Publications by authors named "Caitrin W McDonough"

68 Publications

Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking β-blockers.

Pharmacogenomics J 2021 Oct 12. Epub 2021 Oct 12.

Center for Pharmacogenomics and Precision Medicine, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA.

Single nucleotide polymorphisms (SNPs) have been associated with differential beta-blocker (BB) effects on heart rate, blood pressure, and left ventricular ejection fraction in various patient populations. This study aimed to determine if SNPs previously associated with BB response are also associated with differential survival in heart failure (HF) patients receiving BBs. HF patient data were derived from electronic health records and the Social Security Death Index. Associations and interactions between BB dose, SNP genotype, and the outcome of death were assessed using a Cox proportional-hazard model adjusting for covariates known to be associated with differential survival in HF patients. Two SNPs, ADRB1 Arg389Gly and ADRB2 Glu27Gln, displayed significant interactions (P = 0.043 and P = 0.017, respectively) with BB dose and their association with mortality. Our study suggests that ADRB2 27Glu and ADRB1 389Arg may confer a larger survival benefit with higher BB doses in patients with HF.
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http://dx.doi.org/10.1038/s41397-021-00257-1DOI Listing
October 2021

Excessive White Matter Hyperintensity Increases Susceptibility to Poor Functional Outcomes After Acute Ischemic Stroke.

Front Neurol 2021 10;12:700616. Epub 2021 Sep 10.

Centogene AG, Rostock, Germany.

To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), < 0.01, respectively]. The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.
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http://dx.doi.org/10.3389/fneur.2021.700616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461233PMC
September 2021

Metabolomics Signature of Plasma Renin Activity and Linkage with Blood Pressure Response to Beta Blockers and Thiazide Diuretics in Hypertensive European American Patients.

Metabolites 2021 Sep 21;11(9). Epub 2021 Sep 21.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.

Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European-American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to β-blockers and thiazides. Using data from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) trial, multivariable linear regression adjusting for age, sex and baseline systolic-BP (SBP) was performed on European-American individuals treated with metoprolol ( = 198) and chlorthalidone ( = 181), to test associations between 856 metabolites and baseline PRA. Metabolites with a false discovery rate (FDR) < 0.05 or < 0.01 were tested for replication in 463 European-American individuals treated with atenolol or hydrochlorothiazide. Replicated metabolites were then tested for validation based on the directionality of association with BP response. Sixty-three metabolites were associated with baseline PRA, of which nine, including six lipids, were replicated. Of those replicated, two metabolites associated with higher baseline PRA were validated: caprate was associated with greater metoprolol SBP response (β = -1.7 ± 0.6, = 0.006) and sphingosine-1-phosphate was associated with reduced hydrochlorothiazide SBP response (β = 7.6 ± 2.8, = 0.007). These metabolites are clustered with metabolites involved in sphingolipid, phospholipid, and purine metabolic pathways. The identified metabolic signatures provide insights into the mechanisms underlying BP response.
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http://dx.doi.org/10.3390/metabo11090645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466669PMC
September 2021

Cox-sMBPLS: An Algorithm for Disease Survival Prediction and Multi-Omics Module Discovery Incorporating -Regulatory Quantitative Effects.

Front Genet 2021 2;12:701405. Epub 2021 Aug 2.

Informatics Institute, University of Florida, Gainesville, FL, United States.

Background: The development of high-throughput techniques has enabled profiling a large number of biomolecules across a number of molecular compartments. The challenge then becomes to integrate such multimodal Omics data to gain insights into biological processes and disease onset and progression mechanisms. Further, given the high dimensionality of such data, incorporating prior biological information on interactions between molecular compartments when developing statistical models for data integration is beneficial, especially in settings involving a small number of samples.

Results: We develop a supervised model for time to event data (e.g., death, biochemical recurrence) that simultaneously accounts for redundant information within Omics profiles and leverages prior biological associations between them through a multi-block PLS framework. The interactions between data from different molecular compartments (e.g., epigenome, transcriptome, methylome, etc.) were captured by using -regulatory quantitative effects in the proposed model. The model, coined Cox-sMBPLS, exhibits superior prediction performance and improved feature selection based on both simulation studies and analysis of data from heart failure patients.

