candidate-gene study

Prospective trial/ Candidate-gene study

Prospective study/ GWAS

Prospective study/ Candidate-gene study

Ser49Gly Arg389Gly

rs3758785 rs11649420 rs1799998 (-344T/C)

rs11020821

rs1403543 rs5194 G3726 (no rs available) rs5522

Prospective study/ Candidate-gene study

Study type

ADRB1

GPR83 SCNN1G CYP11B2

Angiotensin II receptor blockers FUT4

NR3C2

AGTR1

Angiotensin-converting enzyme inhibitors AGT rs7079

Nearest Gene

(Continued )

Antihypertensive classes

Table. 1.

Ser49Arg389/Ser49Arg389 diplotype showed greater BP reduction compared to Gly49Arg389/Ser49Gly389 diplotype. Both genotypes were predictors of BP response to metoprolol.37 The genetic score composed of the four BP-lowering alleles (T,T,T and G, respectively) was associated home BP response to atenolol monotherapy in white PEAR participants, explaining 8.5% for SBP response and 8.2% for DBP. rs871606 was marginally associated with DBP in blacks (P = 0.06).19 Wild-type carriers showed the greatest SBP reduction after atenolol therapy. After sex stratification, the association was found only in females. GNB3 haplotypes are associated with ΔSBP response to atenolol in females.40 Increasing copies of the variant 65L-142V haplotype were associated with reduced DBP reduction with atenolol in a combined analysis with white and black subjects. Also, higher risk for cardiovascular events were found in

CC homozygotes for rs1799998 showed significant better response to candesartan treatment.33

Those SNPs were significantly associated with candesartan response at opposite direction to HCTZ response in whites participants of GERA.32

The reductions in DBP were significantly greater in AA homozygotes compared with AG+GG genotype carriers for the SNP rs5522 in hypertensive subjects treated with enalapril.23

CC homozygotes for rs7079 showed a decreased DBP reduction compared with A carriers after 3 years benazepril treatment. AGTR1 haplotypes were associated with BP response.22

Results

P = 0.0204 for SBP P = 0.0088 for DBP OR: 1.73 (1.09−2.73); P = 0.0192 for 65L OR: 1.59 (1.01−2.48); P = 0.0426 for 142V OR: 2.29 (1.48−3.55); P = 0.0002 for 486V

P = 0.004 P = 0.004 P = 0.005

P = 3.3 × 10–6 for SBP P = 1.6 × 10–6 for DBP

P = 0.0018

P = 2.04 × 10 − 4 P = 7.81 × 10 − 4 P = 0.013

P = 8.98 × 10 − 7

P = 0.009

P = 0.04 (AGTR1 GAG haplotype)

P = 0.021 (rs7079)

P value/OR/HR

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© 2014 Macmillan Publishers Limited

© 2014 Macmillan Publishers Limited

rs1051375

rs12946454

CACNA1C

PLCD3

1990 Caucasians

2076 whites, 2598 Hispanics and 588 blacks INVEST participants (258 cases and 774 controls)

265 Japanese hypertensive subjects

Study subjects

Home BP response to 2-4 weeks of treatment with calcium channel blockers (n = 93) was associated with C, G, C and C, respectively, alleles in GWAS study. The findings were replicated in GEANE (n = 79) on amlodipine treatment (Po 0.05).42 Leu110 variant was associated with 32% lower risk of primary outcome in INVEST participants.43 AA individuals randomized to verapamil SR were less likely to experience primary outcome than those randomized to atenolol. GG individuals randomized to verapamil SR were more likely to experience the primary outcome than those randomized to atenolol.44 Higher systolic (1.53mmHg per allele) and diastolic BP (0.73mmHg per allele) response was found in T allele carriers in Swedish NORDIL trial participants treated with diltiazem.45

homozygotes for 65L, 142V and 486V in poolled white and Hispanics.41

Results

for for for for

SBP SBP DBP DBP

P = 0.010 for SBP P = 0.014 for DBP

P = 0.001 for interaction OR = 0.54 (0.32−0.92) for AA genotype OR = 4.59 (1.67−12.67) for GG genotype

