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Pharmacogenomic

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https://www.readbyqxmd.com/read/28440344/toxicogenomic-module-associations-with-pathogenesis-a-network-based-approach-to-understanding-drug-toxicity
#1
J J Sutherland, Y W Webster, J A Willy, G H Searfoss, K M Goldstein, A R Irizarry, D G Hall, J L Stevens
Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP')...
April 25, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28440343/cyp3a4-genotype-is-associated-with-sildenafil-concentrations-in-patients-with-heart-failure-with-preserved-ejection-fraction
#2
S de Denus, J L Rouleau, D L Mann, G S Huggins, N L Pereira, S H Shah, T P Cappola, R Fouodjio, I Mongrain, M-P Dubé
Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0...
April 25, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28440342/significant-variation-between-snp-based-hla-imputations-in-diverse-populations-the-last-mile-is-the-hardest
#3
D J Pappas, A Lizee, V Paunic, K R Beutner, A Motyer, D Vukcevic, S Leslie, J Biesiada, J Meller, K D Taylor, X Zheng, L P Zhao, P-A Gourraud, J A Hollenbach, S J Mack, M Maiers
Four single nucleotide polymorphism (SNP)-based human leukocyte antigen (HLA) imputation methods (e-HLA, HIBAG, HLA*IMP:02 and MAGPrediction) were trained using 1000 Genomes SNP and HLA genotypes and assessed for their ability to accurately impute molecular HLA-A, -B, -C and -DRB1 genotypes in the Human Genome Diversity Project cell panel. Imputation concordance was high (>89%) across all methods for both HLA-A and HLA-C, but HLA-B and HLA-DRB1 proved generally difficult to impute. Overall, <27.8% of subjects were correctly imputed for all HLA loci by any method...
April 25, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28440341/quantitative-profiling-of-the-ugt-transcriptome-in-human-drug-metabolizing-tissues
#4
A Tourancheau, M Rouleau, S Guauque-Olarte, L Villeneuve, I Gilbert, A Droit, C Guillemette
Alternative splicing as a mean to control gene expression and diversify function is suspected to considerably influence drug response and clearance. We report the quantitative expression profiles of the human UGT genes including alternatively spliced variants not previously annotated established by deep RNA-sequencing in tissues of pharmacological importance. We reveal a comprehensive quantification of the alternative UGT transcriptome that differ across tissues and among individuals. Alternative transcripts that comprise novel in-frame sequences associated or not with truncations of the 5'- and/or 3'- termini, significantly contribute to the total expression levels of each UGT1 and UGT2 gene averaging 21% in normal tissues, with expression of UGT2 variants surpassing those of UGT1...
April 25, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28439573/systematic-review-of-cyclosporin-a-induced-%C3%A2-gingival-overgrowth-and-genetic-predisposition
#5
Georgios S Chatzopoulos, Vasiliki P Koidou, Larry F Wolff
OBJECTIVE: This systematic review aimed to investigate the influence of gene polymorphisms on the development of gingival overgrowth in renal transplant patients treated with cyclosporin A. METHOD AND MATERIALS: Electronic and hand literature searches were conducted by two independent reviewers in MEDLINE-Pubmed, Cochrane Library, ISI Web of Science, and SCOPUS Elsevier for prospective (case-control studies, cohort studies), cross-sectional, and retrospective studies published up to June 2016 (first week) in any language...
April 24, 2017: Quintessence International
https://www.readbyqxmd.com/read/28427468/learning-from-biomedical-linked-data-to-suggest-valid-pharmacogenes
#6
Kevin Dalleau, Yassine Marzougui, Sébastien Da Silva, Patrice Ringot, Ndeye Coumba Ndiaye, Adrien Coulet
BACKGROUND: A standard task in pharmacogenomics research is identifying genes that may be involved in drug response variability, i.e., pharmacogenes. Because genomic experiments tended to generate many false positives, computational approaches based on the use of background knowledge have been proposed. Until now, only molecular networks or the biomedical literature were used, whereas many other resources are available. METHOD: We propose here to consume a diverse and larger set of resources using linked data related either to genes, drugs or diseases...