Conclusion: The proposed supervised Cox-sMBPLS model can effectively incorporate prior biological information in the survival prediction system, leading to improved prediction performance and feature selection. It also enables the identification of multi-Omics modules of biomolecules that impact the patients' survival probability and also provides insights into potential relevant risk factors that merit further investigation.
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http://dx.doi.org/10.3389/fgene.2021.701405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366414PMC
August 2021

Genome-wide Association Study Identified Chromosome 8 Locus Associated with Medication-Related Osteonecrosis of the Jaw.

Clin Pharmacol Ther 2021 12 31;110(6):1558-1569. Epub 2021 Aug 31.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious drug-related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genomewide association study (GWAS) meta-analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates, which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the patients with cancer and replication GWAS was performed in the remaining 30% of the patients with cancer treated with intravenous bisphosphonates followed by meta-analysis of all 3,639 patients with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with oral bisphosphonates. The lead single-nucleotide polymorphism (SNP), rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90-3.86 (P = 3.57*10 ) in the meta-analysis of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with osteoporosis (OR: 2.82, 95% CI: 1.55-4.09, P = 6.84*10 ). The meta-analysis combining patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09-3.39, P = 9.65*10 ). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane-associated enzyme, which is implicated in the bisphosphonate pathway. This study provides insights into the potential mechanism of MRONJ.
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http://dx.doi.org/10.1002/cpt.2397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630710PMC
December 2021

MRI Radiomic Signature of White Matter Hyperintensities Is Associated With Clinical Phenotypes.

Front Neurosci 2021 12;15:691244. Epub 2021 Jul 12.

Department of Neurology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO, United States.

Objective: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes.

Methods: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask-WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA).

Results: Radiomic features were predictive of WMH burden ( = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected -values < 0.001, -value = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes.

Conclusion: Radiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of stroke patients' brain health.
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http://dx.doi.org/10.3389/fnins.2021.691244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312571PMC
July 2021

Pharmacogenomics in Cardiovascular Diseases.

Curr Protoc 2021 Jul;1(7):e189

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida.

Cardiovascular pharmacogenomics is the study and identification of genomic markers that are associated with variability in cardiovascular drug response, cardiovascular drug-related outcomes, or cardiovascular drug-related adverse events. This overview presents an introduction and historical background to cardiovascular pharmacogenomics, and a protocol for designing a cardiovascular pharmacogenomics study. Important considerations are also included for constructing a cardiovascular pharmacogenomics phenotype, designing the replication or validation strategy, common statistical approaches, and how to put the results in context with the cardiovascular drug or cardiovascular disease under investigation. © 2021 Wiley Periodicals LLC. Basic Protocol: Designing a cardiovascular pharmacogenomics study.
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http://dx.doi.org/10.1002/cpz1.189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344365PMC
July 2021

Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies.

Clin Pharmacol Ther 2021 09 15;110(3):723-732. Epub 2021 Aug 15.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

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 ). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10 , Beta = 3.09, diastolic BP response P = 5 × 10 , 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 , 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.
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http://dx.doi.org/10.1002/cpt.2355DOI Listing
September 2021

Outcome after acute ischemic stroke is linked to sex-specific lesion patterns.

Nat Commun 2021 06 2;12(1):3289. Epub 2021 Jun 2.

Department of Neurology, Washington University School of Medicine & Barnes-Jewish Hospital, St Louis, MO, USA.

Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n = 503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.
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http://dx.doi.org/10.1038/s41467-021-23492-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172535PMC
June 2021

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Eur Heart J 2021 05;42(18):1742-1756

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA.

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.

Methods And Results: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.

Conclusion: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehab107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244638PMC
May 2021

SIRT1 Gene SNP rs932658 Is Associated With Medication-Related Osteonecrosis of the Jaw.

