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Pharmacogenet Genomics 2019 Feb 4. Epub 2019 Feb 4.

Department of Cardiovascular Medicine.

Objective: To evaluate perceptions toward pharmacogenetic testing of patients undergoing percutaneous coronary intervention (PCI) who are prescribed dual antiplatelet therapy (DAPT) and whether geographical differences in these perceptions exist.

Participants And Methods: TAILOR-PCI is the largest genotype-based cardiovascular clinical trial randomizing participants to conventional DAPT or prospective genotyping-guided DAPT. Enrolled patients completed surveys before and 6 months after randomization. Read More

Pharmacogenet Genomics 2019 Feb 1. Epub 2019 Feb 1.

Departments of Epidemiology.

Objective: Antituberculosis (anti-TB) drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction, and its pathogenic mechanism has not been elucidated thoroughly to date. A recent genome-wide association study reported that seven single-nucleotide polymorphisms (SNPs) in the family with sequence similarity 65, member B gene (FAM65B), ATP/GTP-binding protein-like 4 gene (AGBL4), and cut-like homeobox 2 gene (CUX2) were associated strongly with ATDH in Ethiopian patients. We validated this relationship in a Chinese Han anti-TB treatment population. Read More

Pharmacogenet Genomics 2019 Jan 28. Epub 2019 Jan 28.

Department of Medical Bioscience, Graduate School, Soonchunhyang University, Asan.

Background: We previously found differences in the minor allele frequency (MAF) of single-nucleotide polymorphisms (SNPs) in transmembrane protein 196 (TMEM196) between 995 patients with aspirin-tolerant asthma (ATA) and 141 asthmatic patients with NSAID-exacerbated respiratory disease (NERD). In this study, we statistically analyzed the distributions of the genotypes and haplotypes of these SNPs to determine the exact association between TMEM196 genetic variants and the risk for NERD.

Materials And Methods: Lewontin's D' and r values were used to measure linkage disequilibrium between the biallelic loci having MAFs more than 0. Read More

Pharmacogenet Genomics 2019 Jan 21. Epub 2019 Jan 21.

Departments of Biomedical Data Sciences.

Pharmacogenet Genomics 2019 Jan 11. Epub 2019 Jan 11.

Channing Division of Network Medicine.

Asthma is the most common chronic disease in children. Inhaled corticosteroids (ICS) are the first-line treatment for asthma control, but up to one-third of children have a poor treatment response. The mechanism of ICS resistance is poorly understood, and the role of DNA methylation in ICS treatment response is not known. Read More

Pharmacogenet Genomics 2018 Dec 15. Epub 2018 Dec 15.

Department of Medicine, Channing Division of Network Medicine.

Background: Human Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) have been thought to be a useful model system for pharmacogenomics studies. The purpose of this study was to determine the effect of Epstein-Barr virus transformation on gene expression changes by dexamethasone (Dex) in LCLs and primary B cells (PBCs) derived from the same individuals.

Patients And Methods: We prepared LCLs and purified PBCs from the same six male donors participating in the Childhood Asthma Management Program clinical trial, and compared mRNA profiles after 6 h incubation with Dex (10 mol/l) or sham buffer. Read More

Pharmacogenet Genomics 2018 Dec 17. Epub 2018 Dec 17.

Coriell Institute for Medical Research, Camden, New Jersey.

Objectives: The objectives of this study were to determine whether differences in CYP2C8 and CYP2C9 haplotype influence the dose of ibuprofen self-administered by individuals, and to examine the potential relationship between CYP2C8 and CYP2C9 reduced metabolism haplotypes and adverse events.

Participants And Methods: We investigated relationships between genetic variations in CYP2C8 and CYP2C9 and ibuprofen use, dose, and side effects (reported by questionnaire) in 445 participants from the Coriell Personalized Medicine Collaborative.

Results: Carriers of reduced metabolism haplotypes for CYP2C8 (*2, *3, *4) and CYP2C9 (*2, *3) were significantly (P=0. Read More

Pharmacogenet Genomics 2019 Feb;29(2):23-30

Center for Personalized Therapeutics.

Introduction: In-hospital adverse medication events result in increased morbidity and mortality. Many implicated drugs carry pharmacogenomic information. We hypothesized that comprehensive pre-emptive pharmacogenomic profiling could have high relevance for in-hospital prescribing. Read More

Pharmacogenet Genomics 2019 Feb;29(2):31-38

Center for Personalized Therapeutics.

Objective: The objective of this study was to study provider attitudes of and perceived barriers to the clinical use of pharmacogenomics before and during participation in an implementation program.

