Pharmacogenomics of Hypertension: A Genome‐Wide, Placebo‐Controlled Cross‐Over Study, Using Four Classes of Antihypertensive Drugs

Hiltunen, Timo P.; Donner, Kati; Sarin, Antti Pekka; Saarela, Janna; Ripatti, Samuli; Chapman, Arlene B.; Gums, John G.; Gong, Yan; Cooper‐DeHoff, Rhonda M.; Frau, Francesca; Glorioso, Valeria; Zaninello, Roberta; Salvi, Erika; Glorioso, Nicola; Boerwinkle, Eric; Turner, Stephen T.; Johnson, Julie A.; Kontula, Kimmo

doi:10.1161/jaha.114.001521

Cited by 78 publications

(88 citation statements)

References 40 publications

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“…Six study cohorts contributed data to the meta-analysis: the Genetics of Drug Responsiveness in Essential Hypertension Study (GENRES) 15,19 ; the Genetic Epidemiology of Responses to Antihypertensives study (GERA-1) 20 ; The Milan Hydrochlorothiazide study (HCTZ-Milan) 13 ; the Nordic Diltiazem study (NORDIL) 9,21 ; the Pharmacogenomic Evaluation of Antihypertensive Responses study (PEAR-1) 22 and the Pharmacogenomics of Hydrochlorothiazide Sardinian Study (PHSS). 13 Detailed information regarding each of six cohorts is included in the Supplement.…”

Section: Methodsmentioning

confidence: 99%

“…6 Many groups have conducted pharmacogenetic studies on BP response to TD using candidate gene(s) 7–11 or genome wide association studies (GWAS). 12–15 These studies, recently reviewed 6,16–18 , have advanced the knowledge surrounding hypertension pharmacogenomics and suggest several genetic variants that may be important determinants of response to TD. Nevertheless, only a small percentage of the variability in BP response has been explained to date.…”

Section: Introductionmentioning

confidence: 99%

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Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Wang¹,

Rizzi²,

Gong³

et al. 2017

Hypertension

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This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure response to hydrochlorothiazide was performed in 1739 white hypertensives from six clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS), making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10−8) and the suggestive regions (P<10−5) were cross-validated in two black cohorts treated with hydrochlorothiazide. Additionally, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in blood pressure regulation or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified two suggestive regulatory regions linked to GJA1 and FOXA1, relevant for cardiovascular and kidney function. With the gene-based approach, we identified HSD3B1 as significantly associated with blood pressure response (P<2.28×10−4). HSD3B1 encodes the 3beta-HSD enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of blood pressure response to hydrochlorothiazide, and using two different analytical approaches, we identified three novel loci influencing blood pressure response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, and which was not identified in the single-SNP analysis due to high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Wang¹,

Rizzi²,

Gong³

et al. 2017

Hypertension

Self Cite

View full text Add to dashboard Cite

show abstract

“…These SNPs lie within the coding and regulatory regions of ACY3 , which encodes aminoacylase III 78 . This chromosome 11 signal was not replicated within PEAR (which investigated the pharmacogenomic response to atenolol), and more research is necessary to validate this GWAS signal.…”

Section: Other Promising Gene–drug Interactionsmentioning

confidence: 99%

“…ICAPS promotes the discovery of genes that influence response to antihypertensive drugs with the primary goal of advancing pharmacogenomics discoveries that will lead to definitive evidence regarding the use of genetic information to guide antihypertensive treatment decisions. Through ICAPS collaborations, several cohorts have successfully identified pharmacogenomic associations 59,60,78 , demonstrating the importance of the consortial approach for successful pharmacogenomics discoveries.…”

Section: Future Directionsmentioning

confidence: 99%

Hypertension pharmacogenomics: in search of personalized treatment approaches

Cooper‐DeHoff

Johnson

2015

Nat Rev Nephrol

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Cardiovascular and renal diseases are associated with many risk factors, of which hypertension is one of the most prevalent. Worldwide, blood pressure control is only achieved in ~50% of those treated for hypertension, despite the availability of a considerable number of antihypertensive drugs from different pharmacological classes. Although many reasons exist for poor blood pressure control, a likely contributor is the inability to predict to which antihypertensive drug an individual is most likely to respond. Hypertension pharmacogenomics and other ‘omics’ technologies have the potential to identify genetic signals that are predictive of response or adverse outcome to particular drugs, and guide selection of hypertension treatment for a given individual. Continued research in this field will enhance our understanding of how to maximally deploy the various antihypertensive drug classes to optimize blood pressure response at the individual level. This Review summarizes the available literature on the most convincing genetic signals associated with antihypertensive drug responses and adverse cardiovascular outcomes. Future research in this area will be facilitated by enhancing collaboration between research groups through consortia such as the International Consortium for Antihypertensives Pharmacogenomics Studies, with the goal of translating replicated findings into clinical implementation.

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“…While pharmacogenomics research in HTN has witnessed advancement in recent years and many genetic variants for different antihypertensive drug classes have been discovered [15–19], there has been slow progress in the application of pharmacogenomics research to the RHTN phenotype. Nevertheless, there are a handful of genetic studies that included patients with RHTN, the majority of them focused on revealing the genetic basis of RHTN.…”

Section: Introductionmentioning

confidence: 99%

Genetics of Resistant Hypertension: a Novel Pharmacogenomics Phenotype

Rouby

Cooper‐DeHoff

2015

Curr Hypertens Rep

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Resistant hypertension (RHTN), defined as an uncontrolled blood pressure despite the use of multiple antihypertensive medications, is an increasing clinical problem associated with increased cardiovascular (CV) risk, including stroke and target organ damage. Genetic variability in blood pressure (BP)-regulating genes and pathways may, in part, account for the variability in BP response to antihypertensive agents, when taken alone or in combination, and may contribute to the RHTN phenotype. Pharmacogenomics focuses on the identification of genetic factors responsible for inter-individual variability in drug response. Expanding pharmacogenomics research to include patients with RHTN taking multiple BP-lowering medications may identify genetic markers associated with RHTN. To date, the available evidence surrounding pharmacogenomics in RHTN is limited and primarily focused on candidate genes. In this review, we summarize the most current data in RHTN pharmacogenomics and offer some recommendations on how to advance the field.

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Pharmacogenomics of Hypertension: A Genome‐Wide, Placebo‐Controlled Cross‐Over Study, Using Four Classes of Antihypertensive Drugs

Cited by 78 publications

References 40 publications

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Hypertension pharmacogenomics: in search of personalized treatment approaches

Genetics of Resistant Hypertension: a Novel Pharmacogenomics Phenotype

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