J Bone Miner Res 2021 02 23;36(2):347-356. Epub 2020 Oct 23.

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug reaction. Our previous whole-exome sequencing study found SIRT1 intronic region single-nucleotide polymorphism (SNP) rs7896005 to be associated with MRONJ in cancer patients treated with intravenous (iv) bisphosphonates (BPs). This study aimed to identify causal variants for this association. In silico analyses identified three SNPs (rs3758391, rs932658, and rs2394443) in the SIRT1 promoter region that are in high linkage disequilibrium (r  > 0.8) with rs7896005. To validate the association between these SNPs and MRONJ, we genotyped these three SNPs on the germline DNA from 104 cancer patients of European ancestry treated with iv BPs (46 cases and 58 controls). Multivariable logistic regression analysis showed the minor alleles of these three SNPs were associated with lower odds for MRONJ. The odds ratios (95% confidence interval) and p values were 0.351 (0.164-0.751; p = 0.007) for rs3758391, 0.351 (0.164-0.751; p = 0.007) for rs932658, and 0.331 (0.157-0.697; p = 0.0036) for rs2394443, respectively. In the reporter gene assays, constructs containing rs932658 with variant allele A had higher luciferase activity than the reference allele, whereas constructs containing SNP rs3758391 and/or rs2394443 did not significantly affect activity. These results indicate that the promoter SNP rs932658 regulates the expression of SIRT1 and presumably lowers the risk of MRONJ by increasing SIRT1 expression. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4185DOI Listing
February 2021

Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Clin Pharmacol Ther 2021 03 2;109(3):705-715. Epub 2020 Oct 2.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida, USA.

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.
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http://dx.doi.org/10.1002/cpt.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902344PMC
March 2021

Optimizing identification of resistant hypertension: Computable phenotype development and validation.

Pharmacoepidemiol Drug Saf 2020 11 26;29(11):1393-1401. Epub 2020 Aug 26.

Department of Health Outcomes & Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA.

Purpose: Computable phenotypes are constructed to utilize data within the electronic health record (EHR) to identify patients with specific characteristics; a necessary step for researching a complex disease state. We developed computable phenotypes for resistant hypertension (RHTN) and stable controlled hypertension (HTN) based on the National Patient-Centered Clinical Research Network (PCORnet) common data model (CDM). The computable phenotypes were validated through manual chart review.

Methods: We adapted and refined existing computable phenotype algorithms for RHTN and stable controlled HTN to the PCORnet CDM in an adult HTN population from the OneFlorida Clinical Research Consortium (2015-2017). Two independent reviewers validated the computable phenotypes through manual chart review of 425 patient records. We assessed precision of our computable phenotypes through positive predictive value (PPV) and test validity through interrater reliability (IRR).

Results: Among the 156 730 HTN patients in our final dataset, the final computable phenotype algorithms identified 24 926 patients with RHTN and 19 100 with stable controlled HTN. The PPV for RHTN in patients randomly selected for validation of the final algorithm was 99.1% (n = 113, CI: 95.2%-99.9%). The PPV for stable controlled HTN in patients randomly selected for validation of the final algorithm was 96.5% (n = 113, CI: 91.2%-99.0%). IRR analysis revealed a raw percent agreement of 91% (152/167) with Cohen's kappa statistic = 0.87.

Conclusions: We constructed and validated a RHTN computable phenotype algorithm and a stable controlled HTN computable phenotype algorithm. Both algorithms are based on the PCORnet CDM, allowing for future application to epidemiological and drug utilization based research.
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http://dx.doi.org/10.1002/pds.5095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754782PMC
November 2020

Optimizing Antihypertensive Medication Classification in Electronic Health Record-Based Data: Classification System Development and Methodological Comparison.

JMIR Med Inform 2020 Feb 27;8(2):e14777. Epub 2020 Feb 27.

Department of Health Outcomes & Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL, United States.

