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Soo Min Han, Joonhee Park, Ji Hyun Lee, Sang Seop Lee, Hyoki Kim, Hyojun Han, Yuhnam Kim, Sojeong Yi, Joo-Youn Cho, In-Jin Jang, Min Goo Lee
Phenotypic differences in drug responses have been associated with known pharmacogenomic loci, but many remain to be characterized. We therefore developed next-generation sequencing (NGS) panels to enable broad and unbiased inspection of genes that are involved in pharmacokinetics (PK) and pharmacodynamics (PD). These panels feature repetitively optimized probes to capture up to 114 PK/PD-related genes with high coverage (99.6%) and accuracy (99.9%). Sequencing of a Korean cohort (n = 376) with the panels enabled profiling of actionable variants as well as rare variants of unknown functional consequences...
October 11, 2016: Clinical Pharmacology and Therapeutics
İbrahim Ömer Barlas, Orhan Sezgin, Collet Dandara, Gözde Türköz, Emre Yengel, Zinhle Cindi, Handan Ankaralı, Semra Şardaş
Pharmacogenomics harnesses the utility of a patient's genome (n = 1) in decisions on which therapeutic drugs and in what amounts should be administered. Often, patients with shared ancestry present with comparable genetic profiles that predict drug response. However, populations are not static, thus, often, population mobility through migration, especially enmasse as is seen for refugees, changes the pharmacogenetic profiles of resultant populations and therefore observed responses to commonly used therapeutic drugs...
October 2016: Omics: a Journal of Integrative Biology
Clint Mizzi, Eleni Dalabira, Judit Kumuthini, Nduna Dzimiri, Istvan Balogh, Nazli Başak, Ruwen Böhm, Joseph Borg, Paola Borgiani, Nada Bozina, Henrike Bruckmueller, Beata Burzynska, Angel Carracedo, Ingolf Cascorbi, Constantinos Deltas, Vita Dolzan, Anthony Fenech, Godfrey Grech, Vytautas Kasiulevicius, Ľudevít Kádaši, Vaidutis Kučinskas, Elza Khusnutdinova, Yiannis L Loukas, Milan Macek, Halyna Makukh, Ron Mathijssen, Konstantinos Mitropoulos, Christina Mitropoulou, Giuseppe Novelli, Ioanna Papantoni, Sonja Pavlovic, Giuseppe Saglio, Jadranka Setric, Maja Stojiljkovic, Andrew P Stubbs, Alessio Squassina, Maria Torres, Marek Turnovec, Ron H van Schaik, Konstantinos Voskarides, Salma M Wakil, Anneke Werk, Maria Del Zompo, Branka Zukic, Theodora Katsila, Ming Ta Michael Lee, Alison Motsinger-Rief, Howard L Mc Leod, Peter J van der Spek, George P Patrinos
Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes...
2016: PloS One
Stefan Winter, Pascale Fisel, Florian Büttner, Steffen Rausch, Debora D'Amico, Jörg Hennenlotter, Stephan Kruck, Anne T Nies, Arnulf Stenzl, Kerstin Junker, Marcus Scharpf, Ute Hofmann, Heiko van der Kuip, Falko Fend, German Ott, Abbas Agaimy, Arndt Hartmann, Jens Bedke, Matthias Schwab, Elke Schaeffeler
Current therapies for metastatic clear cell renal cell carcinoma (ccRCC) show limited efficacy. Drug efficacy, typically investigated in preclinical cell line models during drug development, is influenced by pharmacogenes involved in targeting and disposition of drugs. Here we show through genome-wide DNA methylation profiling, that methylation patterns are concordant between primary ccRCC and macro-metastases irrespective of metastatic sites (rs ≥ 0.92). However, 195,038 (41%) of all investigated CpG sites, including sites within pharmacogenes, were differentially methylated (adjusted P < 0...
2016: Scientific Reports
Tianbo Jin, Ruimin Zhao, Xugang Shi, Na He, Xue He, Yongri Ouyang, Hong Wang, Bo Wang, Longli Kang, Dongya Yuan
BACKGROUND: Multiple factors include genetic and non-genetic interactions induce to different drug response among different individuals. Lots of researches proved that different frequencies of genetic variants exists different ethnic groups. The aim of this study was to screen Han volunteers in Shaanxi for VIP gene polymorphisms. MATERIALS AND METHODS: We genotyped 80 Very Important Pharmacogenes (VIP) (selected from the PharmGKB database) in 192 unrelated, healthy Han ethnic adults from Shaanxi, the northwest of China, and then analyzed genotyping data wtih Structure and F-statistics (Fst) analysis...