April 20, 2017: Journal of Biomedical Semantics
https://www.readbyqxmd.com/read/28425954/inherited-variation-in-vitamin-d-genes-and-type-1-diabetes-predisposition
#7
REVIEW
Marissa Penna-Martinez, Klaus Badenhoop
The etiology and pathophysiology of type 1 diabetes remain largely elusive with no established concepts for a causal therapy. Efforts to clarify genetic susceptibility and screening for environmental factors have identified the vitamin D system as a contributory pathway that is potentially correctable. This review aims at compiling all genetic studies addressing the vitamin D system in type 1 diabetes. Herein, association studies with case control cohorts are presented as well as family investigations with transmission tests, meta-analyses and intervention trials...
April 20, 2017: Genes
https://www.readbyqxmd.com/read/28423632/the-genetic-variants-in-the-pten-pi3k-akt-pathway-predict-susceptibility-and-ce-a-f-chemotherapy-response-to-breast-cancer-and-clinical-outcomes
#8
Xiang Li, Ruishan Zhang, Zhuangkai Liu, Shuang Li, Hong Xu
The PI3K/PTEN/AKT pathway play a critical role in balancing cell growth and death. Epidemiologic studies suggested that mutations of the PI3K/PTEN/AKT pathway genes are associated with cancer risk, yet no data are available for PTEN rs701848, PIK3CA rs2699887, and AKT1 rs2494752 polymorphism and breast cancer(BC) risk. A case-control study was performed in 920 BC patients and 908 healthy controls using the TaqMan assay method. Overall, individuals with PTEN rs701848 TC, CC and TC/CC genotypes showed significant increased BC risk (P=0...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418012/cyp3a4-is-a-crosslink-between-vitamin-d-and-calcineurin-inhibitors-in-solid-organ-transplant-recipients-implications-for-bone-health
#9
REVIEW
A Prytuła, K Cransberg, A Raes
The use of calcineurin inhibitors (CNIs) and vitamin D deficiency may contribute to the pathogenesis of post-transplant bone disease. CNIs and 1,25-dihydroxyvitamin D₃ (1,25(OH)2D3) are substrates of the drug-metabolizing enzyme CYP3A4. This review summarizes the indications for the use of activated vitamin D analogs in post-transplant care and the current knowledge on the impact of CNIs on bone. We searched for clinical evidence of the interaction between CNIs and 1,25(OH)2D3. We also provide an overview of the literature on the interplay between vitamin D metabolism and CYP3A4 in experimental and clinical settings and discuss its possible implications for solid organ transplant recipients...
April 18, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28418011/more-than-25-years-of-genetic-studies-of-clozapine-induced-agranulocytosis
#10
REVIEW
S A J de With, S L Pulit, W G Staal, R S Kahn, R A Ophoff
Clozapine is one of the most effective atypical antipsychotic drugs prescribed to patients with treatment-resistant schizophrenia. Approximately 1% of patients experience potential life-threatening adverse effects in the form of agranulocytosis, greatly hindering its applicability in clinical practice. The etiology of clozapine-induced agranulocytosis (CIA) remains unclear, but is thought to be a heritable trait. We reviewed the genetic studies of CIA published thus far. One recurrent finding from early candidate gene study to more recent genome-wide analysis is that of the involvement of human leukocyte antigen locus...
April 18, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28418010/interaction-between-nudt15-and-abcc4-variants-enhances-intolerability-of-6-mercaptopurine-in-japanese-patients-with-childhood-acute-lymphoblastic-leukemia
#11
Y Tanaka, H Nakadate, K Kondoh, K Nakamura, K Koh, A Manabe
6-Mercaptopurine (6-MP) is a main component of childhood acute lymphoblastic leukemia (ALL) treatment. Some candidate gene variants are associated with its toxicities, but the major variants and effects of combined variants remain unclear. We used Cox regression analysis to evaluate the time-dependent association between candidate variants and the cumulative incidence of 6-MP intolerability in 95 Japanese patients. The major risk factors for severe leukopenia were ABCC4 rs3765534, NUDT15 rs116855232 and rs186364861 in multi-covariate analysis (P<0...