Background: Computable phenotypes have the ability to utilize data within the electronic health record (EHR) to identify patients with certain characteristics. Many computable phenotypes rely on multiple types of data within the EHR including prescription drug information. Hypertension (HTN)-related computable phenotypes are particularly dependent on the correct classification of antihypertensive prescription drug information, as well as corresponding diagnoses and blood pressure information.

Objective: This study aimed to create an antihypertensive drug classification system to be utilized with EHR-based data as part of HTN-related computable phenotypes.

Methods: We compared 4 different antihypertensive drug classification systems based off of 4 different methodologies and terminologies, including 3 RxNorm Concept Unique Identifier (RxCUI)-based classifications and 1 medication name-based classification. The RxCUI-based classifications utilized data from (1) the Drug Ontology, (2) the new Medication Reference Terminology, and (3) the Anatomical Therapeutic Chemical Classification System and DrugBank, whereas the medication name-based classification relied on antihypertensive drug names. Each classification system was applied to EHR-based prescription drug data from hypertensive patients in the OneFlorida Data Trust.

Results: There were 13,627 unique RxCUIs and 8025 unique medication names from the 13,879,046 prescriptions. We observed a broad overlap between the 4 methods, with 84.1% (691/822) to 95.3% (695/729) of terms overlapping pairwise between the different classification methods. Key differences arose from drug products with multiple dosage forms, drug products with an indication of benign prostatic hyperplasia, drug products that contain more than 1 ingredient (combination products), and terms within the classification systems corresponding to retired or obsolete RxCUIs.

Conclusions: In total, 2 antihypertensive drug classifications were constructed, one based on RxCUIs and one based on medication name, that can be used in future computable phenotypes that require antihypertensive drug classifications.
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http://dx.doi.org/10.2196/14777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068459PMC
February 2020

Response to: Heterogeneous Treatment Response by Race Cannot Be Claimed in the Absence of Evidence.

Am J Hypertens 2020 02;33(2):e2

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida.

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http://dx.doi.org/10.1093/ajh/hpz168DOI Listing
February 2020

Combination Antihypertensive Therapy Prescribing and Blood Pressure Control in a Real-World Setting.

Am J Hypertens 2020 04;33(4):316-324

Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, Florida, USA.

Background: Specific combinations of two drug classes are recommended in a variety of clinical situations in the management of hypertension. These preferred combinations are based on complimentary blood pressure (BP) lowering mechanisms or benefit for a concomitant disease.

Methods: Using electronic health records (EHRs) data from 27,579 ambulatory hypertensive patients, we investigated antihypertensive therapy prescribing patterns and associations of preferred two drug classes with BP control.

Results: Overall, BP control, defined as BP <140/90 mm Hg, was 65% among treated patients. Preferred dual antihypertensive therapy was prescribed in 55% of patients with uncomplicated hypertension, 49% of patients with diabetes, and 47% of patients with a history of myocardial infarction (MI); these prescribing frequencies of preferred combinations were not explained by worse BP control on those combinations. In fact, we found suggestive evidence of association between prescribing of preferred two drug classes and improved BP control among post-MI (OR: 1.21, 95% CI: 0.99-1.48, P = 0.061) and uncomplicated hypertensive (OR: 1.11, 95% CI: 0.98-1.26, P = 0.089) patients.

Conclusions: Prescribing of guideline-recommended antihypertensive drug classes for concomitant diseases is suboptimal and prescribing of preferred/optimized drug class combinations was moderate. We did not find a clear association between the use of optimized drug class combinations and greater BP control. Overall, using EHR data, we identified potential opportunities for re-examining prescribing practices with implications for clinical decision support and healthcare improvement at the community and health system-wide levels.
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http://dx.doi.org/10.1093/ajh/hpz196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109351PMC
April 2020

Genome Wide Analysis Approach Suggests Chromosome 2 Locus to be Associated with Thiazide and Thiazide Like-Diuretics Blood Pressure Response.

Sci Rep 2019 11 21;9(1):17323. Epub 2019 Nov 21.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA.