Participants And Methods: From 2012 to 2017, providers were recruited. After completing semistructured interviews (SSIs) about pharmacogenomics, providers received training on and access to a clinical decision support tool housing patient-specific pharmacogenomic results. Read More

Pharmacogenet Genomics 2019 Feb;29(2):39-47

Department of Cancer Biology and Genetics, Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus, Ohio.

Introduction: CYP2D6 metabolizes ∼25% of all clinically used drugs, with numerous genetic polymorphisms affecting enzyme activity and drug response. Clinical utility of current CYP2D6 genotyping is partially compromised the unresolved complex haplotype structure of the CYP2D6 locus. We have identified a distal enhancer single-nucleotide polymorphism rs5758550 that robustly increases CYP2D6 expression, whereas rs16947 (CYP2D6*2), previously considered inert, reduces correct mRNA splicing and expression, thereby affecting presumed activity of other alleles on the *2 haplotype. Read More

Pharmacogenet Genomics 2019 Jan;29(1):18-22

Departments of Medicine.

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. Read More

Pharmacogenet Genomics 2019 Jan;29(1):9-17

Discipline of Pharmacology, Adelaide Medical School, University of Adelaide.

Background: CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression. Read More

Pharmacogenet Genomics 2018 Dec;28(12):268-269

Functional Genomics Group, Genomic Medicine Section, National Heart and Lung Institute, Imperial College London, London, UK.

Pharmacogenet Genomics 2018 Dec;28(12):268

Departments of Nephrology.

Pharmacogenet Genomics 2019 Jan;29(1):1-8

School of Pharmacy.

Aim: Human leukocyte antigen (HLA-B*58:01) allele screening before allopurinol administration is recommended to prevent gene-mediated severe cutaneous adverse reactions (SCARs). The objective of the analysis was to examine the clinical utility and effects of HLA-B*58:01 genotyping on patient's outcomes in a practice setting.

Patients And Methods: The electronic medical records covering diagnosis, laboratory results, and prescription dispensing for patients who were newly treated with allopurinol or tested for HLA-B*58:01 were obtained from a large medical organization in Taiwan between 2010 and 2014. Read More

Pharmacogenet Genomics 2018 Dec;28(12):261-267

Department of Pharmacy, Peking University First Hospital, Beijing, China.

Objective: The aim of this study was to determine the impact of the SLCO1B1, apolipoprotein E (ApoE), and CYP2C9 genotypes on the lipid-lowering efficacy of fluvastatin.

Methods: We performed electronic searches on the PubMed, Embase, and Cochrane Library databases to identify studies published through October 2017. Studies that reported the effect estimates with 95% confidence intervals (CIs) of total cholesterol (TC), triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein were included so that the different genotype categories could be compared. Read More

Pharmacogenet Genomics 2018 Nov;28(11):256-259

Center for Applied Genomics, Children's Hospital of Philadelphia.

Asthma is the leading chronic disease in children. Several studies have identified genetic biomarkers associated with susceptibility and severity in both adult and pediatric cases. In this study, we evaluated outcomes in 400 African American and European American pediatric cases all of whom were regular users of inhaled corticosteroids. Read More

Pharmacogenet Genomics 2018 Nov;28(11):245-250

Human Genotyping Unit-CeGen.

Objectives: Taxanes and anthracyclines are widely used in the treatment of breast cancer, although the benefit is limited to a proportion of patients and predictive biomarkers for clinical outcome remain elusive.

Patients And Methods: We carried out a pharmacogenetic study in 181 patients with locally advanced breast cancer enrolled in a phase 2 randomized clinical trial (NCT00123929), where patients were randomly assigned to receive neoadjuvant single-agent docetaxel 100 mg/m (n=84) or doxorubicin 75 mg/m (n=97). We studied the association of 226 single nucleotide polymorphisms (SNPs) in 15 key drug biotransformation genes with neoadjuvant pathological tumor response residual cancer burden index to docetaxel and to doxorubicin. Read More

Pharmacogenet Genomics 2018 Nov;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. Read More

Pharmacogenet Genomics 2018 Oct;28(10):223-229

Department of Clinical Chemistry, Erasmus University Medical Center.

Objective: Methotrexate (MTX) is an important drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). MTX is cytotoxic as it impairs DNA and RNA synthesis by inhibiting the enzymes dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS). The association between genetic variants within the TYMS gene and MTX-induced toxicity has been studied, but results are inconsistent. Read More

Pharmacogenet Genomics 2018 Oct;28(10):238-244

Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.

