WorldWideScience

Sample records for haplotype-based pharmacogenetic analysis

  1. Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    David M. Howard

    2017-08-01

    Full Text Available Background: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants. Methods: In the present analysis, three cohort studies (ntotal = 48,002 were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS, the English Longitudinal Study of Ageing (ELSA, and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions. Results: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator (DAOA gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer’s disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10-7, was the butyrylcholinesterase (BCHE gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognitive ability merits further investigation. Conclusions: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.

  2. Neural network analysis in pharmacogenetics of mood disorders

    Directory of Open Access Journals (Sweden)

    Serretti Alessandro

    2004-12-01

    Full Text Available Abstract Background The increasing number of available genotypes for genetic studies in humans requires more advanced techniques of analysis. We previously reported significant univariate associations between gene polymorphisms and antidepressant response in mood disorders. However the combined analysis of multiple gene polymorphisms and clinical variables requires the use of non linear methods. Methods In the present study we tested a neural network strategy for a combined analysis of two gene polymorphisms. A Multi Layer Perceptron model showed the best performance and was therefore selected over the other networks. One hundred and twenty one depressed inpatients treated with fluvoxamine in the context of previously reported pharmacogenetic studies were included. The polymorphism in the transcriptional control region upstream of the 5HTT coding sequence (SERTPR and in the Tryptophan Hydroxylase (TPH gene were analysed simultaneously. Results A multi layer perceptron network composed by 1 hidden layer with 7 nodes was chosen. 77.5 % of responders and 51.2% of non responders were correctly classified (ROC area = 0.731 – empirical p value = 0.0082. Finally, we performed a comparison with traditional techniques. A discriminant function analysis correctly classified 34.1 % of responders and 68.1 % of non responders (F = 8.16 p = 0.0005. Conclusions Overall, our findings suggest that neural networks may be a valid technique for the analysis of gene polymorphisms in pharmacogenetic studies. The complex interactions modelled through NN may be eventually applied at the clinical level for the individualized therapy.

  3. Haplotype-Based Genotyping in Polyploids

    Directory of Open Access Journals (Sweden)

    Josh P. Clevenger

    2018-04-01

    Full Text Available Accurate identification of polymorphisms from sequence data is crucial to unlocking the potential of high throughput sequencing for genomics. Single nucleotide polymorphisms (SNPs are difficult to accurately identify in polyploid crops due to the duplicative nature of polyploid genomes leading to low confidence in the true alignment of short reads. Implementing a haplotype-based method in contrasting subgenome-specific sequences leads to higher accuracy of SNP identification in polyploids. To test this method, a large-scale 48K SNP array (Axiom Arachis2 was developed for Arachis hypogaea (peanut, an allotetraploid, in which 1,674 haplotype-based SNPs were included. Results of the array show that 74% of the haplotype-based SNP markers could be validated, which is considerably higher than previous methods used for peanut. The haplotype method has been implemented in a standalone program, HAPLOSWEEP, which takes as input bam files and a vcf file and identifies haplotype-based markers. Haplotype discovery can be made within single reads or span paired reads, and can leverage long read technology by targeting any length of haplotype. Haplotype-based genotyping is applicable in all allopolyploid genomes and provides confidence in marker identification and in silico-based genotyping for polyploid genomics.

  4. Analysis of pharmacogenetic traits in two distinct South African populations

    Directory of Open Access Journals (Sweden)

    Ikediobi Ogechi

    2011-05-01

    Full Text Available Abstract Our knowledge of pharmacogenetic variability in diverse populations is scarce, especially in sub-Saharan Africa. To bridge this gap in knowledge, we characterised population frequencies of clinically relevant pharmacogenetic traits in two distinct South African population groups. We genotyped 211 tagging single nucleotide polymorphisms (tagSNPs in 12 genes that influence antiretroviral drug disposition, in 176 South African individuals belonging to two distinct population groups residing in the Western Cape: the Xhosa (n = 109 and Cape Mixed Ancestry (CMA (n = 67 groups. The minor allele frequencies (MAFs of eight tagSNPs in six genes (those encoding the ATP binding cassette sub-family B, member 1 [ABCB1], four members of the cytochrome P450 family [CYP2A7P1, CYP2C18, CYP3A4, CYP3A5] and UDP-glucuronosyltransferase 1 [UGT1A1] were significantly different between the Xhosa and CMA populations (Bonferroni p CYP2C18, CYP3A4, the gene encoding solute carrier family 22 member 6 [SLC22A6] and UGT1A1 between the two South African populations. Characterising the Xhosa and CMA population frequencies of variant alleles important for drug transport and metabolism can help to establish the clinical relevance of pharmacogenetic testing in these populations.

  5. Life-Threatening Adverse Events Following Therapeutic Opioid Administration in Adults: Is Pharmacogenetic Analysis Useful?

    Directory of Open Access Journals (Sweden)

    Parvaz Madadi

    2013-01-01

    Full Text Available BACKGROUND: Systemic approaches are needed to understand how variations in the genes associated with opioid pharmacokinetics and response can be used to predict patient outcome. The application of pharmacogenetic analysis to two cases of life-threatening opioid-induced respiratory depression is presented. The usefulness of genotyping in the context of these cases is discussed.

  6. Population Analysis of Pharmacogenetic Polymorphisms Related to Acute Lymphoblastic Leukemia Drug Treatment

    Directory of Open Access Journals (Sweden)

    Marcela A. Chiabai

    2012-01-01

    Full Text Available This study aimed to evaluate in the Brazilian population, the genotypes and population frequencies of pharmacogenetic polymorphisms involved in the response to drugs used in treatment of acute lymphoblastic leukemia (ALL, and to compare the data with data from the HapMap populations. There was significant differentiation between most population pairs, but few associations between genetic ancestry and SNPs in the Brazilian population were observed. AMOVA analysis comparing the Brazilian population to all other populations retrieved from HapMap pointed to a genetic proximity with the European population. These associations point to preclusion of the use of genetic ancestry as a proxy for predicting drug response. In this way, any study aiming to correlate genotype with drug response in the Brazilian population should be based on pharmacogenetic SNP genotypes.

  7. Pharmacogenetic analysis of opioid dependence treatment dose and dropout rate.

    Science.gov (United States)

    Crist, Richard C; Li, James; Doyle, Glenn A; Gilbert, Alex; Dechairo, Bryan M; Berrettini, Wade H

    2018-01-01

    Currently, no pharmacogenetic tests for selecting an opioid-dependence pharmacotherapy have been approved by the US Food and Drug Administration. Determine the effects of variants in 11 genes on dropout rate and dose in patients receiving methadone or buprenorphine/naloxone (ClinicalTrials.gov Identifier: NCT00315341). Variants in six pharmacokinetic genes (CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4) and five pharmacodynamic genes (HTR2A, OPRM1, ADRA2A, COMT, SLC6A4) were genotyped in samples from a 24-week, randomized, open-label trial of methadone and buprenorphine/naloxone for the treatment of opioid dependence (n = 764; 68.7% male). Genotypes were then used to determine the metabolism phenotype for each pharmacokinetic gene. Phenotypes or genotypes for each gene were analyzed for association with dropout rate and mean dose. Genotype for 5-HTTLPR in the SLC6A4 gene was nominally associated with dropout rate when the methadone and buprenorphine/naloxone groups were combined. When the most significant variants associated with dropout rate were analyzed using pairwise analyses, SLC6A4 (5-HTTLPR) and COMT (Val158Met; rs4860) had nominally significant associations with dropout rate in methadone patients. None of the genes analyzed in the study was associated with mean dose of methadone or buprenorphine/naloxone. This study suggests that functional polymorphisms related to synaptic dopamine or serotonin levels may predict dropout rates during methadone treatment. Patients with the S/S genotype at 5-HTTLPR in SLC6A4 or the Val/Val genotype at Val158Met in COMT may require additional treatment to improve their chances of completing addiction treatment. Replication in other methadone patient populations will be necessary to ensure the validity of these findings.

  8. Pharmacogenetics in clinical practice

    NARCIS (Netherlands)

    Derijks, Luc J. J.; Derijks, H. Jeroen; Touw, Daan J.; Conemans, Jean M. H.; Egberts, Antoine C. G.

    2008-01-01

    The availability of data from pharmacogenetic studies is reflected in therapeutic practice, and pharmacogenetics is slowly entering the medical arena. Preconditions for the utilisation of pharmacogenetic knowledge are that: 1) genetic variation and prevalence are known 2) pharmacological

  9. Role of pharmacogenetics in public health and clinical health care: a SWOT analysis.

    Science.gov (United States)

    Kapoor, Ritika; Tan-Koi, Wei Chuen; Teo, Yik-Ying

    2016-12-01

    Pharmacogenomics has been lauded as an important innovation in clinical medicine as a result of advances in genomic science. As one of the cornerstones in precision medicine, the vision to determine the right medication in the right dosage for the right treatment with the use of genetic information has not exactly materialised, and few genetic tests have been implemented as the standard of care in health systems worldwide. Here we review the findings from a SWOT analysis to examine the strengths, weaknesses, opportunities and threats around the role of pharmacogenetics in public health and clinical health care, at the micro, meso and macro levels corresponding to the perspectives of the individuals (scientists, patients and physicians), the health-care institutions and the health systems, respectively.