Chlorthalidone (CTD) is more potent than hydrochlorothiazide (HCTZ) in reducing blood pressure (BP) in hypertensive patients, though both are plagued with BP response variability. However, there is a void in the literature regarding the genetic determinants contributing to the variability observed in BP response to CTD. We performed a discovery genome wide association analysis of BP response post CTD treatment in African Americans (AA) and European Americans (EA) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and replication in an independent cohort of AA and EA treated with HCTZ from the PEAR study, followed by a race specific meta-analysis of the two studies. Successfully replicated SNPs were further validated in beta-blocker treated participants from PEAR-2 and PEAR for opposite direction of association. The replicated and validated signals were further evaluated by protein-protein interaction network analysis. An intronic SNP rs79237970 in the WDR92 (eQTL for PPP3R1) was significantly associated with better DBP response to CTD (p = 5.76 × 10, β = -15.75) in the AA cohort. This SNP further replicated in PEAR (p = 0.00046, β = -9.815) with a genome wide significant meta-analysis p-value of 8.49 × 10. This variant was further validated for opposite association in two β-blockers treated cohorts from PEAR-2 metoprolol (p = 9.9 × 10, β = 7.47) and PEAR atenolol (p = 0.04, β = 4.36) for association with DBP. Studies have implicated WDR92 in coronary artery damage. PPP3R1 is the regulatory subunit of the calcineurin complex. Use of calcineurin inhibitors is associated with HTN. Studies have also shown polymorphisms in PPP3R1 to be associated with ventricular hypertrophy in AA hypertensive patients. Protein-protein interaction analysis further identified important hypertension related pathways such as inositol phosphate-mediated signaling and calcineurin-NFAT signaling cascade as important biological process associated with PPP3R1 which further strengthen the potential importance of this signal. These data collectively suggest that WDR92 and PPP3R1 are novel candidates that may help explain the genetic underpinnings of BP response of thiazide and thiazide-like diuretics and help identify the patients better suited for thiazide and thiazide-like diuretics compared to β-blockers for improved BP management. This may further help advance personalized approaches to antihypertensive therapy.
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http://dx.doi.org/10.1038/s41598-019-53345-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872535PMC
November 2019

Genome-Wide Meta-Analysis of Blood Pressure Response to β-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies).

J Am Heart Assoc 2019 08 19;8(16):e013115. Epub 2019 Aug 19.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine University of Florida Gainesville FL.

BackgroundThere exists a wide interindividual variability in blood pressure (BP) response to β-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants influencing β-blocker BP response.Methods and ResultsGenome-wide association analysis for systolic BP and diastolic BP response to β-blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta-analysis and single nucleotide polymorphisms (SNPs) with P<10 were tested for replication in 2 independent randomized clinical trials of β-blocker-treated patients of European ancestry (n=1552). Regions harboring the replicated SNPs were validated in a β-blocker-treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST1 was associated with systolic BP response to β-blockers in the discovery meta-analysis (P=9.33×10, β=-3.21 mm Hg) and replicated at Bonferroni significance (P=1.85×10, β=-4.86 mm Hg) in the replication meta-analysis with combined meta-analysis approaching genome-wide significance (P=2.18×10). This SNP in BST1 is in linkage disequilibrium with several SNPs with putative regulatory functions in nearby genes, including CD38, FBXL5, and FGFBP1, all of which have been implicated in BP regulation. SNPs in this genetic region were also associated with BP response in the black cohort.ConclusionsData from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST1 containing locus on chromosome 4 is associated with β-blocker BP response. Given the previous associations of this region with BP, this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.
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http://dx.doi.org/10.1161/JAHA.119.013115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759913PMC
August 2019

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

Clin Transl Sci 2019 09 4;12(5):497-504. Epub 2019 Jun 4.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA.

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 , 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 , 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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http://dx.doi.org/10.1111/cts.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742943PMC
September 2019

Pharmacogenomics of osteonecrosis of the jaw.