HR = 0.68 (0.47–0.99)

P = 7.41 × 10 − 5 P = 2.75 × 10 − 5 P = 1.72 × 10 − 4 P = 9.14 × 10 − 5

P value/OR/HR

Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; GEANE, Gene Evaluation for Antihypertensive Effect of drugs; GENRES, GENetics of drug RESponsiveness in essential hypertension; GERA, Genetic Epidemiology of Responses to Antihypertensive; GWAS, genome-wide association study; HCTZ, hydrochlorothiazide; HR, hazard ratio; INVEST-GENES, The International Verapamil-Trandolapril Study; NORDIL, Nordic Diltiazem Study; OR, odds ratio; PEAR, Pharmacogenomics Evaluation of Antihypertensive Responses; RR, risk ratio; SBP, systolic blood pressure; SNP, single nucleotide polymorphism.

Randomized trial/ Candidate-gene study

Randomized trial/ candidate-gene study Randomized trial/ candidate-gene study

Val110Leu

KCNMB1

Study type

Randomized trial/ GWAS

Polymorphism or genomic region

rs588076 rs2429427 rs10898815 rs564991

Calcium channel blockers PICALM TANC2 NUMA1 APCDD1

Nearest Gene

(Continued )

Antihypertensive classes

Table. 1.

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response.14 Also, another study found the same haplotype associated with HCTZ response in 746 hypertensive subjects randomized to HCTZ and atenolol treatment. The ATT haplotype (for the SNPs rs317689, rs315135 and rs7297610, respectively) was associated with HCTZ response in African-Americans from PEAR. This study also found that CC homozygotes for the SNP rs7297610 had a greater systolic and diastolic BP response to HCTZ (but not to atenolol) than T carriers, and the haplotype association observed was driven by rs7297610. However, these associations were not observed in Caucasians. Moreover, YEATS4 expression was reduced in blood mononuclear cells from African-Americans after HCTZ treatment in CC homozygotes, but not in T carriers, which make this association stronger and suggest a relationship between YEATS4 variants and response to HCTZ.15 Another strong and replicated signal associated with DBP response to HCTZ treatment in white subjects is the SNP rs16960228 near PRKCA. A genome-wide significant result was found in a meta-analysis combining the results from independent white hypertensive populations (P = 3.3 × 10 − 8): Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR), Genetic Epidemiology of Responses to Antihypertensive (GERA), Nordic Diltiazem Study (NORDIL) and Genetics of Drug Responsiveness in Essential Hypertension Study (GENRES). The A allele was significant predictor of greater DBP response to HCTZ. In addition, this study showed functional evidence that the A allele was associated with higher pretreatment PRKCA expression in white PEAR participants.16 A functional variant of NEDDL4 was evaluated in Caucasian hypertensive patients randomized to beta-blockers or thiazide diuretics and followed-up for six months in NORDIL (Nordic Diltiazem) Study. A greater SBP reduction (P = 0.047) and a reduced risk for primary outcome (fatal and nonfatal stroke, fatal and nonfatal myocardial infarction and other cardiovascular deaths) (RR = 0.52, 95% CI (0.36–0.74), P o 0.0001) were observed in G carriers for the SNP rs4149601 in NEDDL4 in patients on betablockers or thiazide diuretics in NORDIL participants.17 These findings were significantly replicated in white participants from PEAR and in the International Verapamil SR Trandolapril Study (INVEST) participants for BP response and cardiovascular outcomes, respectively. Moreover, a greater BP response to HCTZ with increasing copies of the G-C haplotype of NEDD4L (for the SNPs rs4149601 and rs292449, respectively) was observed in white PEAR participants. However, these findings were not replicated in African-Americans. Finally, an increased risk for adverse cardiovascular outcomes (composite of the first occurrence of all-cause death, nonfatal myocardial infarction or nonfatal stroke) was found in AG heterozygous for rs4149601 whites not treated with HCTZ, but not in Hispanics and African-Americans INVEST participants.18 Thirty-seven of the 39 SNPs previously associated in a GWAS for hypertension or BP were assessed in 428 white hypertensive subjects treated with atenolol or HCTZ monotherapy. Genetic risk scores were composed including the SNPs with nominal associations with BP response (Po 0.05). The alleles C, C and G (for the SNPs rs1458038, rs3184504 and rs4551053, respectively) were associated with greater home BP response to HCTZ monotherapy in PEAR participants. The score composed of these three BP-lowering alleles (near genes FGF5, SH2B3, EBF1) explained 4.3% of SBP (P = 0.0006) and 5.3% of DBP (P = 0.0003) response to HCTZ monotherapy in white subjects.19 There is no clear evidence for the association on ACE (angiotensin-converting enzyme) and ADD1 (adducin 1, alpha) polymorphisms and BP response to diuretics. Patients carrying at least one I allele of the ACE insertion/deletion (I/D) polymorphism (P = 0.02) and one 460Trp allele of ADD1 Gly460Trp SNP (P = 0.003) showed greater mean BP reduction associated with the response to HCTZ treatment in 87 never-treated hypertensive subjects.20 However, another study failed to replicate the association Journal of Human Hypertension (2014), 1 – 9