September 2016: Environmental Toxicology and Pharmacology
Andrea Gaedigk, Katrin Sangkuhl, Michelle Whirl-Carrillo, Teri Klein, J Steven Leeder
PURPOSE: Owing to its highly polymorphic nature and major contribution to the metabolism and bioactivation of numerous clinically used drugs, CYP2D6 is one of the most extensively studied drug-metabolizing enzymes and pharmacogenes. CYP2D6 alleles confer no, decreased, normal, or increased activity and cause a wide range of activity among individuals and between populations. However, there is no standard approach to translate diplotypes into predicted phenotype. METHODS: We exploited CYP2D6 allele-frequency data that have been compiled for Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (>60,000 subjects, 173 reports) in order to estimate genotype-predicted phenotype status across major world populations based on activity score (AS) assignments...
July 7, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
W Yang, G Wu, U Broeckel, C A Smith, V Turner, C E Haidar, S Wang, R Carter, S E Karol, G Neale, K R Crews, J J Yang, C G Mullighan, J R Downing, W E Evans, M V Relling
We compared whole exome sequencing (WES, n = 176 patients) and whole genome sequencing (WGS, n = 68) and clinical genotyping (DMET array-based approach) for interrogating 13 genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. We focused on 127 CPIC important variants: 103 single nucleotide variations (SNV), 21 insertion/deletions (Indel), HLA-B alleles, and two CYP2D6 structural variations. WES and WGS provided interrogation of nonoverlapping sets of 115 SNV/Indels with call rate >98%...
October 2016: Clinical Pharmacology and Therapeutics
N A Helsby
The study of pharmacogenetic variants in populations which reside in Oceania has been mainly focused on CYP2C19 and CYP2D6. Statements about the high prevalence of CYP2C19 no function genotype in "Pacific Islanders" can be found in the literature. This review article summarizes the published information about these pharmacogenes in this geographical region and highlights the differences observed between Melanesian and Polynesian populations. It is not appropriate to combine the prevalence data of pharmacogenetic variants, particularly CYP2C19, across this region...
June 15, 2016: British Journal of Clinical Pharmacology
Matthew T Oetjens, William S Bush, Joshua C Denny, Kelly Birdwell, Nuri Kodaman, Anurag Verma, Holli H Dilks, Sarah A Pendergrass, Marylyn D Ritchie, Dana C Crawford
AIM: We sought to identify potential pleiotropy involving pharmacogenes. METHODS: We tested 184 functional variants in 34 pharmacogenes for associations using a custom grouping of International Classification and Disease, Ninth Revision billing codes extracted from deidentified electronic health records of 6892 patients. RESULTS: We replicated several associations including ABCG2 (rs2231142) and gout (p = 1.73 × 10(-7); odds ratio [OR]: 1...
June 2016: Pharmacogenomics
Volker M Lauschke, Magnus Ingelman-Sundberg
Recent research highlighted the large extent of rare variants in pharmacogenes and, on this basis, it was estimated that rare variants account for 30-40% of the functional variability in pharmacogenes. It has been proposed that comprehensive next-generation sequencing (NGS)-based sequencing of pharmacogenes could soon be a cost-effective methodology for clinical routine genotyping. Yet, multiple challenges on technical, interpretative and ethical levels need to be overcome to enable the reasonable dissemination of comprehensive pharmacogenetic genotyping, that includes rare genetic variation, into clinical practice...
June 2016: Pharmacogenomics
Mikael Kozyra, Magnus Ingelman-Sundberg, Volker M Lauschke
PURPOSE: In this study we characterized the genetic variability of 146 clinically relevant genes influencing drug pharmacokinetics in African and European subpopulations, which are key determinants for interindividual variations in drug efficacy and adverse drug reactions. METHODS: By integrating data from the 1000 Genomes Project (n = 1,092 individuals) and the Exome Sequencing Project (ESP; n = 6,503 individuals), single-nucleotide variants (SNVs) were identified and analyzed regarding frequency, functional consequences, and ethnic diversity...
April 21, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Vicki Oberg, Jerome Differding, Morgan Fisher, Lindsay Hines, Russell A Wilke
A strong emerging principle in the field of precision medicine is that variation in any one pharmacogene may impact clinical outcome for more than one drug. Variants tested in the acute care setting often have downstream implications for other drugs impacting chronic disease management. A flexible framework is needed as clinicians and scientists move toward deploying automated decision support for gene-based drug dosing in electronic medical records.
April 2016: Pharmacogenomics
Eng Wee Chua, Simone L Cree, Kim N T Ton, Klaus Lehnert, Phillip Shepherd, Nuala Helsby, Martin A Kennedy
Whole-exome sequencing (WES) has been widely used for analysis of human genetic diseases, but its value for the pharmacogenomic profiling of individuals is not well studied. Initially, we performed an in-depth evaluation of the accuracy of WES variant calling in the pharmacogenes CYP2D6 and CYP2C19 by comparison with MiSeq(®) amplicon sequencing data (n = 36). This analysis revealed that the concordance rate between WES and MiSeq(®) was high, achieving 99.60% for variants that were called without exceeding the truth-sensitivity threshold (99%), defined during variant quality score recalibration (VQSR)...