  10. Pharmacogenetics approach to therapeutics.

    Science.gov (United States)

    Koo, Seok Hwee; Lee, Edmund Jon Deoon

    2006-01-01

    1. Pharmacogenetics refers to the study of genetically controlled variations in drug response. Functional variants caused by single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolising enzymes, transporters, ion channels and drug receptors have been known to be associated with interindividual and interethnic variation in drug response. Genetic variations in these genes play a role in influencing the efficacy and toxicity of medications. 2. Rapid, precise and cost-effective high-throughput technological platforms are essential for performing large-scale mutational analysis of genetic markers involved in the aetiology of variable responses to drug therapy. 3. The application of a pharmacogenetics approach to therapeutics in general clinical practice is still far from being achieved today owing to various constraints, such as limited accessibility of technology, inadequate knowledge, ambiguity of the role of variants and ethical concerns. 4. Drug actions are determined by the interplay of several genes encoding different proteins involved in various biochemical pathways. With rapidly emerging SNP discovery technological platforms and widespread knowledge on the role of SNPs in disease susceptibility and variability in drug response, the pharmacogenetics approach to therapeutics is anticipated to take off in the not-too-distant future. This will present profound clinical, economic and social implications for health care.

  11. Clinical implementation of pharmacogenetics.

    Science.gov (United States)

    García-González, Xandra; Cabaleiro, Teresa; Herrero, María José; McLeod, Howard; López-Fernández, Luis A

    2016-03-01

    In the last decade, pharmacogenetic research has been performed in different fields. However, the application of pharmacogenetic findings to clinical practice has not been as fast as desirable. The current situation of clinical implementation of pharmacogenetics is discussed. This review focuses on the advances of pharmacogenomics to individualize cancer treatments, the relationship between pharmacogenetics and pharmacodynamics in the clinical course of transplant patients receiving a combination of immunosuppressive therapy, the needs and barriers facing pharmacogenetic clinical application, and the situation of pharmacogenetic testing in Spain. It is based on lectures presented by speakers of the Clinical Implementation of Pharmacogenetics Symposium at the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society, held in April 20, 2015.

  12. Pharmacogenetics of psychotropic drugs

    National Research Council Canada - National Science Library

    Lerer, Bernard

    2002-01-01

    ... of pharmacogenetics with substance dependence and brain imaging, and consider the impact of pharmacogenetics on the biotechnology and pharmaceutical industries. This book defines the young field of pharmacogenetics as it applies to psychotropic drugs and is, therefore, an essential reference for all clinicians and researchers working in this findings field. Bernard ...

  13. High interpatient variability of raltegravir CSF concentrations in HIV-positive patients: a pharmacogenetic analysis.

    Science.gov (United States)

    Calcagno, Andrea; Cusato, Jessica; Simiele, Marco; Motta, Ilaria; Audagnotto, Sabrina; Bracchi, Margherita; D'Avolio, Antonio; Di Perri, Giovanni; Bonora, Stefano

    2014-01-01

    To analyse the determinants of raltegravir CSF penetration, including the pharmacogenetics of drug transporters located at the blood-brain barrier or blood-CSF barrier. Plasma and CSF raltegravir concentrations were determined by a validated HPLC coupled with mass spectrometry method in adults on raltegravir-based combination antiretroviral therapy undergoing a lumbar puncture. Single nucleotide polymorphisms in the genes encoding drugs transporters (ABCB1 3435, SLCO1A2, ABCC2 and SLC22A6) and the gene encoding hepatocyte nuclear factor 4 α (HNF4α) were determined by real-time PCR. In 41 patients (73.2% male, 95.1% Caucasians), the median raltegravir plasma and CSF concentrations were 165 ng/mL (83-552) and 31 ng/mL (21-56), respectively. CSF-to-plasma ratios (CPRs) ranged from 0.005 to 1.33 (median 0.20, IQR 0.04-0.36). Raltegravir trough CSF concentrations (n = 35) correlated with raltegravir plasma levels (ρ = 0.395, P = 0.019); CPRs were higher in patients with blood-brain barrier damage (0.47 versus 0.18, P = 0.02). HNF4α 613 CG genotype carriers had lower trough CSF concentrations (20 versus 37 ng/mL, P = 0.03) and CPRs (0.12 versus 0.27, P = 0.02). Following multivariate linear regression analysis, the CSF-to-serum albumin ratio was the only independent predictor of raltegravir penetration into the CSF. Raltegravir penetration into the CSF shows a large interpatient variability, although CSF concentrations were above the wild-type IC50 in all patients (and above IC95 in 28.6%). In this cohort, blood-brain barrier permeability is the only independent predictor of raltegravir CPR. The impact of single nucleotide polymorphisms in selected genes on raltegravir penetration warrants further studies.

  14. Attention-deficit hyperactivity disorder in adults: A systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies

    Science.gov (United States)

    Bonvicini, C; Faraone, S V; Scassellati, C

    2016-01-01

    The adult form of attention-deficit/hyperactivity disorder has a prevalence of up to 5% and is the most severe long-term outcome of this common disorder. Family studies in clinical samples as well as twin studies suggest a familial liability and consequently different genes were investigated in association studies. Pharmacotherapy with methylphenidate (MPH) seems to be the first-line treatment of choice in adults with attention-deficit hyperactive disorder (ADHD) and some studies were conducted on the genes influencing the response to this drug. Finally some peripheral biomarkers were identified in ADHD adult patients. We believe this work is the first systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed in adults with ADHD to identify potential genetic, predictive and peripheral markers linked specifically to ADHD in adults. After screening 5129 records, we selected 87 studies of which 61 were available for candidate gene association studies, 5 for pharmacogenetics and 21 for biochemical studies. Of these, 15 genetic, 2 pharmacogenetic and 6 biochemical studies were included in the meta-analyses. We obtained an association between adult ADHD and the gene BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), even after Bonferroni correction, with any heterogeneity in effect size and no publication bias. If we did not apply the Bonferroni correction, a trend was found for the carriers allele 9R of dopamine transporter SLC6A3 40 bp variable tandem repeat polymorphism (VNTR) and for 6/6 homozygotes of SLC6A3 30 bp VNTR. Negative results were obtained for the 9-6 haplotype, the dopamine receptor DRD4 48 bp VNTR, and the enzyme COMT SNP rs4680. Concerning pharmacogenetic studies, no association was found for the SLC6A3 40 bp and response to MPH with only two studies selected. For the metabolomics studies, no differences between ADHD adults and controls were

  15. Pharmacogenetics-based warfarin dosing algorithm decreases time to stable anticoagulation and the risk of major hemorrhage: an updated meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Wang, Zhi-Quan; Zhang, Rui; Zhang, Peng-Pai; Liu, Xiao-Hong; Sun, Jian; Wang, Jun; Feng, Xiang-Fei; Lu, Qiu-Fen; Li, Yi-Gang

    2015-04-01

    Warfarin is yet the most widely used oral anticoagulant for thromboembolic diseases, despite the recently emerged novel anticoagulants. However, difficulty in maintaining stable dose within the therapeutic range and subsequent serious adverse effects markedly limited its use in clinical practice. Pharmacogenetics-based warfarin dosing algorithm is a recently emerged strategy to predict the initial and maintaining dose of warfarin. However, whether this algorithm is superior over conventional clinically guided dosing algorithm remains controversial. We made a comparison of pharmacogenetics-based versus clinically guided dosing algorithm by an updated meta-analysis. We searched OVID MEDLINE, EMBASE, and the Cochrane Library for relevant citations. The primary outcome was the percentage of time in therapeutic range. The secondary outcomes were time to stable therapeutic dose and the risks of adverse events including all-cause mortality, thromboembolic events, total bleedings, and major bleedings. Eleven randomized controlled trials with 2639 participants were included. Our pooled estimates indicated that pharmacogenetics-based dosing algorithm did not improve percentage of time in therapeutic range [weighted mean difference, 4.26; 95% confidence interval (CI), -0.50 to 9.01; P = 0.08], but it significantly shortened the time to stable therapeutic dose (weighted mean difference, -8.67; 95% CI, -11.86 to -5.49; P pharmacogenetics-based algorithm significantly reduced the risk of major bleedings (odds ratio, 0.48; 95% CI, 0.23 to 0.98; P = 0.04), but it did not reduce the risks of all-cause mortality, total bleedings, or thromboembolic events. Our results suggest that pharmacogenetics-based warfarin dosing algorithm significantly improves the efficiency of International Normalized Ratio correction and reduces the risk of major hemorrhage.

  16. Pharmacogenetics of clozapine response and induced weight gain: A comprehensive review and meta-analysis.

    Science.gov (United States)

    Gressier, Florence; Porcelli, Stefano; Calati, Raffaella; Serretti, Alessandro

    2016-02-01

    Clozapine (CLZ) is the prototype atypical antipsychotic and it has many advantages over other antipsychotic drugs. Several data suggest that both CLZ response and induced weight gain are strongly determined by genetic variability. However, results remain mainly inconclusive. We aim to review the literature data about pharmacogenetics studies on CLZ efficacy, focusing on pharmacodynamic genes. Further, we performed meta-analyses on response when at least three studies for each polymorphism were available. Sensitivity analyses were conducted on Caucasian population when feasible. Electronic literature search was performed to identify pertinent studies published until May 2014 using PubMed, ISI Web of Knowledge and PsycINFO databases. For meta-analyses, data were entered and analyzed through RevMan version 5.2 using a random-effect model. Our literature search yielded 9266 articles on CLZ; among these, we identified 59 pertinent pharmacogenetic studies. Genotype data were retrieved for 14 polymorphisms in 9 genes. Among these, we had available data from at least three independent samples for 8 SNPs in 6 genes to perform meta-analyses: DRD2 rs1799732, DRD3 rs6280, HTR2A rs6313, rs6311, rs6314, HTR2C rs6318, HTR3A rs1062613, TNFa rs1800629. Although literature review provided conflicting results, in meta-analyses three genetic variants within serotonin genes resulted associated to CLZ response: rs6313 and rs6314 within HTR2A gene and rs1062613 within HT3A gene. On the other hand, no clear finding emerged for CLZ-induced weight gain. Our results suggest a possible serotonergic modulation of CLZ clinical response. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  17. Strategies for haplotype-based association mapping in complex pedigreed populations

    DEFF Research Database (Denmark)

    Boleckova, J; Christensen, Ole Fredslund; Sørensen, Peter

    2012-01-01

    In association mapping, haplotype-based methods are generally regarded to provide higher power and increased precision than methods based on single markers. For haplotype-based association mapping most studies use a fixed haplotype effect in the model. However, an increase in haplotype length inc...