between 460Trp of ADD1 and ACE I/D polymorphisms and thiazide response in 208 GENRES participants.21 ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS Drugs acting on the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are one of the first line treatments of hypertension. BP response to benazepril after three years of treatment was evaluated in a prospective study in Chinese individuals. Fourteen SNPs in AGT (angiotensinogen), AGTR1 (angiotensin II receptor, type 1) and AGTR2 (angiotensin II receptor, type 2) were analyzed in this study. The CC homozygotes for the SNP rs7079 in AGT showed a decreased DBP reduction compared to A carriers. This variation explained 9.6% of the DBP variation in the studied population. However, no association was found for any individual SNPs in AGTR1 and AGTR2. In addition, the GAG haplotype (for the SNPs rs1403543, rs5194 and G3726, respectively) in AGTR1 showed higher SBP reduction compared to the GAC haplotype and to the group with neither GAG nor GAC haplotypes. In this study, the AGRT1 haplotype explained 13% of systolic and 9.6% of diastolic BP reduction in response to benazepril.22 In another study including Han Chinese subjects, AA homozygotes for the SNP rs5522 of NR3C2 (mineralocorticoid receptor) showed greater diastolic BP reduction after the treatment with enalapril than G carriers (P = 0.009).23 Furthermore, polymorphisms in RAAS genes have also been associated with ACEi-induced adverse effects. Polymorphisms in BDKRB2 (bradykinin receptor B2) were associated with increased risk for cough in different populations.24–26 Impaired metabolism of bradykinin may be the mediator of adverse effects, such as dry cough and angioedema in patients treated with ACEi. A meta-analysis revealed no significant association between ACEi-induced cough and the ACE insertion/deletion (I/D) polymorphism.27 XPNPEP2 (aminopeptidade P) genotypes and haplotypes were associated with angioedema induced by ACEi in two independent studies.28,29 Moreover, reduced cardiovascular events were associated with the SNPs rs275651 and rs5182 of AGTR1, and the SNP rs12050217 of BDKRB1 in hypertensive subjects treated with perindopril in the PERindopril GENEtic association study (PERGENE).30 Hypertensive patients with the CYP2C9*1/*30 genotype showed impaired BP reduction after three months of treatment with losartan.31 CYP2C9 is responsible for the oxidation of losartan in a higher potent metabolite, suggesting that the *30 allele has reduced activity, which may be responsible for impaired response to losartan. BP response to candesartan was associated with the SNP rs11020821 of FUT4 (fucosyltransferase 4) in white subjects (P = 8.98 × 10 − 7), out of the 273 polymorphisms with opposite associations with HCTZ response in a GWA study with GERA participants. The same study reported that the SNP rs3758785 of GPR83 (G protein-coupled receptor 83) was the most significantly associated with candesartan response at opposite direction to HCTZ response in whites (P = 7.10 × 10 − 3). The odds of good response to candesartan for GG homozygotes was 16 fold higher than AA homozygotes, while the odds of good response to thiazide was 8 fold less than GG genotype. Moreover, GG homozygotes for the SNP rs11649420 of SCNN1G (sodium channel, non-voltage-gated 1, gamma subunit) showed greater BP response to candesartan and reduced response to HCTZ compared to A carriers (P = 7.81 × 10 − 4).32 Finally, in a prospective trial of 116 subjects of non-declared race/ethnicity, the CC homozygotes for the SNP rs1799998 of CYP11B2 (aldosterone synthase) showed improved response to candesartan (P = 0.013).33 In spite the positive results on genes associated with ACEi and ARB response in hypertension, there is a lack of replication of © 2014 Macmillan Publishers Limited