2016: Frontiers in Pharmacology
W S Bush, D R Crosslin, A Owusu-Obeng, J Wallace, B Almoguera, M A Basford, S J Bielinski, D S Carrell, J J Connolly, D Crawford, K F Doheny, C J Gallego, A S Gordon, B Keating, J Kirby, T Kitchner, S Manzi, A R Mejia, V Pan, C L Perry, J F Peterson, C A Prows, J Ralston, S A Scott, A Scrol, M Smith, S C Stallings, T Veldhuizen, W Wolf, S Volpi, K Wiley, R Li, T Manolio, E Bottinger, M H Brilliant, D Carey, R L Chisholm, C G Chute, J L Haines, H Hakonarson, J B Harley, I A Holm, I J Kullo, G P Jarvik, E B Larson, C A McCarty, M S Williams, J C Denny, L J Rasmussen-Torvik, D M Roden, M D Ritchie
Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function...
August 2016: Clinical Pharmacology and Therapeutics
A Chhibber, C E French, S W Yee, E R Gamazon, E Theusch, X Qin, A Webb, A C Papp, A Wang, C Q Simmons, A Konkashbaev, A S Chaudhry, K Mitchel, D Stryke, T E Ferrin, S T Weiss, D L Kroetz, W Sadee, D A Nickerson, R M Krauss, A L George, E G Schuetz, M W Medina, N J Cox, S E Scherer, K M Giacomini, S E Brenner
Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies...
February 9, 2016: Pharmacogenomics Journal
Anna O Basile, John R Wallace, Peggy Peissig, Catherine A McCarty, Murray Brilliant, Marylyn D Ritchie
Next-generation sequencing technology has presented an opportunity for rare variant discovery and association of these variants with disease. To address the challenges of rare variant analysis, multiple statistical methods have been developed for combining rare variants to increase statistical power for detecting associations. BioBin is an automated tool that expands on collapsing/binning methods by performing multi-level variant aggregation with a flexible, biologically informed binning strategy using an internal biorepository, the Library of Knowledge (LOKI)...
2016: Pacific Symposium on Biocomputing
Maria L Alvarellos, Ronald M Krauss, Russell A Wilke, Russ B Altman, Teri E Klein
No abstract text is available yet for this article.
March 2016: Pharmacogenetics and Genomics
Amani AlBakri, Mohammad Karaoui, Fowzan S Alkuraya, Arif O Khan
Malignant hyperthermia susceptibility is a rare pharmacogenic disorder of skeletal muscle calcium regulation caused by mutations in the skeletal muscle ryanodine receptor 1 gene (RYR1). It is important to identify children who are candidates for ophthalmic surgery who might harbor RYR1 mutations because intraoperative malignant hyperthermia is potentially lethal. We report 2 siblings with congenital ptosis and scoliosis who were considered for ptosis surgery but were found to harbor underlying recessive RYR1 mutations...
December 2015: Journal of AAPOS: the Official Publication of the American Association for Pediatric Ophthalmology and Strabismus
Tianbo Jin, Ainiwaer Aikemu, Mingxi Zhang, Tingting Geng, Tian Feng, Longli Kang, Man Lin Luo
BACKGROUND Genetic polymorphisms have a potential clinical role in determining both inter-individual and inter-ethnic differences in drug efficacy, but we have not found any pharmacogenomics information regarding minorities, such as the Miao ethnic group. Our study aimed to screen numbers of the Miao ethnic group for genotype frequencies of VIP variants and to determine differences between the Miao and other human populations worldwide. MATERIAL AND METHODS In this study, we genotyped 66 Very Important Pharmacogene (VIP) variants selected from PharmGKB in 98 unrelated, healthy Miao individuals from the Guizhou province and compared our data with 12 other populations, including 11 populations from the HapMap data set and Xi'an Han Chinese...
2015: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Xugang Shi, Li Wang, Shuli Du, Huijuan Wang, Tian Feng, Tianbo Jin, Longli Kang
Little is known about polymorphic distribution of pharmacogenes among ethnicities, including the Deng people. In this study, we recruited 100 unrelated, healthy Deng people and genotyped them with respect to 76 different single-nucleotide polymorphisms by the PharmGKB database. Our results first indicated that the polymorphic distribution of pharmacogenes of the Deng people is most similar to CHD, suggesting that Deng people have a closest genetic relationship with CHD. Our data will enrich the database of pharmacogenomics and provide a theoretical basis for safer drug administration and individualized treatment plans, promoting the development of personalized medicine...
2015: Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals
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