  18. Meta-Analysis on Pharmacogenetics of Platinum-Based Chemotherapy in Non Small Cell Lung Cancer (NSCLC) Patients

    Science.gov (United States)

    Yin, Ji-Ye; Huang, Qiong; Zhao, Ying-Chun; Zhou, Hong-Hao; Liu, Zhao-Qian

    2012-01-01

    Aim To determine the pharmacogenetics of platinum-based chemotherapy in Non Small Cell Lung Cancer (NSCLC) patients. Methods Publications were selected from PubMed, Cochrane Library and ISI Web of Knowledge. A meta-analysis was conducted to determine the association between genetic polymorphisms and platinum-based chemotherapy by checking odds ratio (OR) and 95% confidence interval (CI). Results Data were extracted from 24 publications, which included 11 polymorphisms in 8 genes for meta-analysis. MDR1 C3435T (OR = 1.97, 95% CI: 1.11–3.50, P = 0.02), G2677A/T (OR = 2.61, 95% CI: 1.44–4.74, P = 0.002) and GSTP1 A313G (OR = 0.32, 95% CI: 0.17–0.58, P = 0.0002) were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients. Conclusion Attention should be paid to MDR1 C3435T, G2677A/T and GSTP1 A313G for personalized chemotherapy treatment for NSCLC patients in Asian population in the future. PMID:22761669

  19. Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis.

    Science.gov (United States)

    Dymond, Angela W; Elks, Cathy; Martin, Paul; Carlile, David J; Mariani, Gabriella; Lovick, Susan; Huang, Yifan; Lorch, Ulrike; Brown, Helen; So, Karen

    2017-06-01

    Emerging data on selumetinib, a MEK1/2 inhibitor in clinical development, suggest a possible difference in pharmacokinetics (PK) between Japanese and Western patients. This pooled analysis sought to assess the effect of ethnicity on selumetinib exposure in healthy Western and Asian subjects, and to identify any association between genetic variants in the UGT1A1, CYP2C19 and ABCG2 genes and observed differences in selumetinib PK. A pooled analysis of data from ten Phase I studies, one in Asian subjects (encompassing Japanese, non-Japanese Asian and Indian Asian subjects) and nine in Western subjects, was conducted. Key findings were derived from the collective exposure data across doses of 25, 35, 50 and 75 mg selumetinib; primary variables were dose-normalized AUC and C max . PK data from 308 subjects (10 studies) were available for the pooled analysis; genetic data from 87 subjects (3 studies) were available for the pharmacogenetic analysis. Dose-normalized AUC and C max were 35% (95% CI: 25-47%) and 39% (95% CI: 24-56%) higher in the pooled Asian group, respectively, compared with Western subjects. PK exposure parameters were similar between the Japanese, non-Japanese Asian and Indian groups. There was no evidence that the polymorphisms assessed in the genes UGT1A1, CYP2C19 and ABCG2 account for observed PK differences. Selumetinib exposure was higher in healthy Asian subjects compared with Western subjects, and these data provide valuable insight for clinicians to consider when treating patients of Asian ethnicity with selumetinib.

  20. The Pharmacogenetics of Metformin

    DEFF Research Database (Denmark)

    Christensen, Mette Marie Hougaard

    2015-01-01

    the sum of results from three pharmacogenetic trials conducted to evaluate this specific hypothesis. The objective of the first study was to evaluate the effect of genetic variations in organic cation transporter 1 and 2 (OCT 1 and 2), multidrug and toxin extrusion transporters 1 and 2-K (MATE 1 and 2-K...... with a more robust type 2 diabetic phenotype, some of the variants may end up as relevant covariates that potentially decrease the observed variability in the metformin response. Our results warrant a pharmacogenetic tracer study in type 2 diabetic patients with different numbers of reduced-function alleles...

  1. Pharmacogenetics of antidepressant response: An update

    Directory of Open Access Journals (Sweden)

    Drago Antonio

    2009-04-01

    Full Text Available Abstract The past few decades have witnessed much progress in the field of pharmacogenetics. The identification of the genetic background that regulates the antidepressant response has benefited from these advances. This review focuses on the pharmacogenetics of the antidepressant response through the analysis and discussion of the most compelling evidence in this line of research. Online databases (Medline and PsycINFO have been searched and the most replicated association findings relating to the genetics of the antidepressant response have been reported and discussed. Some replicated findings in the literature have suggested the serotonin transporter promoter (5-HTTLPR, serotonin receptor 1A (HTR1A, serotonin receptor 2A (HTR2A, brain derived neurotrophic factor (BDNF, corticotropin releasing hormone receptor 1 (CRHR1 and FK506 binding protein 5 (FKBP5 as putative regulators of the antidepressant response. A high rate of failure of replication has also been reported. Pharmacogenetics will hopefully provide the basis for personalised antidepressant treatment that is able to maximise the probability of a good response and to minimise side effects; however, this goal is not achievable at the moment. The extent of the validity of the replicated findings and the reasons for the poor results obtained from studies of the pharmacogenetics of the antidepressant response are discussed.

  2. Knowledge of Pharmacogenetics among Healthcare Professionals ...

    African Journals Online (AJOL)

    Background: Pharmacogenetics has a potential for optimizing drug response and identifying risk of toxicity for patients. Pharmacogenetics knowledge of healthcare professionals and the unmet need for pharmacogenetics education in health training institutions are some of the challenges of integrating pharmacogenetics ...

  3. Personalizing medicine with clinical pharmacogenetics

    Science.gov (United States)

    Scott, Stuart A.

    2012-01-01

    Clinical genetic testing has grown substantially over the past 30 years as the causative mutations for Mendelian diseases have been identified, particularly aided in part by the recent advances in molecular-based technologies. Importantly, the adoption of new tests and testing strategies (e.g., diagnostic confirmation, prenatal testing, and population-based carrier screening) has often been met with caution and careful consideration before clinical implementation, which facilitates the appropriate use of new genetic tests. Although the field of pharmacogenetics was established in the 1950s, clinical testing for constitutional pharmacogenetic variants implicated in interindividual drug response variability has only recently become available to help clinicians guide pharmacotherapy, in part due to US Food and Drug Administration-mediated product insert revisions that include pharmacogenetic information for selected drugs. However, despite pharmacogenetic associations with adverse outcomes, physician uptake of clinical pharmacogenetic testing has been slow. Compared with testing for Mendelian diseases, pharmacogenetic testing for certain indications can have a lower positive predictive value, which is one reason for underutilization. A number of other barriers remain with implementing clinical pharmacogenetics, including clinical utility, professional education, and regulatory and reimbursement issues, among others. This review presents some of the current opportunities and challenges with implementing clinical pharmacogenetic testing. PMID:22095251

  4. Pharmacogenetics and forensic toxicology.

    Science.gov (United States)

    Musshoff, Frank; Stamer, Ulrike M; Madea, Burkhard

    2010-12-15

    Large inter-individual variability in drug response and toxicity, as well as in drug concentrations after application of the same dosage, can be of genetic, physiological, pathophysiological, or environmental origin. Absorption, distribution and metabolism of a drug and interactions with its target often are determined by genetic differences. Pharmacokinetic and pharmacodynamic variations can appear at the level of drug metabolizing enzymes (e.g., the cytochrome P450 system), drug transporters, drug targets or other biomarker genes. Pharmacogenetics or toxicogenetics can therefore be relevant in forensic toxicology. This review presents relevant aspects together with some examples from daily routines. Copyright © 2010. Published by Elsevier Ireland Ltd.

  5. Pharmacogenetics of Antipsychotics

    Science.gov (United States)

    Brandl, Eva J; Kennedy, James L; Müller, Daniel J

    2014-01-01

    Objective: During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. Methods: We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses. Results: Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. Conclusion: First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings. PMID:24881126

  6. Progress and prospects in pharmacogenetics of antidepressant drugs.

    Science.gov (United States)

    Fabbri, Chiara; Crisafulli, Concetta; Calabrò, Marco; Spina, Edoardo; Serretti, Alessandro

    2016-10-01

    Depression is responsible for the most part of the personal and socio-economic burden due to psychiatric disorders. Since antidepressant response clusters in families, pharmacogenetics represents a meaningful tool to provide tailored treatments and improve the prognosis of depression. This review aims to summarize and discuss the pharmacogenetics of antidepressant drugs in major depressive disorder, with a focus on the most replicated genes, genome-wide association studies (GWAS), but also on the findings provided by new and promising analysis methods. In particular, multimarker tests such as pathway analysis and polygenic risk scores increase the power of detecting associations compared to the analysis of individual polymorphisms. Since genetic variants are not necessarily associated with a change in protein level, gene expression studies may provide complementary information to genetic studies. Finally, the pharmacogenetic tests that have been investigated for clinical application are discussed. Despite the lack of widespread clinical applications, preliminary results suggest that pharmacogenetics may be useful to guide antidepressant treatment. The US Food and Drug Administration included pharmacogenetic indications in the labeling of several antidepressants. This represented an important official recognition of the clinical relevance of genetic polymorphisms in antidepressant treatment.