April 18, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28418009/effect-of-umod-genotype-on-long-term-graft-survival-after-kidney-transplantation-in-patients-treated-with-cyclosporine-based-therapy
#12
E Abdel-Hady Algharably, J Beige, R Kreutz, J Bolbrinker
The genetic rs12917707-G>T variant in uromodulin (UMOD) has been associated with renal function, chronic kidney disease and hypertension with the minor T-allele showing a protective effect. Hypertension and nephrotoxicity are adverse effects of chronic cyclosporine treatment. We tested whether UMOD rs12917707-T in donor kidneys associates with long-term graft survival in 393 Caucasian patients with stable graft function for more than 10 weeks after kidney transplantation treated with a cyclosporine-based maintenance therapy (mean graft survival 9 years)...
April 18, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28413963/overview-of-cantharidin-and-its-analogues
#13
Guofang Wang, Jian Dong, Liping Deng
Canthiridin has significant anti-cancer effects and only limited use due to its toxicity. In spite of some side effects such as hematochezia and tenesmus, cantharidin can efficiently inhibit various tumor cell lines, therefore, its importance can never be overemphasized. Several of its analogues show functions similar to cantharidin without high toxicity. In order to utilize cantharidin to treat cancer, some viable methods are found to reduce its side effects. Since cantharidin can inhibit the activity of protein phosphatases, new researches for the inhibition of protein phosphatases have been implemented...
April 14, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28406961/pharmacogenetic-variants-in-tpmt-alter-cellular-responses-to-cisplatin-in-inner-ear-cell-lines
#14
Amit P Bhavsar, Erandika P Gunaretnam, Yuling Li, Jafar S Hasbullah, Bruce C Carleton, Colin J D Ross
Cisplatin is a highly-effective and widely-used chemotherapeutic agent that causes ototoxicity in many patients. Pharmacogenomic studies of key genes controlling drug biotransformation identified variants in thiopurine methyltransferase (TPMT) as predictors of cisplatin-induced ototoxicity, although the mechanistic basis of this interaction has not been reported. Expression constructs of TPMT*3A, *3B and *3C variants were generated and monitored in cultured cells. Cellular TPMT*3A levels were detected at >20-fold lower amounts than the wild type confirming the unstable nature of this variant...
2017: PloS One
https://www.readbyqxmd.com/read/28405170/hepatitis-c-virus-pharmacogenomics-in-latin-american-populations-implications-in-the-era-of-direct-acting-antivirals
#15
REVIEW
Julieta Trinks, Mariela Caputo, María L Hulaniuk, Daniel Corach, Diego Flichman
In recent years, great progress has been made in the field of new therapeutic options for hepatitis C virus (HCV) infection. The new direct-acting antiviral agents (DAAs) represent a great hope for millions of chronically infected individuals because their use may lead to excellent cure rates with fewer side effects. In Latin America, the high prevalence of HCV genotype 1 infection and the significant association of Native American ancestry with risk predictive single-nucleotide polymorphisms (SNPs) in IFNL4 and ITPA genes highlight the need to implement new treatment regimens in these populations...
2017: Pharmacogenomics and Personalized Medicine
https://www.readbyqxmd.com/read/28401703/tacrolimus-population-pharmacokinetics-according-to-cyp3a5-genotype-and-clinical-factors-in-chinese-adult-kidney-transplant-recipients
#16
REVIEW
H J Zhang, D Y Li, H J Zhu, Y Fang, T S Liu
WHAT IS KNOWN AND OBJECTIVES: Tacrolimus is characterized by a narrow therapeutic index and a considerable inter- and intraindividual pharmacokinetic variability. The aim of our study was to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant of Chinese patients, identify factors especially CYP3A5*3 genetic polymorphism that explain variability, and determine dosage regimens. METHODS: Pharmacogenomic data obtained from 83 Chinese kidney transplant patients treated with tacrolimus were determined using polymerase chain reaction-restriction fragment length polymorphism analysis...