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these findings and further studies are needed to confirm the associations in different populations. BETA-BLOCKERS The Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association has evaluated therapeutic dose recommendations for metoprolol based on CYP2D6 genotype. Because metoprolol is largely metabolized by CYP2D6, they recommended either selecting another drug or dose reduction for poor and intermediate metabolizers, defined by at least one inactive or two decreased activity alleles. As for the ultra-rapid metabolizers, they recommended a dose tritation.34 However, other studies show that there should be no dose adjustment in terms of BP goals for metoprolol.35,36 Several studies demonstrated the association among ADRB1 (beta-1 adrenergic receptor) polymorphisms and differential BP reduction with beta-blocker treatment. In a study population including white, African American, and Hispanic subjects, the Arg homozygotes for Arg389Gly had greater reduction in diastolic BP compared to Gly carriers (P = 0.0018). Moreover, Arg389Gly and Ser49Gly genotypes were significant predictors of BP response to metoprolol.37 A further study showed that patients carrying Ser49/Arg389 haplotype had higher death rates in patients assigned to verapamil, but not to atenolol (HR = 2.31, 95% CI (0.82–6.55).38 These two SNPs show important evidence for functional consequences related with intracellular signaling in response to beta-agonists.39 The BP response to atenolol in 768 hypertensive participants of the PEAR study was associated with a genetic score composed by four loci (near the genes FGF5, CHIC2, MOV10 and HFE) of 37 SNPs previously associated with hypertension or BP trait, which explained 8.5% of SBP (P = 3.3 × 10 − 6) and 8.2% of DBP (P = 1.6 × 10 − 6) response to beta-blocker monotherapy. The alleles T, T, T and G (for the SNPs rs1458038, rs871606, rs2932538, rs1799945, respectively) was associated with greater home BP response to atenolol monotherapy in white PEAR participants. Moreover, rs871606 was marginally associated with DBP in blacks (P = 0.06).19 A pharmacogenetic study with essential hypertension individuals treated with atenolol showed greater systolic BP response in subjects carrying wild type alleles and haplotypes of A3882C, G5249A and C825T polymorphisms of GNB3 (G-protein beta3 subunit). Also, after stratification by sex, the association was significant in women, but not in men. The same study did not found association of ADRB1 and ADRB2 polymorphisms in both genders.40 The BP response and risk for cardiovascular outcomes in response to atenolol was evaluated in PEAR white and black participants and in the INVEST study. A reduced atenolol-induced systolic and diastolic BP was reported with increasing copies of the 65L-142V haplotype GRK4 (G protein-coupled receptor kinase 4) in white and black hypertensive subjects (P = 0.0204 for SBP and P = 0.0088 for DBP. Moreover, the three GRK4 polymorphisms were associated with increased risk of cardiovascular events (death, nonfatal myocardial infarction and nonfatal stroke). Homozygous for 65L (OR = 1.73; P = 0.0192), 142V (OR = 1.59; P = 0.0426) and 486V (OR = 2.29; P = 0.0002) had increased risk for primary outcomes in pooled whites and Hispanics from the INVEST study.41 CALCIUM CHANNEL BLOCKERS The HOMED-BP-GENE study identified by GWAS the alleles C for rs588076, G for rs2429427, C for rs10898815 and C for rs564991 of the PICALM, TANC2, NUMA1 and APCDD1 genes, respectively, to be associated with response to calcium channel blocker for 2-4 weeks in monotherapy in Japanese patients. These findings were replicated in an independent population from GEANE study.42 © 2014 Macmillan Publishers Limited