  7. Pharmacogenetics of asthma: toward precision medicine.

    Science.gov (United States)

    Kersten, Elin T G; Koppelman, Gerard H

    2017-01-01

    Although currently available drugs to treat asthma are effective in most patients, a proportion of patients do not respond or experience side-effects; which is partly genetically determined. Pharmacogenetics is the study of how genetic variations influence drug response. In this review, we summarize prior results and recent studies in pharmacogenetics to determine if we can use genetic profiles for personalized treatment of asthma. The field of pharmacogenetics has moved from candidate gene studies in single populations toward genome-wide association studies and meta-analysis of multiple studies. New technologies have been used to enrich results, and an expanding number of genetic loci have been associated with therapeutic responses to asthma drugs. Prospective, genotype-stratified treatment studies have been conducted for β2-agonists, showing attenuated response in children carrying the Arg16 variant in the β2-adrenoreceptor gene. Although there has been much progress, many findings have not been replicated and currently known genetic loci only account for a fraction of variability in drug response. More research is necessary to translate into clinical practice. A polygenic predictive approach integrated in complex networks with other 'omics' technologies could aid to achieve this goal. Finally, to change clinical practice, studies that compare precision medicine with traditional medicine are needed.

  8. Data science approaches to pharmacogenetics.

    Science.gov (United States)

    Penrod, N M; Moore, J H

    2014-01-01

    Pharmacogenetic studies rely on applied statistics to evaluate genetic data describing natural variation in response to pharmacotherapeutics such as drugs and vaccines. In the beginning, these studies were based on candidate gene approaches that specifically focused on efficacy or adverse events correlated with variants of single genes. This hypothesis driven method required the researcher to have a priori knowledge of which genes or gene sets to investigate. According to rational design, the focus of these studies has been on drug metabolizing enzymes, drug transporters, and drug targets. As technology has progressed, these studies have transitioned to hypothesis-free explorations where markers across the entire genome can be measured in large scale, population based, genome-wide association studies (GWAS). This enables identification of novel genetic biomarkers, therapeutic targets, and analysis of gene-gene interactions, which may reveal molecular mechanisms of drug activities. Ultimately, the challenge is to utilize gene-drug associations to create dosing algorithms based individual genotypes, which will guide physicians and ensure they prescribe the correct dose of the correct drug the first time eliminating trial-and-error and adverse events. We review here basic concepts and applications of data science to the genetic analysis of pharmacologic outcomes.

  9. Pharmacogenetics and the print media: what is the public told?

    Science.gov (United States)

    Almomani, Basima; Hawwa, Ahmed F; Goodfellow, Nicola A; Millership, Jeffrey S; McElnay, James C

    2015-05-09

    Pharmacogenetics is a rapidly growing field that aims to identify the genes that influence drug response. This science can be used as a powerful tool to tailor drug treatment to the genetic makeup of individuals. The present study explores the coverage of the topic of pharmacogenetics and its potential benefit in personalised medicine by the UK newsprint media. The LexisNexis database was used to identify and retrieve full text articles from the 10 highest circulation national daily newspapers and their Sunday equivalents in the UK. Content analysis of newspaper articles which referenced pharmacogenetic testing was carried out. A second researcher coded a random sample (21%) of newspaper articles to establish the inter-rater reliability of coding. Of the 256 articles captured by the search terms, 96 articles (with pharmacogenetics as a major component) met the study inclusion criteria. The majority of articles over-stated the benefits of pharmacogenetic testing while paying less attention to the associated risks. Overall beneficial effects were mentioned 5.3 times more frequently than risks (p pharmacogenetically based personalised medicine was discussed were cancer, cardiovascular disease and CNS diseases. Only 13% of newspaper articles that cited a specific scientific study mentioned this link in the article. There was a positive correlation between the size of the article and both the number of benefits and risks stated (P < 0.01). More comprehensive coverage of the area of personalised medicine within the print media is needed to inform public debate on the inclusion of pharmacogentic testing in routine practice.

  10. Pharmacogenetics of lipid diseases

    Directory of Open Access Journals (Sweden)

    Ordovas Jose M

    2004-01-01

    Full Text Available Abstract The genetic basis for most of the rare lipid monogenic disorders have been elucidated, but the challenge remains in determining the combination of genes that contribute to the genetic variability in lipid levels in the general population; this has been estimated to be in the range of 40-60 per cent of the total variability. Therefore, the effect of common polymorphisms on lipid phenotypes will be greatly modulated by gene-gene and gene-environment interactions. This approach can also be used to characterise the individuality of the response to lipid-lowering therapies, whether using drugs (pharmacogenetics or dietary interventions (nutrigenetics. In this regard, multiple studies have already described significant interactions between candidate genes for lipid and drug metabolism that modulate therapeutic response--although the outcomes of these studies have been controversial and call for more rigorous experimental design and analytical approaches. Once solid evidence about the predictive value of genetic panels is obtained, risk and therapeutic algorithms can begin to be generated that should provide an accurate measure of genetic predisposition, as well as targeted behavioural modifications or drugs of choice and personalised dosages of these drugs.

  11. Pharmacogenetics of asthma

    Science.gov (United States)

    Lima, John J.; Blake, Kathryn V.; Tantisira, Kelan G.; Weiss, Scott T.

    2009-01-01

    Purpose of review Patient response to the asthma drug classes, bronchodilators, inhaled corticosteroids and leukotriene modifiers, are characterized by a large degree of heterogeneity, which is attributable in part to genetic variation. Herein, we review and update the pharmacogenetics and pharmaogenomics of common asthma drugs. Recent findings Early studies suggest that bronchodilator reversibility and asthma worsening in patients on continuous short-acting and long-acting β-agonists are related to the Gly16Arg genotype for the ADRB2. More recent studies including genome-wide association studies implicate variants in other genes contribute to bronchodilator response heterogeneity and fail to replicate asthma worsening associated with continuous β-agonist use. Genetic determinants of the safety of long-acting β-agonist require further study. Variants in CRHR1, TBX21, and FCER2 contribute to variability in response for lung function, airways responsiveness, and exacerbations in patients taking inhaled corticosteroids. Variants in ALOX5, LTA4H, LTC4S, ABCC1, CYSLTR2, and SLCO2B1 contribute to variability in response to leukotriene modifiers. Summary Identification of novel variants that contribute to response heterogeneity supports future studies of single nucleotide polymorphism discovery and include gene expression and genome-wide association studies. Statistical models that predict the genomics of response to asthma drugs will complement single nucleotide polymorphism discovery in moving toward personalized medicine. PMID:19077707

  12. Pharmacogenetics of β-Blockers

    Science.gov (United States)

    Shin, Jaekyu; Johnson, Julie A.

    2009-01-01

    β-Blockers are an important cardiovascular drug class, recommended as first-line treatment of numerous diseases such as heart failure, hypertension, and angina, as well as treatment after myocardial infarction. However, responses to a β-blocker are variable among patients. Results of numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to β-blockers. This review summarizes the pharmacogenetic data for β-blockers in patients with various diseases and discusses the potential implications of β-blocker pharmacogenetics in clinical practice. PMID:17542770

  13. Some aspects of genetics and pharmacogenetics understanding by ...

    African Journals Online (AJOL)

    The aim of the present work is to analyze students' awareness about pharmacogenetics in the National University of Pharmacy (NUPh) since its development is delayed in Ukraine. Methods: Field investigations have been used in this work. The material analysis based on questioning 637 students of the 1st–4th year ...

  14. [Pharmacogenetics and tailored drug therapy

    DEFF Research Database (Denmark)

    Nielsen, F.C.; Borregaard, N.

    2009-01-01

    Pharmacogenetics traditionally designates the study of genetically determined variation in metabolism of drugs and toxins from the environment. The concept of phamacogenetics has been widened to encompass how essential genetic alterations central to the development of diseases may by used to target...

  15. Challenges and pitfalls in the introduction of pharmacogenetics for cancer.

    Science.gov (United States)

    Loh, Marie; Soong, Richie

    2011-08-01

    There have been several success stories in the field of pharmacogenetics in recent years, including the analysis of HER2 amplification for trastuzumab selection in breast cancer and VKORC1 genotyping for warfarin dosing in thrombosis. Encouraging results from these studies suggest that genetic factors may indeed be important determinants of drug response and toxicity for at least some drugs. However, to apply pharmacogenetics appropriately, a thorough understanding of the scope and limitations of this field is required. The challenges include an appreciation of biological variability, logistical issues pertaining to the proper management of information, the need for robust methods and adequate sample quality with well-designed workflows. At the same time, the economics of pharmacogenetic testing from the perspective of clinicians, patients, governments, insurance companies and pharmaceutical companies will play an important role in determining its future use. Ethical considerations such as informed consent and patient privacy, as well as the role of regulatory bodies in addressing these issues, must be fully understood. Only once these issues are properly dealt with can the full benefits of pharmacogenetics begin to be realised.

  16. Fundamentals of Pharmacogenetics in Personalized, Precision Medicine.

    Science.gov (United States)

    Valdes, Roland; Yin, DeLu Tyler

    2016-09-01

    This article introduces fundamental principles of pharmacogenetics as applied to personalized and precision medicine. Pharmacogenetics establishes relationships between pharmacology and genetics by connecting phenotypes and genotypes in predicting the response of therapeutics in individual patients. We describe differences between precision and personalized medicine and relate principles of pharmacokinetics and pharmacodynamics to applications in laboratory medicine. We also review basic principles of pharmacogenetics, including its evolution, how it enables the practice of personalized therapeutics, and the role of the clinical laboratory. These fundamentals are a segue for understanding specific clinical applications of pharmacogenetics described in subsequent articles in this issue. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib.