April 11, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/28398598/pharmacogenomics-based-point-of-care-clinical-decision-support-significantly-alters-drug-prescribing
#17
Peter H O'Donnell, Nisha Wadhwa, Keith Danahey, Brittany A Borden, Sang Mee Lee, Julianne P Hall, Catherine Klammer, Sheena Hussain, Mark Siegler, Matthew J Sorrentino, Andrew M Davis, Yasmin A Sacro, Rita Nanda, Tamar S Polonsky, Jay L Koyner, Deborah L Burnet, Kristen Lipstreuer, David T Rubin, Cathleen Mulcahy, Mary E Strek, William Harper, Adam S Cifu, Blase Polite, Linda Patrick-Miller, Kiang-Teck J Yeo, Edward K Y Leung, Samuel L Volchenboum, Russ B Altman, Olufunmilayo I Olopade, Walter M Stadler, David O Meltzer, Mark J Ratain
Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green/genomically favorable, yellow/genomic caution, red/high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint...
April 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28398356/snp-based-hla-allele-tagging-imputation-and-association-with-antiepileptic-drug-induced-cutaneous-reactions-in-hong-kong-han-chinese
#18
H Gui, M Kwok, L Baum, P C Sham, P Kwan, S S Cherny
Human leukocyte antigen (HLA) genes control the regulation of the human immune system and are involved in immune-related diseases. Population surveys on relationships between single nucleotide polymorphisms (SNP) and HLA alleles are essential to conduct genetic association between HLA variants and diseases. Samples were obtained from our in-house database for epilepsy genetics and pharmacogenetics research. Using 184 epilepsy patients with both genome-wide SNP array and HLA-A/B candidate gene sequencing data, we sought tagging SNPs that completely represent sixHLA risk alleles; in addition, a Hong Kong population-specific reference panel was constructed for SNP-based HLA imputation...
April 11, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28398355/prognostic-impact-of-foxf1-polymorphisms-in-gastric-cancer-patients
#19
S Matsusaka, A H Wu, S Cao, D L Hanna, K Chin, D Yang, W Zhang, Y Ning, S Stintzing, A Sebio, Y Sunakawa, S Stremitzer, S Yamauchi, S Okazaki, M D Berger, A Parekh, Y Miyamoto, N Mizunuma, H-J Lenz
A recent genome-wide association study identified seven single-nucleotide polymorphisms (SNPs) in region 16q24, near the Forkhead box-F1 (FOXF1) gene, which confer susceptibility to esophageal adenocarcinoma. We examined whether these SNPs are associated with clinical outcomes in gastric cancer (GC) patients in Japan and the United States. A total of 362 patients were included in this study: 151 Japanese GC patients treated with first-line S1 plus CDDP (training cohort) and 211 GC patients from Los Angeles County (LAC; validation cohort)...
April 11, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28398354/global-genetic-variation-of-select-opiate-metabolism-genes-in-self-reported-healthy-individuals
#20
F R Wendt, G Pathak, A Sajantila, R Chakraborty, B Budowle
CYP2D6 is a key pharmacogene encoding an enzyme impacting poor, intermediate, extensive and ultrarapid phase I metabolism of many marketed drugs. The pharmacogenetics of opiate drug metabolism is particularly interesting due to the relatively high incidence of addiction and overdose. Recently, trans-acting opiate metabolism and analgesic response enzymes (UGT2B7, ABCB1, OPRM1 and COMT) have been incorporated into pharmacogenetic studies to generate more comprehensive metabolic profiles of patients. With use of massively parallel sequencing, it is possible to identify additional polymorphisms that fine tune, or redefine, previous pharmacogenetic findings, which typically rely on targeted approaches...
April 11, 2017: Pharmacogenomics Journal
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