The arylamine N-acetyltransferase (NAT) nomenclature committee assigns functional phenotypes for human arylamine N-acetyltransferase 1 (NAT1) alleles in those instances in which the committee determined a consensus has been achieved in the scientific literature. In the most recent nomenclature update, the committee announced that functional phenotypes for NAT1*10 and NAT1*11 alleles were not provided owing to a lack of consensus. Phenotypic inconsistencies observed among various studies for NAT1*10 and NAT1*11 may be owing to variable allelic expression among different tissues, the limitations of the genotyping assays (which mostly relied on techniques not involving direct DNA sequencing), the differences in recombinant protein expression systems used (bacteria, yeast, and mammalian cell lines) and/or the known inherent instability of human NAT1 protein, which requires very careful handling of native and recombinant cell lysates. Read More

Pharmacogenet Genomics 2018 Oct;28(10):230-237

Departments of Biomedical Data Sciences.

Pharmacogenet Genomics 2018 Sep;28(9):207-213

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

Objectives: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the risk for recurrent cardiovascular events after acute coronary syndrome (ACS). However, there is significant variation in response to DAPT that may be influenced by both genetic and nongenetic factors. This study aimed to assess the effect of genetic polymorphisms in PON-1, PEAR-1, P2Y12, CES1, and CYP2C19, along with clinical, demographic, and social factors, on variation in response to DAPT in Egyptians. Read More

Pharmacogenet Genomics 2018 Sep;28(9):199-206

Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin.

Objectives: Iron-burden-induced arrhythmia and heart failure are among the leading causes of morbidity and mortality in β-thalassaemia major patients. T2* cardiac magnetic resonance remains the only reliable noninvasive method for the heart iron excess assessment. We explored the role of single nucleotide polymorphisms involved in vitamin D metabolism, transport and activity and in deferasirox (DFX) metabolism on cardiac iron burden. Read More

Pharmacogenet Genomics 2018 Aug;28(8):198

Pharmacogenet Genomics 2018 Aug;28(8):196-197

Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

Pharmacogenet Genomics 2018 Sep;28(9):214-222

Departments of Biomedical Data Sciences.

Pharmacogenet Genomics 2018 Aug;28(8):189-195

Pediatrics and Adolescent Medicine.

Objective: The aim of this study was to evaluate the potential association between candidate genetic polymorphisms and vincristine-related peripheral neuropathy in Arab children with acute lymphoblastic leukemia (ALL).

Patients And Methods: This is a retrospective evaluation of 133 Arab children treated for ALL at the Children's Cancer Center of Lebanon. Incidence and severity of, as well as the timing (in weeks) at which grade 2 or higher peripheral neuropathy occurred were recorded. Read More

Pharmacogenet Genomics 2018 Jul;28(7):188

Pharmacogenet Genomics 2018 Jul;28(7):177-178

Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Pharmacogenet Genomics 2018 Jul;28(7):179-187

Department of Genetics.

Objective: We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA.

Participants And Methods: Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Read More

Pharmacogenet Genomics 2018 Jul;28(7):167-176

Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo.

Background: NAT2 slow acetylator is a confirmed risk of anti-tuberculosis drug-induced liver injury (ATDILI). However, NAT2 ultra-slow acetylators, a new refinement among NAT2 slow acetylators, have been recently proposed. The patients with NAT2 genotypes of *6A/*6A, *6A/*7B and *7B/*7B are referred to in this group. Read More

Pharmacogenet Genomics 2018 Jun;28(6):153-164

Discipline of Pharmacology, Adelaide Medical School, University of Adelaide.

Papua New Guinea (PNG) can be roughly divided into highland, coastal and island peoples with significant mitochondrial DNA differentiation reflecting early and recent distinct migrations from Africa and East Asia, respectively. Infectious diseases such as tuberculosis, malaria and HIV severely impact on the health of its peoples for which drug therapy is the major treatment and pharmacogenetics has clinical relevance for many of these drugs. Although there is generally little information about known single nucleotide polymorphisms in the population, in some instances, their frequencies have been shown to be higher than anywhere worldwide. Read More

Pharmacogenet Genomics 2018 Jun;28(6):147-152

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.

Neoadjuvant chemotherapy (NAC) for breast cancer is widely utilized, and we performed genome-wide association studies (GWAS) to determine whether germ-line genetic variability was associated with benefit in terms of pathological complete response (pCR), disease-free survival, and overall survival in patients entered on the NSABP B-40 NAC trial, wherein patients were randomized to receive, or not, bevacizumab in addition to chemotherapy. Patient DNA samples were genotyped with the Illumina OmniExpress BeadChip. Replication was attempted with genotyping data from 1398 HER2-negative patients entered on the GeparQuinto NAC study in which patients were also randomized to receive, or not, bevacizumab in addition to chemotherapy. Read More

Pharmacogenet Genomics 2018 Jun;28(6):139-146

Department of Medicine, Mount Scopus.