7 In a study performed with samples from the INVEST patients, the Glu65Lys and Val110Leu genotypes of KCNMB1 (potassium large conductance calcium-activated channel, subfamily M, beta member 1) did not affect BP response to verapamil. However, Leu110 carriers showed reduced risk of the primary outcome (all cause mortality, nonfatal myocardial infarction or nonfatal stroke); HR = 0.68, 95% CI (0.47–0.998).43 Another study in INVEST evaluated eight SNPs in the CACNA1C (calcium channel, voltagedependent, L type, alpha 1C subunit) coding region and intronexon junctions. No association with the main effect on outcome was found for the studied polymorphisms, but a significant interaction between rs1051375 with treatment strategy was observed. The AA genotype for the SNP rs1051375 was associated with a 45% reduced risk of the primary outcome (death, nonfatal myocardial infarction or nonfatal stroke) among subjects randomized to verapamil SR compared to atenolol in the INVEST-GENES participants. On the other hand, GG individuals randomized to verapamil SR had a 4.5-fold increase in risk of the primary outcome than those randomized to atenolol. The allelic mRNA expression of CACNA1C in heart tissues was similar among the genotypes for this SNP.44 This study suggests that AA homozygotes would be benefit from treatment with verapamil and GG homozygotes would benefit from treatment with atenolol in order to reduce the incidence of adverse outcomes. Eight SNPs previously associated with BP in GWAS studies were evaluated in 1,990 Swedish hypertensive individuals from the NORDIL study. A nominal evidence of association with systolic BP response after six months of treatment with diltiazem was found for the SNP rs12946454 of PLCD3 (phospholipase C, delta 3). An additive effect for increasing copies of T allele and higher BP reduction (1.53 mmHg per allele for SBP and 0.73 mmHg per allele for DBP) on diltiazem treatment was found in this Caucasian population.45 RESISTANCE TO MULTIPLE ANTIHYPERTENSIVE REGIMENS Resistant hypertension (RH) is defined as lack of BP control despite the use of three antihypertensive drugs or any BP level requiring four or more antihypertensive drugs. Those patients with multiple antihypertensive resistance have a worse clinical prognosis compared to responder, masked and false resistant hypertension patients.46 The Genetics of Hypertension Associated Treatment Study (GenHAT) evaluated 78 candidate SNPs and two variants in AGT (rs699 and rs5051) were associated with resistant hypertension in white subjects (P = 0.0001).47 However, the pharmacogenetics of multiple antihypertensives resistance is largely understudied. This could be explained by the low prevalence of this condition, coupled with difficulties in the exclusion of pseudoresistance caused mainly by poor BP measurements, the low adherence and suboptimal dosing. Few studies showing positive findings were performed with small samples sizes,48 which need to be further replicated in larger populations. Antihypertensive therapy for hypertensive disorders of pregnancy includes methyldopa, nifedipine, hydralazine and labetalol. Notably, nonresponsive gestational hypertensive and preeclamptic women have different distributions of NOS3 (nitric oxide synthase 3), MMP-9 (matrix metalloproteinase 9) and TIMP-1 (tissue-inhibitor of matrix metalloproteinase 1) polymorphisms compared to the responsive group,49–51 which also need to be further replicated in larger populations. CONCLUSIONS AND PERSPECTIVES Only a small percentage of the variability on response to antihypertensive drugs has been explained, and the majority of the genetic variants associated with antihypertensives efficacy and toxicity remains to be identified. Moreover, further Journal of Human Hypertension (2014), 1 – 9