    Directory of Open Access Journals (Sweden)

    Astrid Yeo

    Full Text Available Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2 inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY and one in acute coronary syndrome (SOLID-TIMI 52. No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%. We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1 and identified three novel loci (TOMM5, FRMD5 and LPL using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2 within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores and one common locus (minor allele frequency 0.24 with genotype by treatment interaction effect passing the GWAS

  18. PHARMACOGENETIC TESTING OPPORTUNITIES IN CARDIOLOGY BASED ON EXOME SEQUENCING

    Directory of Open Access Journals (Sweden)

    N. V. Shcherbakova

    2014-01-01

    Full Text Available Aim. To study what cardiac drugs currently have any comments on biomarkers and what information can be obtained by pharmacogenetic testing using data exome sequencing in patients with cardiac diseases.Material and methods. Exome sequencing in random participant of the ATEROGEN IVANOVO study and bioinformatics analysis of the data were performed. Point mutations were annotated using ANNOVAR program, as well as comparison with a number of specialized databases was done on the basis of user protocols.Results. 11 cardiac drugs and 7 genes which variants can influence cardiac drug metabolism were analyzed. According to exome sequencing of the participant we did not reveal allelic variants that require dose regime correction and careful efficacy control.Conclusion. The exome sequencing application is the next step to a wide range of personalized therapy. Future opportunities for improvement of the risk-benefit ratio in each patient are the main purpose of the collection and analysis of pharmacogenetic data.

  19. Economics of Pharmacogenetic-Guided Treatments: Underwhelming or Overstated?

    Science.gov (United States)

    Hughes, Dyfrig A

    2018-05-01

    Economic evaluations have dispelled a perception that precision medicine, achieved through pharmacogenetic testing, reduces healthcare costs. For many tests aimed at preventing adverse drug reactions, cost-effectiveness analyses predict modest improvements in health benefits and increases in total costs. While there are many uncertainties in estimating the value of testing, factors that influence cost-effectiveness include the rarity of the outcome, the effectiveness of alternative treatments, and the scope and perspective of analysis. © 2018 ASCPT.

  20. Pharmacogenetics in Europe: barriers and opportunities.

    Science.gov (United States)

    Gurwitz, D; Zika, E; Hopkins, M M; Gaisser, S; Ibarreta, D

    2009-01-01

    This paper reviews the current situation in the field of pharmacogenetics/pharmacogenomics (PGx) in Europe. High expectations surrounding the clinical application of PGx remain largely unmet, as only a limited number of such applications have actually reached the market and clinical practice. Thus, the potential impact of PGx-based diagnostics on healthcare and its socio-economic implications are still unclear. With the aim of shedding some light on these uncertainties, the Institute for Prospective Technological Studies (IPTS) of the European Commission's Joint Research Centre (JRC) has conducted a review of the 'state of the art' and a further analysis on the use of pharmacogenetics diagnostics for preventing toxic drug reactions and improving drug efficacy in Europe. The paper presents highlights from the JRC-IPTS studies and discusses possibilities for improving translation of PGx research in Europe by comparing some experiences in the USA. We also illustrate the related barriers for the clinical uptake of PGx in Europe with specific case-studies. Most of the barriers identified extend beyond the European context. This reflects the global problems of scarcity of data demonstrating proven clinical validity or utility and favorable cost-effectiveness studies to support the clinical application of PGx diagnostic tests in the clinical setting. Another key barrier is the lack of incentives for the private sector to invest in the development and licensing of PGx diagnostic tests for improving the safety and efficacy of out-of-patent drugs. It therefore seems that one key aspect where policy can affect the clinical uptake of PGx is via sustaining large-scale industry-academia collaborations for developing and proving the utility of PGx diagnostics. Copyright 2009 S. Karger AG, Basel.

  1. Analysis of polymorphisms and haplotype structure of the human thymidylate synthase genetic region: a tool for pharmacogenetic studies.

    Directory of Open Access Journals (Sweden)

    Soma Ghosh

    Full Text Available 5-Fluorouracil (5FU, a widely used chemotherapeutic drug, inhibits the DNA replicative enzyme, thymidylate synthase (Tyms. Prior studies implicated a VNTR (variable numbers of tandem repeats polymorphism in the 5'-untranslated region (5'-UTR of the TYMS gene as a determinant of Tyms expression in tumors and normal tissues and proposed that these VNTR genotypes could help decide fluoropyrimidine dosing. Clinical associations between 5FU-related toxicity and the TYMS VNTR were reported, however, results were inconsistent, suggesting that additional genetic variation in the TYMS gene might influence Tyms expression. We thus conducted a detailed genetic analysis of this region, defining new polymorphisms in this gene including mononucleotide (poly A:T repeats and novel single nucleotide polymorphisms (SNPs flanking the VNTR in the TYMS genetic region. Our haplotype analysis of this region used data from both established and novel genetic variants and found nine SNP haplotypes accounting for more than 90% of the studied population. We observed non-exclusive relationships between the VNTR and adjacent SNP haplotypes, such that each type of VNTR commonly occurred on several haplotype backgrounds. Our results confirmed the expectation that the VNTR alleles exhibit homoplasy and lack the common ancestry required for a reliable marker of a linked adjacent locus that might govern toxicity. We propose that it may be necessary in a clinical trial to assay multiple types of genetic polymorphisms in the TYMS region to meaningfully model linkage of genetic markers to 5FU-related toxicity. The presence of multiple long (up to 26 nt, polymorphic monothymidine repeats in the promoter region of the sole human thymidylate synthetic enzyme is intriguing.

  2. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems.

    Science.gov (United States)

    Luzum, J A; Pakyz, R E; Elsey, A R; Haidar, C E; Peterson, J F; Whirl-Carrillo, M; Handelman, S K; Palmer, K; Pulley, J M; Beller, M; Schildcrout, J S; Field, J R; Weitzel, K W; Cooper-DeHoff, R M; Cavallari, L H; O'Donnell, P H; Altman, R B; Pereira, N; Ratain, M J; Roden, D M; Embi, P J; Sadee, W; Klein, T E; Johnson, J A; Relling, M V; Wang, L; Weinshilboum, R M; Shuldiner, A R; Freimuth, R R

    2017-09-01

    Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs. © 2017, The American Society for Clinical Pharmacology and Therapeutics.

  3. Pharmacogenetics of posttransplant diabetes mellitus.

    Science.gov (United States)

    Lancia, P; Adam de Beaumais, T; Jacqz-Aigrain, E

    2017-06-01

    Many factors (physiological, pathological, environmental or genetic) are associated with variability in drug effect. Most patients respond to a standard treatment but the drug may be ineffective or toxic. In this review, we focused on genetic markers of posttransplant diabetes mellitus (PTDM) after renal transplantation, a frequent complication of immunosuppressive therapy and important risk factor of graft loss and mortality. An initial literature search identified 100 publications and among them 32 association studies were retrieved under 'Pharmacogenetics and PTDM'. Thirty-five variants in 25 genes with an impact on insulin secretion, disposition or effect were significantly associated with PTDM. The population studied, immunosuppressive regimen, follow-up, PTDM diagnostic and genetic variations tested were highly variable between studies. Although pharmacogenetic biomarkers are key tools of great promise for preventing toxicities and improving event-free survival rates, replication studies are required to select validated biomarkers linked to the occurrence of PTDM and select appropriate immusuppressive treatment to improve renal graft and patient outcome.

  4. Understanding the pharmacogenetics of selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Fabbri, Chiara; Minarini, Alessandro; Niitsu, Tomihisa; Serretti, Alessandro

    2014-08-01

    The genetic background of antidepressant response represents a unique opportunity to identify biological markers of treatment outcome. Encouraging results alternating with inconsistent findings made antidepressant pharmacogenetics a stimulating but often discouraging field that requires careful discussion about cumulative evidence and methodological issues. The present review discusses both known and less replicated genes that have been implicated in selective serotonin reuptake inhibitors (SSRIs) efficacy and side effects. Candidate genes studies and genome-wide association studies (GWAS) were collected through MEDLINE database search (articles published till January 2014). Further, GWAS signals localized in promising genetic regions according to candidate gene studies are reported in order to assess the general comparability of results obtained through these two types of pharmacogenetic studies. Finally, a pathway enrichment approach is applied to the top genes (those harboring SNPs with p pharmacogenetics, the present review discusses the proposal of moving from the analysis of individual polymorphisms to genes and molecular pathways, and from the separation across different methodological approaches to their combination. Efforts in this direction are justified by the recent evidence of a favorable cost-utility of gene-guided antidepressant treatment.

  5. Haplotype-based case-control study on human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 gene and essential hypertension.

    Science.gov (United States)

    Naganuma, Takahiro; Nakayama, Tomohiro; Sato, Naoyuki; Fu, Zhenyan; Soma, Masayoshi; Yamaguchi, Mai; Shimodaira, Masanori; Aoi, Noriko; Usami, Ron

    2010-02-01

    Oxidative DNA damage is involved in the pathophysiology of essential hypertension (EH), which is a multifactorial disorder. Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) is an essential endonuclease in the base excision repair pathway of oxidatively damaged DNA, in addition to having reducing properties that promote the binding of redox-sensitive transcription factors. Blood pressure in APE1/REF-1-knockout mice is reported to be significantly higher than in wild-type mice. The aim of this study was to investigate the relationship between EH and the human APE1/REF-1 gene through a haplotype-based case-control study using single-nucleotide polymorphisms (SNPs). We selected five SNPs in the human APE1/REF-1 gene (rs1760944, rs3136814, rs17111967, rs3136817, and rs1130409), and performed case-control studies in 265 EH patients and 266 age-matched normotensive (NT) subjects. rs17111967 was found to show nonheterogeneity among Japanese subjects. There were no significant differences in the overall distribution of genotypes or alleles for each SNP between EH and NT groups. In the overall distribution of the haplotype-based case-control study constructed based on rs1760944, rs3136817, and rs1130409, the frequency of the G-T-T haplotype was significantly higher in the EH group than in the NT group (2.1% vs. 0.0%, P = 0.001). Multiple logistic regression analysis also revealed significant differences for the G-T-T haplotype, even after adjustment for confounding factors (OR = 8.600, 95% CI: 1.073-68.951, P = 0.043). Based on the present results, the G-T-T haplotype appears to be a genetic marker of EH, and the APE1/REF-1 gene appears to be a susceptibility gene for EH.

