PTPRD gene associated with blood pressure response to atenolol and resistant hypertension

Gong, Yan; McDonough, Caitrin W.; Beitelshees, Amber L.; Rouby, Nihal El; Hiltunen, Timo P.; O’Connell, Jeffrey R.; Padmanabhan, Sandosh; Langaee, Taimour; Hall, Karen; Schmidt, Siegfried; Curry, R. B.; Gums, John G.; Donner, Kati; Kontula, Kimmo; Bailey, Kent R.; Boerwinkle, Eric; Takahashi, Atsushi; Tanaka, Toshihiro; Kubo, Michiaki; Chapman, Arlene B.; Turner, Stephen T.; Pepine, Carl J.; Cooper‐DeHoff, Rhonda M.

doi:10.1097/hjh.0000000000000714

Cited by 39 publications

(33 citation statements)

References 24 publications

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“…Analogously, a GWAS examining atenolol monotherapy was conducted in white participants of the PEAR trials 86 . This analysis identified two polymorphisms, rs12346562 and rs1104514, near the PTPRD gene that were associated with improved atenolol BP reduction in whites.…”

Section: Plausible Variants Uncovered In Unbiased Analysesmentioning

confidence: 99%

A Physiologic Approach to the Pharmacogenomics of Hypertension

Eadon

Chapman

2016

Advances in Chronic Kidney Disease

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Section: Plausible Variants Uncovered In Unbiased Analysesmentioning

confidence: 99%

A Physiologic Approach to the Pharmacogenomics of Hypertension

Eadon

Chapman

2016

Advances in Chronic Kidney Disease

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“…changes in diet, exercise, time-of-day, combinations of prescribed drugs, alcohol usage, etc .). Several PGx GWAS have reported variants in plausible genes associated with thiazide diuretics (Chittani et al, 2015; Turner et al, 2008; Turner et al, 2013), angiotensin II receptor blockers (Frau et al, 2014; Turner et al, 2012), and beta-blockers (Gong et al, 2015; Gong et al, 2016); yet, most of these studies involve relatively small discovery sample-sizes and are underpowered, as far as detecting associations having genome-wide significance ( i.e. P < 5 × 10 −8 ).…”

Section: Genetic Studies Of Pgx Traitsmentioning

confidence: 99%

Personalized medicine: Genetic risk prediction of drug response

Zhang

Nebert

2017

Pharmacology & Therapeutics

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Pharmacogenomics (PGx), a substantial component of “personalized medicine”, seeks to understand each individual's genetic composition to optimize drug therapy reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants. [b] Predominantly oligogenic traits represent variation largely influenced by a small number of major pharmacokinetic or pharmacodynamic genes. [c] Complex PGx traits resemble most multifactorial quantitative traits –– influenced by numerous small-effect variants, together with epigenetic effects and environmental factors. Prediction of monogenic drug responses is relatively simple, involving detection of underlying mutations; due to rarity of these events and incomplete penetrance, however, prospective tests based on genotype will have high false-positive rates, plus pharmacoeconomics will require justification. Prediction of predominantly oligogenic traits is slowly improving. Although a substantial fraction of variation can be explained by limited numbers of large-effect genetic variants, uncertainty in successful predictions and overall cost-benefit ratios will make such tests elusive for everyday clinical use. Prediction of complex PGx traits is almost impossible in the foreseeable future. Genome-wide association studies of large cohorts will continue to discover relevant genetic variants; however, these small-effect variants, combined, explain only a small fraction of phenotypic variance –– thus having limited predictive power and clinical utility.

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“…A multistaged GWAS analysis plan was used to identify genetic variants associated with BP response to β‐blockers, the details of which are represented in Figure . We have previously published pharmacogenomic findings related to β‐blocker BP response using only PEAR as the discovery cohort because this was before the PEAR‐2 trial was completed . Hence, in this study, PEAR‐2 was used as the discovery and PEAR as the replication cohort.…”

Section: Methodsmentioning

confidence: 99%

Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta‐Blockers in European Americans

Singh

Rouby

McDonough

et al. 2019

Clinical Translational Sci

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European Americans (EA) have a better antihypertensive response to β‐blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post–metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses‐2 (PEAR‐2) study and tested for replication in the atenolol‐treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β‐blockers in the PEAR‐2 study (P = 3.41 × 10−6, β = −2.70) and replicated (P = 0.01, β = −1.17) in the PEAR study. Post–meta‐analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β‐blockers (P = 3.43 × 10−6, β = 4.57) and was replicated in the atenolol add‐on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β‐blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β‐blockers.

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PTPRD gene associated with blood pressure response to atenolol and resistant hypertension

Cited by 39 publications

References 24 publications

A Physiologic Approach to the Pharmacogenomics of Hypertension

A Physiologic Approach to the Pharmacogenomics of Hypertension

Personalized medicine: Genetic risk prediction of drug response

Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta‐Blockers in European Americans

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