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8

replications of the initial findings are needed to confirm the associations in populations of different race groups and ethnicities. The International Consortium for Antihypertensives Pharmacogenomics Studies (ICAPS) was created in 2012 to promote the collaboration among different research groups. The Consortium might facilitate the identification and replication of pharmacogenetic findings for the variability on antihypertensive drug response and might reveal strong signals to be further used to guide treatment selection (http://www.pharmgkb.org/page/icaps). Together, these efforts may reveal new therapeutic strategies and drug/dose optimization for hypertension treatment. Furthermore, the preemptive availability of genetic information in patient's medical records may favor the prescription based on genomic information that might be more cost-effective than the trial and error in current practice.12 Finally, the pharmacogenetics of antihypertensive drugs is a field in progress and future efforts are needed to unravel additional genes and variants, as well as identify epigenetic and regulatory pathways involved in the responsiveness to antihypertensive drugs. CONFLICT OF INTEREST The authors declare no conflict of interest.

ACKNOWLEDGEMENTS This study was funded by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and the Fundaçao de Amparo a Pesquisa do Estado de São Paulo (FAPESP-Brazil).

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45 Hamrefors V, Sjögren M, Almgren P, Wahlstrand B, Kjeldsen S, Hedner T et al. Pharmacogenetic implications for eight common blood pressure-associated single-nucleotide polymorphisms. J Hypertens 2012; 30(6): 1151–1160. 46 Pierdomenico SD, Lapenna D, Bucci A, Di Tommaso R, Di Mascio R, Manente BM et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens 2005; 18 (11): 1422–1428. 47 Lynch AI, Irvin MR, Davis BR, Ford CE, Eckfeldt JH, Arnett DK. Genetic and Adverse Health Outcome Associations with Treatment Resistant Hypertension in GenHAT. Int J Hypertens 2013; 2013: 578578. 48 Yugar-Toledo JC, Martin JF, Krieger JE, Pereira AC, Demacq C, Coelho OR et al. Gene variation in resistant hypertension: multilocus analysis of the angiotensin 1-converting enzyme, angiotensinogen, and endothelial nitric oxide synthase genes. DNA Cell Biol 2011; 30(8): 555–564. 49 Sandrim VC, Palei AC, Luizon MR, Izidoro-Toledo TC, Cavalli RC, Tanus-Santos JE. eNOS haplotypes affect the responsiveness to antihypertensive therapy in preeclampsia but not in gestational hypertension. Pharmacogenomics J 2010; 10(1): 40–45. 50 Palei AC, Sandrim VC, Amaral LM, Machado JS, Cavalli RC, Lacchini R et al. Matrix metalloproteinase-9 polymorphisms affect plasma MMP-9 levels and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy. Pharmacogenomics J 2012; 12(6): 489–498. 51 Luizon MR, Palei ACT, Sandrim VC, Amaral LM, Machado JSR, Lacchini R et al. Tissue inhibitor of matrix metalloproteinase-1 polymorphism, plasma TIMP-1 levels, and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy. Pharmacogenomics J (e-pub ahead of print 10 June 2014; doi:10.1038/tpj.2014.26).

Journal of Human Hypertension (2014), 1 – 9

An update on the pharmacogenetics of treating hypertension.

Hypertension is a leading cause of cardiovascular mortality, but only one third of patients achieve blood pressure goals despite antihypertensive ther...
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