  6. Some aspects of genetics and pharmacogenetics understanding by ...

    African Journals Online (AJOL)

    O.V. Filiptsova

    2014-11-18

    Nov 18, 2014 ... aspects of pharmacogenetics when training competent up to date specialists in the ..... In Spain, the monitoring protocol of anticonvulsants, including the cor- ... attempts of the economic efficiency of pharmacogenetic testing.

  7. Pharmacogenetics in Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Cheok, Meyling H.; Pottier, Nicolas; Kager, Leo

    2009-01-01

    Progress in the treatment of acute leukemia in children has been remarkable, from a disease being lethal four decades ago to current cure rates exceeding 80%. This exemplary progress is largely due to the optimization of existing treatment modalities rather than the discovery of new antileukemic agents. However, despite these high cure rates, the annual number of children whose leukemia relapses after their initial therapy remains greater than that of new cases of most types of childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize treatment and tailor therapy to individual patients, with the goal of optimizing efficacy and safety through better understanding of human genome variability and its influence on drug response. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute lymphoblastic leukemia. These studies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm. PMID:19100367

  8. Pharmacogenetics in the Brazilian population

    Directory of Open Access Journals (Sweden)

    Guilherme eSuarez-Kurtz

    2010-10-01

    Full Text Available Brazil is the 5th largest country in the world and its present population, in excess of 190 million, is highly heterogeneous, as a result of centuries of admixture between Amerindians, Europeans and Sub-Saharan Africans. The estimated individual proportions of biogeographical ancestry vary widely and continuously among Brazilians, most individuals - irrespective of self-identification as White, Brown or Black, the major categories of the Brazilian Census race/color system - having significant degrees of European and African ancestry, while a sizeable number display also Amerindian ancestry. These features have important pharmacogenetic (PGx implications: first, extrapolation of PGx data from relatively well-defined ethnic groups is clearly not applicable to the majority of Brazilians; second, the frequency distribution of polymorphisms in pharmacogenes (e.g. CYP3A5, CYP2C9, GSTM1, ABCB1, GSTM3, VKORC, etc varies continuously among Brazilians and is not captured by race/color self-identification; third, the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of PGx studies in order to avoid spurious conclusions based on improper matching of study cohorts. The peculiarities of PGx in Brazilians are illustrated with data for different therapeutic groups, such as anticoagulants, HIV-protease inhibitors and nonsteroidal antinflammatory drugs, and the challenges and advantages created by population admixture for the study and implementation of PGx are discussed. PGx data for Amerindian groups and Brazilian-born, first generation Japanese are presented to illustrate the rich diversity of the Brazilian population. Finally, I introduce the reader to the Brazilian Pharmacogenetic Network or Refargen (www.refargen.org.br, a nationwide consortium of research groups, with the mission to provide leadership in PGx research and education in Brazil, with a population health impact.

  9. Implementation of inpatient models of pharmacogenetics programs.

    Science.gov (United States)

    Cavallari, Larisa H; Lee, Craig R; Duarte, Julio D; Nutescu, Edith A; Weitzel, Kristin W; Stouffer, George A; Johnson, Julie A

    2016-12-01

    The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted. Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics. Pharmacists have assumed important roles in implementing inpatient pharmacogenetics programs. This includes programs designed to incorporate genetic test results to optimize antiplatelet drug selection after percutaneous coronary intervention and personalize warfarin dosing. Pharmacist involvement occurs on many levels, including championing and leading pharmacogenetics implementation efforts, establishing clinical processes to support genotype-guided therapy, assisting the clinical staff with interpreting genetic test results and applying them to prescribing decisions, and educating other healthcare providers and patients on genomic medicine. The three inpatient pharmacogenetics programs described use reactive versus preemptive genotyping, the most feasible approach under the current third-party payment structure. All three sites also follow Clinical Pharmacogenetics Implementation Consortium guidelines for drug therapy recommendations based on genetic test results. With the clinical emergence of pharmacogenetics into the inpatient setting, it is important that pharmacists caring for hospitalized patients are well prepared to serve as experts in interpreting and applying genetic test results to guide drug therapy decisions. Since genetic test results may not be available until after patient discharge, pharmacists practicing in the ambulatory care setting should also be prepared to assist with genotype-guided drug therapy as part of transitions in care. Copyright © 2016 by the American Society of Health

  10. Pharmacogenetics of drug-induced arrhythmias

    DEFF Research Database (Denmark)

    De Bruin, Marie L; van Puijenbroek, Eugene P; Bracke, Madelon

    2006-01-01

    PURPOSE: The bottleneck in pharmacogenetic research on rare adverse drug reactions (ADR) is retrieval of patients. Spontaneous reports of ADRs may form a useful source of patients. We investigated the feasibility of a pharmacogenetic study, in which cases were selected from the database...... of a spontaneous reporting system for ADRs, using drug-induced arrhythmias as an example. METHODS: Reports of drug-induced arrhythmias to proarrhythmic drugs were selected from the database of the Netherlands Pharmacovigilance Centre (1996-2003). Information on the patient's general practitioner (GP) was obtained...... be included in the study, giving an overall participation rate of 9% (4/45). The main reason for GPs not being willing to participate was lack of time. Variants were identified in KCNH2, SCN5A and KCNE1. CONCLUSIONS: Spontaneous reporting systems for ADRs may be used for pharmacogenetic research. The methods...

  11. Pharmacogenetics in electroconvulsive therapy and adjunctive medications.

    Science.gov (United States)

    Mirzakhani, Hooman; van Noorden, Martijn S; Swen, Jesse; Nozari, Ala; Guchelaar, Henk-Jan

    2015-01-01

    Electroconvulsive therapy (ECT) has shown apparent efficacy in treatment of patients with depression and other mental illnesses who do not respond to psychotropic medications or need urgent control of their symptoms. Pharmacogenetics contributes to an individual's sensitivity and response to a variety of drugs. Clinical insights into pharmacogenetics of ECT and adjunctive medications not only improves its safety and efficacy in the indicated patients, but can also lead to the identification of novel treatments in psychiatric disorders through understanding of potential molecular and biological mechanisms involved. In this review, we explore the indications of pharmacogenetics role in safety and efficacy of ECT and present the evidence for its role in patients with psychiatric disorders undergoing ECT.

  12. Knowledge and attitude regarding pharmacogenetics among formerly pregnant women in the Netherlands and their interest in pharmacogenetic research.

    Science.gov (United States)

    Daud, Aizati N A; Bergsma, Eefke L; Bergman, Jorieke E H; De Walle, Hermien E K; Kerstjens-Frederikse, Wilhelmina S; Bijker, Bert J; Hak, Eelko; Wilffert, Bob

    2017-04-14

    Pharmacogenetics is an emerging field currently being implemented to improve safety when prescribing drugs. While many women who take drugs during pregnancy would likely benefit from such personalized drug therapy, data is lacking on the awareness towards pharmacogenetics among women. We aim to determine the level of knowledge and acceptance of formerly pregnant women in the Netherlands regarding pharmacogenetics and its implementation, and their interest in pharmacogenetic research. A population-based survey using postal questionnaires was conducted among formerly pregnant women in the Northern parts of the Netherlands. A total of 986 women were invited to participate. Of the 219 women who returned completed questionnaires (22.2% response rate), only 22.8% had heard of pharmacogenetics, although the majority understood the concept (64.8%). Women who had experience with drug side-effects were more likely to know about pharmacogenetics [OR = 2.06, 95% CI 1.16, 3.65]. Of the respondents, 53.9% were positive towards implementing pharmacogenetics in their future drug therapy, while 46.6% would be willing to participate in pharmacogenetic research. Among those who were either not willing or undecided in this regard, their concerns were about the consequences of the pharmacogenetic test, including the privacy and anonymity of their genetic information. The knowledge and attitude regarding the concept of pharmacogenetics among our population of interest is good. Also, their interest in pharmacogenetic research provides opportunities for future research related to drug use during pregnancy and fetal outcome.

  13. β-Blocker pharmacogenetics in heart failure

    Science.gov (United States)

    Shin, Jaekyu

    2009-01-01

    β-Blockers (metoprolol, bisoprolol, and carvedilol) are a cornerstone of heart failure (HF) treatment. However, it is well recognized that responses to a β-blocker are variable among patients with HF. Numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to a β-blocker, including left ventricular ejection fraction improvement, survival, and hospitalization due to HF exacerbation. This review summarizes the pharmacogenetic data for β-blockers in patients with HF and discusses the potential implications of β-blocker pharmacogenetics for HF patients. PMID:18437562

  14. The Pharmacist's Perspective on Pharmacogenetics Implementation.

    Science.gov (United States)

    Weitendorf, Frederick; Reynolds, Kristen K

    2016-09-01

    The future for pharmacogenetics will continue to expand. Pharmacists can apply and incorporate drug knowledge in collaboration with other health providers using pharmacogenetics. Patients benefit with enhanced therapeutic outcomes that could lead to more streamlined drug approaches, fewer follow-up visits, cost savings, and shorter times to achieve therapeutic outcomes. As more drug-gene pathways are discovered and use of this knowledge increases, the potential for algorithm development for medication use will occur, resulting in better patient outcomes, higher standard of care, and reflect evidence-based medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Pharmacogenetic considerations in the treatment of HIV.

