Pharmacogenomic studies of hypertension: paving the way for personalized antihypertensive treatment

Eadon, Michael T.; Kanuri, Sri Harsha; Chapman, Arlene B.

doi:10.1080/23808993.2018.1420419

Cited by 13 publications

(14 citation statements)

References 99 publications

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“…Antihypertensive pharmacogenomic variants were included for metoprolol ( CYP2D6 ), other beta-blockers ( GRK4 , ADRB1 ), hydralazine ( NAT2 ), losartan ( CYP2C9 ), amlodipine ( F7 ), thiazide diuretics ( YEATS4 , FGF5 / SH2B3 / EBF1 ), diuretics ( NEDD4L ), angiotensin-converting-enzyme inhibitors ( F7 ), and angiotensin II receptor blockers ( NPHS1 ) (Table 1) [3-11]. The clinical validity of these variants has been previously reviewed and their associated levels of evidence vary [12, 13]. For example, CYP2D6 -guided dosing of metoprolol has been recommended by the DPWG.…”

Section: Variant Selectionmentioning

confidence: 99%

Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy

Collins¹,

Pratt

Stansberry

et al. 2019

Pharmacogenetics and Genomics

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Hypertension and chronic kidney disease are inextricably linked. Hypertension is a well-recognized contributor to chronic kidney disease progression and, in turn, renal disease potentiates hypertension. A generalized approach to drug selection and dosage has not proven effective in managing these conditions, in part, because patients with heterogeneous kidney disease and hypertension etiologies are frequently grouped according to functional or severity classifications. Genetic testing may serve as an important tool in the armamentarium of clinicians who embrace precision medicine. Increasing scientific evidence has supported the utilization of genomic information to select efficacious antihypertensive therapy and understand hereditary contributors to chronic kidney disease progression. Given the wide array of antihypertensive agents available and diversity of genetic renal disease predictors, a panel-based approach to genotyping may be an efficient and economic means of establishing an individualized blood pressure response profile for patients with various forms of chronic kidney disease and hypertension. In this manuscript, we discuss the validation process of a Clinical Laboratory Improvement Amendments (CLIA)-approved genetic test to relay information on 72 genetic variants associated with kidney disease progression and hypertension therapy. These genomic-based interventions, in addition to routine clinical data, may help inform physicians to provide personalized therapy.

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Section: Variant Selectionmentioning

confidence: 99%

Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy

Collins¹,

Pratt

Stansberry

et al. 2019

Pharmacogenetics and Genomics

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“…A complete list of genes, variants, and clinical phenotypes provided is included in Table 1. Evidence for these variants has been previously reviewed [11,17]. Variants with abundant evidence relevant to cardiovascular drugs were also included in the panel.…”

Section: Methodsmentioning

confidence: 99%

Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance

Spiech

Tripathy

Woodcock

et al. 2020

Life

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A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers.

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“…The KCNMB1 gene encodes the β1 subunit of the large-conductance potassium (BKor Maxi-K type) channel. It has been shown that reduced function of this protein is associated with diminished calcium sensitivity, higher BP, and cardiac hypertrophy [ 19 , 24 ]. Two nonsynonymous polymorphisms in the KCNMB1 gene—Glu65Lys (rs11739136) and Val110Leu (rs2301149)—were found to modulate inter-patient variability in BP response to verapamil.…”

Section: Calcium Channel Blocking Agentsmentioning

confidence: 99%

“…Candidate association studies revealed variants in the calcium channels that could facilitate the selection of a CCB or β-blocker—for example, in CACNA1C , which encodes the alpha1c-subunit of the L-type calcium channel [ 24 ]. Beitelshees et al [ 25 ] screened eight single-nucleotide polymorphisms within CACNA1C to search for the relationship between verapamil and atenolol treatment efficacy and the occurrence of primary outcomes of stroke, myocardial infarction, and death.…”

Section: Calcium Channel Blocking Agentsmentioning

confidence: 99%

“…In those who better responded to HCTZ or chlorthalidone, an up-regulation in the transcription of the aforementioned genes was observed. In turn, a GWAS analysis of two Italian cohorts (Milan Hypertension Pharmacogenomics of hydrochlorothiazide; MIHYPHCTZ and Pharmacogenomics of Hydrochlorothiazide Sardinian Study; PHSS), which assessed the response to HCTZ treatment in Caucasian individuals with an office SBP > 140 mmHg and a DBP > 90 mmHg without prior treatment [ 116 ], revealed six variants that are predictive of the SBP response and five variants predictive of DBP [ 24 ]. The strongest effect on the SBP response was observed for the intronic polymorphisms within TET2 (Tet methylcytosine dioxygenase 2) (rs12505746) and two SNPs in CSMD1 (CUB and Sushi multiple domains protein 1) (rs7387065 and rs11993031) [ 116 ].…”

Section: Diureticsmentioning

confidence: 99%

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Pharmacogenomics of Hypertension Treatment

Rysz

Franczyk

Rysz-Górzyńska

et al. 2020

IJMS

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Hypertension is one of the strongest modifiable cardiovascular risk factors, affecting an increasing number of people worldwide. Apart from poor medication adherence, the low efficacy of some therapies could also be related to inter-individual genetic variability. Genetic studies of families revealed that heritability accounts for 30% to 50% of inter-individual variation in blood pressure (BP). Genetic factors not only affect blood pressure (BP) elevation but also contribute to inter-individual variability in response to antihypertensive treatment. This article reviews the recent pharmacogenomics literature concerning the key classes of antihypertensive drugs currently in use (i.e., diuretics, β-blockers, ACE inhibitors, ARB, and CCB). Due to the numerous studies on this topic and the sometimes-contradictory results within them, the presented data are limited to several selected SNPs that alter drug response. Genetic polymorphisms can influence drug responses through genes engaged in the pathogenesis of hypertension that are able to modify the effects of drugs, modifications in drug–gene mechanistic interactions, polymorphisms within drug-metabolizing enzymes, genes related to drug transporters, and genes participating in complex cascades and metabolic reactions. The results of numerous studies confirm that genotype-based antihypertension therapies are the most effective and may help to avoid the occurrence of major adverse events, as well as decrease the costs of treatment. However, the genetic heritability of drug response phenotypes seems to remain hidden in multigenic and multifactorial complex traits. Therefore, further studies are required to analyze all associations and formulate final genome-based treatment recommendations.

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Pharmacogenomic studies of hypertension: paving the way for personalized antihypertensive treatment

Abstract: The polygenic nature of antihypertensive drug response is a major barrier to clinical implementation. Further studies examining clinical effectiveness are required to support broad-based implementation of genotype-based prescribing in medical practice.

Cited by 13 publications

References 99 publications

Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy

Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy

Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance

Pharmacogenomics of Hypertension Treatment

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