Bone 2019 07 22;124:75-82. Epub 2019 Apr 22.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, USA; UF Health Cancer Center, Gainesville, FL, USA. Electronic address:

Osteonecrosis of the jaw (ONJ) is a rare but serious drug induced adverse event, mainly associated with the use of antiresorptive medications, such as intravenous (IV) bisphosphonates (BPs) in cancer patients. In this review, we evaluated all the pharmacogenomic association studies for ONJ published up to December 2018. To date, two SNPs (CYP2C8 rs1934951 and RBMS3 rs17024608) were identified to be associated with ONJ by two genome-wide association studies (GWAS). However, all six subsequent candidate gene studies failed to replicate these results. In addition, six discovery candidate gene studies tried to identify the genetic markers in several genes associated with bone remodeling, bone mineral density, or osteoporosis. After evaluating the results of these 6 studies, none of the SNPs was significantly associated with ONJ. Recently, two whole-exome sequencing (WES) analysis (including one from our group) were performed to identify variants associated with ONJ. So far, only our study successfully replicated discovery result indicating SIRT1 SNP rs7896005 to be associated with ONJ. However, this SNP also did not reach genome-wide significance. The major limitations of these studies include lack of replication phases and limited sample sizes. Even though some studies had larger sample sizes, they recruited healthy individuals as controls, not subjects treated with BPs. We conclude that a GWAS with a larger sample size followed by replication phase will be needed to fully investigate the pharmacogenomic markers of ONJ.
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http://dx.doi.org/10.1016/j.bone.2019.04.010DOI Listing
July 2019

IGNITE network: Response of patients to genomic medicine interventions.

Mol Genet Genomic Med 2019 05 20;7(5):e636. Epub 2019 Mar 20.

National Human Genome Research Institute, Bethesda, Maryland.

Background: The IGNITE network funds six genomic medicine projects. Though interventions varied, we hypothesized that synergies across projects could be leveraged to better understand the participant experiences with genomic medicine interventions. Therefore, we performed cross-network analyses to identify associations between participant demographics and attitudes toward the intervention (attitude), plan to share results (share), and quality of life (QOL).

Methods: Data collection for demographics, attitude, share, and QOL surveys were standardized across projects. Recruitment and survey administration varied by each project's protocol.

Results: Participants (N = 6,817) were 67.2% (N = 4,584) female, and 37.4% (N = 3,544) were minority. Mean age = 54.0 (sd 14.a). Younger participants were as follows: (1) more positive in attitude pre-intervention (1.15-fold decrease/10-year age increase (OR)) and more negative after (1.14-fold increase OR); (2) higher in QOL pre-intervention (1.07-fold increase OR) and postintervention; (3) more likely to share results (1.12-fold increase OR). Race was significant when sharing results (white participants increased OR = 1.88), but not for change in QOL pre-postintervention or attitude.

Conclusion: Our findings demonstrate the feasibility of this approach and identified a few key themes which are as follows: age was consistently significant across the three outcomes, whereas race had less of an impact than expected. However, these are only associations and thus warrant further study.
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http://dx.doi.org/10.1002/mgg3.636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503007PMC
May 2019

Plasma Renin Activity Is a Predictive Biomarker of Blood Pressure Response in European but not in African Americans With Uncomplicated Hypertension.

Am J Hypertens 2019 06;32(7):668-675

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Background: Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood.

Methods: Using systematic-phased approach, PRA's clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed.

Results: EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by -15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%.

Conclusions: PRA at the previously established 0.60-0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs.

Trial Registration: NCT01203852, NCT00246519, NCT00005520.
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http://dx.doi.org/10.1093/ajh/hpz022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558666PMC
June 2019

Antihypertensive therapy prescribing patterns and correlates of blood pressure control among hypertensive patients with chronic kidney disease.

J Clin Hypertens (Greenwich) 2019 01 14;21(1):91-101. Epub 2018 Nov 14.

Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, Florida.