    Science.gov (United States)

    Mattevi, Vanessa S; Tagliari, Carmela Fs

    2017-01-01

    After the introduction of highly active antiretroviral therapy in the 1990s, the perception of the diagnosis of HIV infection gradually shifted from a 'death sentence' to a chronic disease requiring long-term treatment. The host genetic variability has been shown to play a relevant role in both antiretroviral drugs bioavailability and adverse effects susceptibility. Knowledge about pharmacogenetics role in HIV infection treatment has largely increased over the last years, and is reviewed in the present report, as well as future perspectives for the inclusion of pharmacogenetics information in the directing of HIV infection treatment.

  16. Potential of adaptive clinical trial designs in pharmacogenetic research, A simulation based on the IPASS trial

    NARCIS (Netherlands)

    Van Der Baan, Frederieke H.; Knol, Mirjam J.|info:eu-repo/dai/nl/304820350; Klungel, Olaf H.|info:eu-repo/dai/nl/181447649; Egberts, Toine C.G.|info:eu-repo/dai/nl/162850050; Grobbee, Diederick E.; Roes, Kit C.B.

    2011-01-01

    Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary

  17. Reprogenetics and pharmacogenetics: in whose best interests?

    Science.gov (United States)

    Mackenzie, Robin

    2005-06-01

    Reprogenetics involves embryonic pre-implantation genetic diagnosis, provoking controversy over the creation of saviour siblings, eugenics and genetic enhancement. It will soon ascertain pharmacogenetic susceptibilities. Pharmacogenetics impacts upon public health initiatives underpinned by resource allocation constraints in that genetic epidemiological studies assist in administering health care resources and public health strategies. Knowing how likely sections of the population are to develop specific medical conditions so that lifestyle and environmental factors influencing these conditions can be targeted has the potential to save public money and improve public health. Aligning population groups with genetic susceptibilities with specific medications would enable cost-effective prescribing. Reprogenetics and pharmacogenetics also possess great commercial potential for nation states and biotechnology companies. Hence ethical legal safeguards for members of the public whose reproductive or genetic tissue is a research or health care resource are essential. Both legal measures such as informed consent and mechanisms for including the public in policy decisions over reprogenetics and pharmacogenetics must be rethought to ensure that they provide protection rather than function as rubber stamps which preclude deeper inquiry into justifications of projects.

  18. Pharmacogenetics of asthma : toward precision medicine

    NARCIS (Netherlands)

    Kersten, Elin T. G.; Koppelman, Gerard H.

    PURPOSE OF REVIEW: Although currently available drugs to treat asthma are effective in most patients, a proportion of patients do not respond or experience side-effects; which is partly genetically determined. Pharmacogenetics is the study of how genetic variations influence drug response. In this

  19. The pharmacogenetics of alcohol use disorder.

    Science.gov (United States)

    Jones, Jermaine D; Comer, Sandra D; Kranzler, Henry R

    2015-03-01

    Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the susceptibility to the disorder and its response to treatment, studies have been conducted to assess the contribution of a variety of candidate genetic variants. These variants, which we review here, were chosen based upon their observed or hypothesized functional relevance to alcohol use disorder (AUD) risk or to the mechanism by which medications used to treat the disorder exert their effects. This qualitative review examines studies in which candidate polymorphisms were tested as moderator variables to identify pharmacogenetic effects on either the subjective response to alcohol or the outcomes of pharmacotherapy. Although findings from these studies provide evidence of a number of clinically relevant pharmacogenetic effects, the literature is limited and there are conflicting findings that require resolution. Pharmacogenetic studies of AUD treatment that use greater methodological rigor and better statistical controls, such as corrections for multiple testing, may help to resolve inconsistent findings. These procedures could also lead to the discovery of more robust and clinically meaningful moderator effects. As the field evolves through methodological standardization and the use of larger study samples, pharmacogenetic research has the potential to inform clinical care by enhancing therapeutic effects and personalizing treatments. These efforts may also provide insights into the mechanisms by which medications reduce heavy drinking or promote abstinence in patients with an AUD. Copyright © 2015 by the Research Society on Alcoholism.

  20. Pharmacogenetics of Anti-Diabetes Drugs

    Directory of Open Access Journals (Sweden)

    Johanna K. DiStefano

    2010-08-01

    Full Text Available A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D. In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs, meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4 inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of ‘response’ can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for “individualized medicine” for patients with T2D.

  1. Pharmacogenetics and rational drug use around the world.

    Science.gov (United States)

    Roederer, Mary W; Sanchez-Giron, Francisco; Kalideen, Kusha; Kudzi, William; McLeod, Howard L; Zhang, Wei

    2011-06-01

    The WHO embraces evidence-based medicine to formulate an essential medicines list (EML) considering disease prevalence, drug efficacy, drug safety and cost-effectiveness. The EML is used by developing countries to build a national formulary. As pharmacogenetics in developed countries evolves, the Pharmacogenetics for Every Nation Initiative (PGENI) convened with representatives from China, Mexico, Ghana and South Africa in August 2009 to evaluate the use of human pharmacogenetics to enhance global drug use policy. The diseases causing mortality, the lack of integration of pharmacovigilance at the national formulary level, the pharmacogenetics research agenda and pharmacogenetics clinician education did not differ greatly among the countries. While there are many unanswered questions, systematically incorporating pharmacogenetics at the national formulary level promises to improve global drug use.

  2. Pharmacogenetics and Imaging-Pharmacogenetics of Antidepressant Response: Towards Translational Strategies.

    Science.gov (United States)

    Lett, Tristram A; Walter, Henrik; Brandl, Eva J

    2016-12-01

    Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic variants, among these the SCL6A4, BDNF, FKBP5, GNB3, GRIK4, and ABCB1 genes, have come to the forefront in this regard. However, small effects sizes, mixed results in independent samples, and conflicting meta-analyses results led to inherent difficulties in the field of pharmacogenetics translating these findings into clinical practice. Nearly all antidepressant pharmacogenetic variants have potentially pleiotropic effects in which they are associated with major depressive disorder, intermediate phenotypes involved in emotional processes, and brain areas affected by antidepressant treatment. The purpose of this article is to provide a comprehensive review of the advances made in the field of pharmacogenetics of antidepressant efficacy and side effects, imaging findings of antidepressant response, and the latest results in the expanding field of imaging-pharmacogenetics studies. We suggest there is mounting evidence that genetic factors exert their impact on treatment response by influencing brain structural and functional changes during antidepressant treatment, and combining neuroimaging and genetic methods may be a more powerful way to detect biological mechanisms of response than either method alone. The most promising imaging-pharmacogenetics findings exist for the SCL6A4 gene, with converging associations with antidepressant response, frontolimbic predictors of affective symptoms, and normalization of frontolimbic activity following antidepressant treatment. More research is required before imaging-pharmacogenetics informed personalized medicine can be applied to antidepressant treatment; nevertheless, inroads have been made towards assessing genetic and neuroanatomical liability and potential clinical application.

  3. A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics.

    Directory of Open Access Journals (Sweden)

    Jorge Duconge

    Full Text Available This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients.A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals.The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day, and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001. The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias.Results supported our rationale to incorporate individual's genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics.ClinicalTrials.gov NCT01318057.

  4. Pharmacogenetics and outcome with antipsychotic drugs.

    Science.gov (United States)

    Pouget, Jennie G; Shams, Tahireh A; Tiwari, Arun K; Müller, Daniel J

    2014-12-01

    Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future.

  5. Haplotype-based approach for noninvasive prenatal tests of Duchenne muscular dystrophy using cell-free fetal DNA in maternal plasma

    DEFF Research Database (Denmark)

    Xu, Yan; Li, Xuchao; Ge, Hui-Juan

    2015-01-01

    Purpose:This study demonstrates noninvasive prenatal testing (NIPT) for Duchenne muscular dystrophy (DMD) using a newly developed haplotype-based approach.Methods:Eight families at risk for DMD were recruited for this study. Parental haplotypes were constructed using target-region sequencing data...

  6. The contribution of pharmacogenetics to pharmacovigilance.

    Science.gov (United States)

    Bondon-Guitton, Emmanuelle; Despas, Fabien; Becquemont, Laurent

    2016-04-01

    Since the beginning of this century, information on pharmacogenetics appears in the summary of product characteristics (SPC) of drugs. Pharmacogenetic tests particularly concern the enzymes involved in the metabolism of drugs, among which P450 cytochromes. Some patients known as poor metabolisers eliminate some drugs more slowly, causing overdoses and adverse drug reactions (ADRs). The best-known examples are AVK and VKORC1-CYP2C9 or clopidogrel and CYP2C19. In the USA, the tests are recommended before the introduction of these drugs to prevent the occurrence of ADRs. Other tests are also commonly performed to address the toxicity of certain anticancer drugs (DPYD-capecitabine, UGT1A1-irinotecan, TPMT 6-mercaptopurine). Pharmacogenetic testing is also available to identify HLA loci that are very strongly associated with the occurrence of immuno-allergic reactions to a specific drug. The best-known example is HLA-B*5701, strongly associated with hypersensitivity to abacavir, and this test is now always prescribed before the instatement of this drug. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  7. Population pharmacogenetics of Ibero-Latinoamerican populations (MESTIFAR 2014).

    Science.gov (United States)

    Sosa-Macias, Martha; Moya, Graciela E; LLerena, Adrián; Ramírez, Ronald; Terán, Enrique; Peñas-LLedó, Eva M; Tarazona-Santos, Eduardo; Galaviz-Hernández, Carlos; Céspedes-Garro, Carolina; Acosta, Hildaura

    2015-01-01

    MESTIFAR 2014 28-30 November 2014, Panama City, Panama The CEIBA consortium was created within the Ibero-American network of Pharmacogenetics (RIBEF) to study population pharmacogenetics. The current status of these initiatives and results of the MESTIFAR project were analyzed in Panama, 28-30 November 2014. The MESTIFAR project focused on studying CYPs genetic polymorphisms in populations of different ethnic origin. So far, more than 6000 healthy volunteers have been evaluated, making this one of the largest population pharmacogenomic studies worldwide. Three symposia were organized, 'Pharmacogenetics of indigenous and mestizos populations and its clinical implications', 'Methodological innovation in pharmacogenetics and its application in health', and 'General discussion and concluding remarks', about mechanisms and proposals for training, diffusion of pharmacogenetics for Spanish- and Portuguese-speaking health professionals, and 'bench to bedside' pilot projects.

