Newly diagnosed cardiovascular disease in patients treated with immune checkpoint inhibitors: a retrospective analysis of patients at an academic tertiary care center.

Background: Immune checkpoint inhibitors (ICIs) are a novel class of anticancer agents that have demonstrated clinical response for both solid and hematological malignancies. ICIs are associated with development of immune-related adverse events including cardiotoxicity. We estimated the incidence of newly diagnosed cardiovascular disease in patients treated with ICIs at a large, tertiary care center.

Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype-Derived Activity Scores.

Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.

Age-Related Changes in miRNA Expression Influence GSTZ1 and Other Drug Metabolizing Enzymes.

Previous work has shown that hepatic levels of human glutathione transferase zeta 1 (GSTZ1) protein, involved in tyrosine catabolism and responsible for metabolism of the investigational drug dichloroacetate, increase in cytosol after birth before reaching a plateau around age 7. However, the mechanism regulating this change of expression is still unknown, and previous studies showed that mRNA levels did not correlate with GSTZ1 protein expression. In this study, we addressed the hypothesis that microRNAs (miRNAs) could regulate expression of GSTZ1.

Effect of plasma MicroRNA on antihypertensive response to beta blockers in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies.

β-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to β-blockers. Expression of 22 β-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery).

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

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.

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

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.

Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics.

Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, <40% of patients treated with thiazide monotherapy achieve BP control. This study uses whole transcriptome sequencing to identify novel molecular markers associated with BP response to TD.

SIRT1/HERC4 Locus Associated With Bisphosphonate-Induced Osteonecrosis of the Jaw: An Exome-Wide Association Analysis.

Osteonecrosis of the jaw (ONJ) is a rare, but serious drug side effect, mainly associated with the use of intravenous (iv) bisphosphonates (BPs). The purpose of this study was to identify genetic variants associated with ONJ in patients of European ancestry treated with iv BPs using whole-exome sequencing (WES). The WES phase 1 included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase 2 included 17 ONJ patients with solid tumors.

Matrix Metalloproteinase Polymorphisms in Patients with Floppy Mitral Valve/Mitral Valve Prolapse (FMV/MVP) and FMV/MVP Syndrome.

Background: It has been suggested that collagen abnormalities of the mitral valve are present in patients with floppy mitral valve (FMV)/mitral valve prolapse (MVP). Genetic factors determining collagen synthesis and degradation have not been well defined in these patients. This study was undertaken to determine whether selective polymorphisms of matrix metalloproteinase-2 (MMP2) or transforming growth factor-β (TGFβ), with known or putative effects on collagen turnover, are more frequent in FMV/MVP.

Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections.

Objectives: Voriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs.

CES1P1 variant -816A>C is not associated with hepatic carboxylesterase 1 expression and activity or antihypertensive effect of trandolapril.

Purpose: The majority of angiotensin-converting enzyme inhibitors (ACEIs) are synthesized as ester prodrugs that must be converted to their active forms in vivo in order to exert therapeutic effects. Hepatic carboxylesterase 1 (CES1) is the primary enzyme responsible for the bioactivation of ACEI prodrugs in humans. The genetic variant -816A>C (rs3785161) is a common variant located in the promoter region of the CES1P1 gene.

Pharmacogenomic Genome-Wide Meta-Analysis of Blood Pressure Response to β-Blockers in Hypertensive African Americans.

African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to β-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy.

CYP2C19 and CES1 polymorphisms and efficacy of clopidogrel and aspirin dual antiplatelet therapy in patients with symptomatic intracranial atherosclerotic disease.

OBJECT Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients.

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

Objective: The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the β-blocker atenolol.

Methods: Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114).

Osteonecrosis of the Jaw in the United States Food and Drug Administration's Adverse Event Reporting System (FAERS).