We used electronic health records (EHRs) data from 5658 ambulatory chronic kidney disease (CKD) patients with hypertension and prescribed antihypertensive therapy to examine antihypertensive drug prescribing patterns, blood pressure (BP) control, and risk factors for resistant hypertension (RHTN) in a real-world setting. Two-thirds of CKD patients and three-fourths of those with proteinuria were prescribed guideline-recommended renoprotective agents including an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB); however, one-third were not prescribed an ACEI or ARB. CKD patients, particularly those with stages 1-2 CKD, who were prescribed regimens including beta-blocker (BB) + diuretic or ACEI/ARB + BB + diuretic were more likely to have controlled BP (<140/90 mm Hg) compared to those prescribed other combinations. Risk factors for RHTN included African American race and major comorbidities. Clinicians may use these findings to tailor antihypertensive therapy to the needs of each patient, including providing CKD stage-specific treatment, and better identify CKD patients at risk of RHTN.
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http://dx.doi.org/10.1111/jch.13429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329007PMC
January 2019

Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide.

Pharmacogenet Genomics 2018 11;28(11):251-255

Departments of Pharmacotherapy and Translational Research and Center for Pharmacogenomics.

Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, β=-1.60, ΔDBP: P=0.023, β=-1.08) and GERA (ΔSBP: P=0.028, β=-1.95, ΔDBP: P=0.032, β=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.
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http://dx.doi.org/10.1097/FPC.0000000000000353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262886PMC
November 2018

Genome-wide association analysis of common genetic variants of resistant hypertension.

Pharmacogenomics J 2019 06 20;19(3):295-304. Epub 2018 Sep 20.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Resistant hypertension (RHTN), defined as uncontrolled blood pressure (BP) ≥ 140/90 using three or more drugs or controlled BP (<140/90) using four or more drugs, is associated with adverse outcomes, including decline in kidney function. We conducted a genome-wide association analysis in 1194 White and Hispanic participants with hypertension and coronary artery disease from the INternational VErapamil-SR Trandolapril STudy-GENEtic Substudy (INVEST-GENES). Top variants associated with RHTN at p < 10 were tested for replication in 585 White and Hispanic participants with hypertension and subcortical strokes from the Secondary Prevention of Subcortical Strokes GENEtic Substudy (SPS3-GENES). A genetic risk score for RHTN was created by summing the risk alleles of replicated RHTN signals. rs11749255 in MSX2 was associated with RHTN in INVEST (odds ratio (OR) (95% CI) = 1.50 (1.2-1.8), p = 7.3 × 10) and replicated in SPS3 (OR = 2.0 (1.4-2.8), p = 4.3 × 10), with genome-wide significance in meta-analysis (OR = 1.60 (1.3-1.9), p = 3.8 × 10). Other replicated signals were in IFLTD1 and PTPRD. IFLTD1 rs6487504 was associated with RHTN in INVEST (OR = 1.90 (1.4-2.5), p = 1.1 × 10) and SPS3 (OR = 1.70 (1.2-2.5), p = 4 × 10). PTPRD rs324498, a previously reported RHTN signal, was among the top signals in INVEST (OR = 1.60 (1.3-2.0), p = 3.4 × 10) and replicated in SPS3 (OR = 1.60 (1.1-2.4), one-sided p = 0.005). Participants with the highest number of risk alleles were at increased risk of RHTN compared to participants with a lower number (p-trend = 1.8 × 10). Overall, we identified and replicated associations with RHTN in the MSX2, IFLTD1, and PTPRD regions, and combined these associations to create a genetic risk score.
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http://dx.doi.org/10.1038/s41397-018-0049-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426691PMC
June 2019

Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies.

BMC Med Genomics 2018 Jun 20;11(1):55. Epub 2018 Jun 20.

Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, P.O.Box 100484, Gainesville, FL, 32610-0486, USA.

Background: Recently, 34 genes had been associated with differential expression relative to blood pressure (BP)/ hypertension (HTN). We hypothesize that some of the genes associated with BP/HTN are also associated with BP response to antihypertensive treatment with thiazide diuretics.

Methods: We assessed these 34 genes for association with differential expression to BP response to thiazide diuretics with RNA sequencing in whole blood samples from 150 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. PEAR white and PEAR-2 white and black participants (n = 50 for each group) were selected based on the upper and lower quartile of BP response to hydrochlorothiazide (HCTZ) and to chlorthalidone.