Objectives: Prolonged activation of the β-1 adrenergic receptor (ADRB1) is associated with receptor desensitization. This process has been suggested to have important pathophysiological and clinical implications in conditions such as congestive heart failure. The contribution of genetic factors to this process is a patient of ongoing research. Read More

Pharmacogenet Genomics 2018 05;28(5):138

Pharmacogenet Genomics 2018 05;28(5):125-126

Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital Hillerød, University of Copenhagen, Hillerød, Denmark.

Pharmacogenet Genomics 2018 05;28(5):117-124

Functional Genomics Group, Genomic Medicine Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.

Background: Hyperuricemia and gout have become increasingly prevalent in China. Allopurinol is an effective urate-lowering therapy, but it has severe side effects. HLA-B*5801 is highly associated with the allopurinol-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. Read More

Pharmacogenet Genomics 2018 04;28(4):110-115

Departments of Biomedical Data Sciences.

Pharmacogenet Genomics 2018 04;28(4):108-109

Department of Psychiatry, Melbourne Neuropsychiatry Centre.

Pharmacogenet Genomics 2018 04;28(4):107-108

OneOme, LLC, Minneapolis, Minnesota, USA.

Pharmacogenet Genomics 2018 05;28(5):127-137

Departments of Biomedical Data Science.

Pharmacogenet Genomics 2018 03;28(3):86-94

Department of Biostatistics, University of Kansas Medical Center.

Objectives: The majority of drug dosing studies are based on adult populations, with modification of the dosing for children based on size and weight. This rudimentary approach for drug dosing children is limited, as biologically a child can differ from an adult in far more aspects than just size and weight. Specifically, understanding the ontogeny of childhood liver development is critical in dosing drugs that are metabolized through the liver, as the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Read More

Pharmacogenet Genomics 2018 03;28(3):78-85

Institute of Medical Sciences, Tzu Chi University, Hualian, Taiwan.

Objective: Although association studies in the general population may be relevant for determining susceptibility to chronic obstructive pulmonary disease (COPD), they may be less applicable for pharmacogenetics research in participants who have already acquired the disease.

Patients And Methods: A genome-wide methylation profiling (generated by HumanMethylation450 BeadChips study was performed on peripheral blood mononuclear cells of 24 patients with AECOPD (acute exacerbation COPD), with good and poor responsiveness to standard corticosteroid treatment. Pyrosequencing was used to replicate the selected CpG sites in 50 patients with AECOPD with standard corticosteroid treatment. Read More

Pharmacogenet Genomics 2018 02;28(2):49-55

Roswell Park Cancer Institute, Buffalo.

Objective: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. Read More

Pharmacogenet Genomics 2018 02;28(2):41-48

Rare Diseases Networking Biomedical Research Centre (CIBERER).

Objective: Cytochrome P450 3A4 (CYP3A4) metabolizes about half of all drugs on the market; however, the impact of CYP3A4 loss-of-function variants on drug exposures remains poorly characterized. Here, we report the effect of the CYP3A4*20 frameshift allele in two Spanish liver transplant patients treated with tacrolimus.

Patients And Methods: A series of 90 transplanted patients (with DNA available for 89 of the recipients and 76 of the liver donors) treated with tacrolimus were included in the study. Read More

Pharmacogenet Genomics 2018 03;28(3):95-98

Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo.

A recent study using the microarray for single-nucleotide polymorphisms (SNPs) genotyping specifically designed for the Japanese population in combination with genome-wide imputation showed the association of several SNPs with cold medicine-related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications. However, it remains to be determined whether these polymorphisms are associated with the onset of antipyretic analgesic (AA)-related SJS/TEN, the progression of severe ocular involvements (SOIs), or both AA-related SJS/TEN and SOI phenotypes. To gain a better understanding of the features of these genetic markers, we compared the allele and carrier frequencies of these SNPs among our original SJS/TEN patient groups: (a) AA-related SJS/TEN with SOIs, (b) AA-related SJS/TEN without SOIs, and (c) AA-unrelated SJS/TEN with SOIs. Read More

Pharmacogenet Genomics 2018 Jan;28(1):7-16

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH).

Objectives: Smoking patterns and cessation rates vary widely across smokers and can be influenced by variation in rates of nicotine metabolism [i.e. cytochrome P450 2A6 (CYP2A6), enzyme activity]. Read More