Osteonecrosis of the jaw (ONJ) is a serious adverse drug event that was initially reported with intravenous bisphosphonates (BPs) and more recently with other classes of drugs such as receptor activator of NF-κB ligand (RANKL) inhibitor, antiangiogenic agents, and mammalian target of rapamycin (m-TOR) inhibitors. The purpose of this study is to analyze the ONJ cases and the associated drugs in the US Food and Drug Administration's adverse event reporting system (FAERS). The FAERS database was queried for the adverse drug events reported from the first quarter of 2010 to the first quarter of 2014.

The influence of human GSTZ1 gene haplotype variations on GSTZ1 expression.

Background/objectives: The zeta-1 family isoform of GST biotransforms the investigational drug dichloroacetate (DCA) and certain other halogenated carboxylic acids. Haplotype variability in GSTZ1 influences the kinetics and, possibly, the toxicity of DCA. DCA metabolism correlates with expression of the GSTZ1 protein, so it is important to document variables that affect expression.

Pyrosequencing of the CYP2C9 -1766T>C polymorphism as a means of detecting the CYP2C9*8 allele.

The CYP2C9 c.449G>A (p.R150H, rs7900194) polymorphism, which confers the CYP2C9*8 allele, is common in persons of African descent and results in reduced clearance of the narrow therapeutic index drugs, warfarin and phenytoin.

Floppy mitral valve/mitral valve prolapse syndrome: Beta-adrenergic receptor polymorphism may contribute to the pathogenesis of symptoms.

Background: Certain patients with floppy mitral valve (FMV)/mitral valve prolapse (MVP) may have symptoms that cannot be explained on the severity of mitral valvular regurgitation (MVR) alone; hypersensitivity to adrenergic stimulation has been suggested in this group defined as the FMV/MVP syndrome.

Methods: Ninety-eight patients (75 men, 23 women) with mitral valve surgery for FMV/MVP were studied. Of those 41 (42%) had symptoms consistent with FMV/MVP syndrome [29 men (39%), 12 women (52%)]; median age of symptom onset was 30 years (range 10-63 years) and median duration of symptoms prior to valve surgery was 16 years (range 3-50 years).

The influence of the CYP2C19*10 allele on clopidogrel activation and CYP2C19*2 genotyping.

Background/objectives: The polymorphic hepatic enzyme CYP2C19 catalyzes the metabolism of clinically important drugs such as clopidogrel, proton-pump inhibitors, and others and clinical pharmacogenetic testing for clopidogrel is increasingly common. The CYP2C19*10 single-nucleotide polymorphism (SNP) is located 1 bp upstream the CYP2C19*2 SNP. Despite the low frequency of the CYP2C19*10 allele, its impact on metabolism of CYP2C19 substrates and CYP2C19*2 genotyping makes it an important SNP to consider for pharmacogenetic testing of CYP2C19.

Clinical pharmacogenetics implementation: approaches, successes, and challenges.

Current challenges exist to widespread clinical implementation of genomic medicine and pharmacogenetics. The University of Florida (UF) Health Personalized Medicine Program (PMP) is a pharmacist-led, multidisciplinary initiative created in 2011 within the UF Clinical Translational Science Institute. Initial efforts focused on pharmacogenetics, with long-term goals to include expansion to disease-risk prediction and disease stratification.

Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations.

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project.

Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide-induced diabetes.

Objective: Thiazide diuretics have been associated with increased risk for new onset diabetes (NOD), but pharmacogenetic markers of thiazide-induced NOD are not well studied. Single nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2) represent the strongest and most reproducible genetic associations with diabetes. We investigated the association of tag SNPs in TCF7L2 with thiazide-induced NOD.

Atenolol induced HDL-C change in the pharmacogenomic evaluation of antihypertensive responses (PEAR) study.

We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with mild to moderate hypertension. We genotyped 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study on the Illumina HumanCVD Beadchip. During PEAR, participants were randomized to receive atenolol or hydrochlorothiazide.

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study.

Background: VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans.

Methods: We did a genome-wide association study of discovery and replication cohorts.