Results: FOS, DUSP1 and PPP1R15A were differentially expressed across all cohorts (meta-analysis p-value < 2.0 × 10), and responders to HCTZ or chlorthalidone presented up-regulated transcripts. Rs11065987 in chromosome 12, a trans-eQTL for expression of FOS, PPP1R15A and other genes, is also associated with BP response to HCTZ in PEAR whites (SBP: β = - 2.1; p = 1.7 × 10; DBP: β = - 1.4; p = 2.9 × 10).

Conclusions: These findings suggest FOS, DUSP1 and PPP1R15A as potential molecular determinants of antihypertensive response to thiazide diuretics.

Trial Registration: NCT00246519 , NCT01203852 www.clinicaltrials.gov.
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http://dx.doi.org/10.1186/s12920-018-0370-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011347PMC
June 2018

Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses).

Circ Genom Precis Med 2018 04;11(4):e001854

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics (C.W.M., O.M., A.C.C.S., N.M.E.R., M.K.-S., M.S., J.G.G., R.M.C.-D., Y.G., J.A.J.), Department of Pharmaceutical Outcomes and Policy (C.D.), Department of Pharmaceutics, College of Pharmacy (A.N.D., R.S.P.S.), Genetics & Genomics Graduate Program, Genetics Institute (A.C.C.S., Y.S.), Department of Biology, College of Liberal Arts and Sciences (W.M.), Department of Community Health and Family Medicine, College of Medicine (J.G.G.), and Division of Cardiovascular Medicine, Department of Medicine (R.M.C.-D., J.A.J.), University of Florida, Gainesville; School of Pharmacy, College of Health Professions, Pacific University, Hillsboro, OR (M.K.-S.); Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (M.S.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Medicine (S.T.T.), Mayo Clinic, Rochester, MN; Human Genetics Center, Institute of Molecular Medicine, University of Texas Health Science Center, Houston (E.B.); Section of Nephrology, Department of Medicine, University of Chicago, IL (A.B.C.); Department of Biomedical Informatics, Center for Pharmacogenomics (A.W.) and Department of Cancer Biology and Genetics, College of Medicine (W.S.), Ohio State University, Columbus; and Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (S.E.S.).

Background: Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses).

Methods: Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2).

Results: Our top SNP rs3784921 was in the gene region. The G allele of rs3784921 was associated with higher baseline PRA (β=0.47; =2.09×10) and smaller systolic BP reduction in response to hydrochlorothiazide (β=2.97; 1-sided =0.006). In addition, expression differed by rs3784921 genotype (=0.007), and rs1802409, a proxy SNP for rs3784921 (=0.98-1.00), replicated in PEAR-2 (β=0.15; 1-sided =0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes and CONCLUSIONS: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.
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http://dx.doi.org/10.1161/CIRCGEN.117.001854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901893PMC
April 2018

Genome Wide Association Study Identifies the Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients.

J Am Heart Assoc 2018 03 9;7(6). Epub 2018 Mar 9.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, FL.

Background: Thiazide and thiazide-like diuretics are first-line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide-like diuretic/chlorthalidone-induced glucose change.

Methods And Results: Genome-wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR-2 (Pharmacogenomic Evaluation of Antihypertensive Responses-2). Single-nucleotide polymorphisms with <5×10 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single-nucleotide polymorphism (rs9943291) in the was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; =4.17×10). G-allele carriers of had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide-treated participants from the PEAR study (ß=5.54; =0.023). A meta-analysis of the 2 studies was performed by race in Meta-Analysis Helper, where this single-nucleotide polymorphism, rs9943291, was genome-wide significant with a meta-analysis value of 3.71×10. , a part of the HMG-CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis.

Conclusions: These results suggest that is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)-induced glucose change. This may provide insights into the mechanisms involved in thiazide-induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.
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http://dx.doi.org/10.1161/JAHA.117.007339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907544PMC
March 2018
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