  8. A pharmacogenetics service experience for pharmacy students, residents, and fellows.

    Science.gov (United States)

    Drozda, Katarzyna; Labinov, Yana; Jiang, Ruixuan; Thomas, Margaret R; Wong, Shan S; Patel, Shitalben; Nutescu, Edith A; Cavallari, Larisa H

    2013-10-14

    To utilize a comprehensive, pharmacist-led warfarin pharmacogenetics service to provide pharmacy students, residents, and fellows with clinical and research experiences involving genotype-guided therapy. First-year (P1) through fourth-year (P4) pharmacy students, pharmacy residents, and pharmacy fellows participated in a newly implemented warfarin pharmacogenetics service in a hospital setting. Students, residents, and fellows provided genotype-guided dosing recommendations as part of clinical care, or analyzed samples and data collected from patients on the service for research purposes. Students', residents', and fellows' achievement of learning objectives was assessed using a checklist based on established core competencies in pharmacogenetics. The mean competency score of the students, residents, and fellows who completed a clinical and/or research experience with the service was 97% ±3%. A comprehensive warfarin pharmacogenetics service provided unique experiential and research opportunities for pharmacy students, residents, and fellows and sufficiently addressed a number of core competencies in pharmacogenetics.

  9. Clinical application of pharmacogenetics: focusing on practical issues.

    Science.gov (United States)

    Chang, Matthew T; McCarthy, Jeanette J; Shin, Jaekyu

    2015-01-01

    Recent large-scale genetic-based studies have transformed the field of pharmacogenetics to identify, characterize and leverage genetic information to inform patient care. Genetic testing can be used to alter drug selection, optimize drug dosing and prevent unnecessary adverse events. As precision medicine becomes the mainstay in the clinic, it becomes critical for clinicians to utilize pharmacogenetics to guide patient care. One primary challenge is identifying patients where genetic tests that can potentially impact patient care. To address this challenge, our review highlights many practical issues clinicians may encounter: identifying candidate patients and clinical laboratories for pharmacogenetic testing, selecting highly curated resources to help asses test validity, reimbursing costs of pharmacogenetic tests, and interpreting of pharmacogenetic test results.

  10. Pharmacogenetics and personalised medicine: maintain a critical approach.

    Science.gov (United States)

    2013-06-01

    The purpose of pharmacogenetics is to offer"personalised" treatment, in which a drug is only prescribed to patients in whom it is very likely to be effective, or to withhold a drug from patients at increased risk of adverse effects. Pharmacogenetics requires the use of genetic tests which, as with any other diagnostic test, must be evaluated for their discriminatory power (sensitivity, specificity, etc.). These evaluations are sometimes biased. Pharmacogenetics has been heralded as a means of tailoring cancer therapy. However large clinical trials with demanding clinical endpoints are often disappointing, despite initially encouraging results. Pharmacogenetic information is included in many summaries of product characteristics for non-cancer drugs, mainly in order to reduce the frequency of certain serious adverse effects. In summary, pharmacogenetics theoretically represents a step forward but must be evaluated in rigorous clinical trials, as is the case with all other "therapeutic tools".

  11. The population genomics of archaeological transition in west Iberia: Investigation of ancient substructure using imputation and haplotype-based methods.

    Directory of Open Access Journals (Sweden)

    Rui Martiniano

    2017-07-01

    Full Text Available We analyse new genomic data (0.05-2.95x from 14 ancient individuals from Portugal distributed from the Middle Neolithic (4200-3500 BC to the Middle Bronze Age (1740-1430 BC and impute genomewide diploid genotypes in these together with published ancient Eurasians. While discontinuity is evident in the transition to agriculture across the region, sensitive haplotype-based analyses suggest a significant degree of local hunter-gatherer contribution to later Iberian Neolithic populations. A more subtle genetic influx is also apparent in the Bronze Age, detectable from analyses including haplotype sharing with both ancient and modern genomes, D-statistics and Y-chromosome lineages. However, the limited nature of this introgression contrasts with the major Steppe migration turnovers within third Millennium northern Europe and echoes the survival of non-Indo-European language in Iberia. Changes in genomic estimates of individual height across Europe are also associated with these major cultural transitions, and ancestral components continue to correlate with modern differences in stature.

  12. Shrinkage Estimators for Robust and Efficient Inference in Haplotype-Based Case-Control Studies

    KAUST Repository

    Chen, Yi-Hau

    2009-03-01

    Case-control association studies often aim to investigate the role of genes and gene-environment interactions in terms of the underlying haplotypes (i.e., the combinations of alleles at multiple genetic loci along chromosomal regions). The goal of this article is to develop robust but efficient approaches to the estimation of disease odds-ratio parameters associated with haplotypes and haplotype-environment interactions. We consider "shrinkage" estimation techniques that can adaptively relax the model assumptions of Hardy-Weinberg-Equilibrium and gene-environment independence required by recently proposed efficient "retrospective" methods. Our proposal involves first development of a novel retrospective approach to the analysis of case-control data, one that is robust to the nature of the gene-environment distribution in the underlying population. Next, it involves shrinkage of the robust retrospective estimator toward a more precise, but model-dependent, retrospective estimator using novel empirical Bayes and penalized regression techniques. Methods for variance estimation are proposed based on asymptotic theories. Simulations and two data examples illustrate both the robustness and efficiency of the proposed methods.

  13. Shrinkage Estimators for Robust and Efficient Inference in Haplotype-Based Case-Control Studies

    KAUST Repository

    Chen, Yi-Hau; Chatterjee, Nilanjan; Carroll, Raymond J.

    2009-01-01

    Case-control association studies often aim to investigate the role of genes and gene-environment interactions in terms of the underlying haplotypes (i.e., the combinations of alleles at multiple genetic loci along chromosomal regions). The goal of this article is to develop robust but efficient approaches to the estimation of disease odds-ratio parameters associated with haplotypes and haplotype-environment interactions. We consider "shrinkage" estimation techniques that can adaptively relax the model assumptions of Hardy-Weinberg-Equilibrium and gene-environment independence required by recently proposed efficient "retrospective" methods. Our proposal involves first development of a novel retrospective approach to the analysis of case-control data, one that is robust to the nature of the gene-environment distribution in the underlying population. Next, it involves shrinkage of the robust retrospective estimator toward a more precise, but model-dependent, retrospective estimator using novel empirical Bayes and penalized regression techniques. Methods for variance estimation are proposed based on asymptotic theories. Simulations and two data examples illustrate both the robustness and efficiency of the proposed methods.

  14. Implementation of pharmacogenetics: the University of Maryland Personalized Anti-platelet Pharmacogenetics Program.

    Science.gov (United States)

    Shuldiner, Alan R; Palmer, Kathleen; Pakyz, Ruth E; Alestock, Tameka D; Maloney, Kristin A; O'Neill, Courtney; Bhatty, Shaun; Schub, Jamie; Overby, Casey Lynnette; Horenstein, Richard B; Pollin, Toni I; Kelemen, Mark D; Beitelshees, Amber L; Robinson, Shawn W; Blitzer, Miriam G; McArdle, Patrick F; Brown, Lawrence; Jeng, Linda Jo Bone; Zhao, Richard Y; Ambulos, Nicholas; Vesely, Mark R

    2014-03-01

    Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine. © 2014 Wiley Periodicals, Inc.

  15. Pharmacogenetic testing, informed consent and the problem of secondary information.

    Science.gov (United States)

    Netzer, Christian; Biller-Andorno, Nikola

    2004-08-01

    Numerous benefits for patients have been predicted if prescribing decisions were routinely accompanied by pharmacogenetic testing. So far, little attention has been paid to the possibility that the routine application of this new technology could result in considerable harm to patients. This article emphasises that pharmacogenetic testing shares both the opportunities and the pitfalls with 'conventional' disease-genetic testing. It demonstrates that performing pharmacogenetic tests as well as interpreting the results are extraordinarily complex issues requiring a high level of expertise. It further argues that pharmacogenetic testing can have a huge impact on clinical decisions and may influence the therapeutic strategy as well as the clinical monitoring of a patient. This view challenges the predominant paradigm that pharmacogenetic testing will predict patients' responses to medicines, but that it will not provide any other significant disease-specific predictive information about the patient or family members. The article also questions published proposals to reduce the consent procedure for pharmacogenetic testing to a simple statement that the physician wishes to test a sample of the patient's DNA to see if a drug will be safe or whether it will work, and presents an alternative model that is better suited to protect patient's interests and to obtain meaningful informed consent. The paper concludes by outlining conditions for the application of pharmacogenetic testing in clinical practice in a way that can make full use of its potential benefits while minimising possible harm to patients and their families.

  16. Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine.

    Science.gov (United States)

    Simeon, Vittorio; Todoerti, Katia; La Rocca, Francesco; Caivano, Antonella; Trino, Stefania; Lionetti, Marta; Agnelli, Luca; De Luca, Luciana; Laurenzana, Ilaria; Neri, Antonino; Musto, Pellegrino

    2015-07-30

    Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL).

  17. [Pharmacogenetics II. Research molecular methods, bioinformatics and ethical concerns].

    Science.gov (United States)

    Daudén, E

    2007-01-01

    Pharmacogenetics refers to the study of the individual pharmacological response based on the genotype. Its objective is to optimize treatment in an individual basis, thereby creating a more efficient and safe personalized therapy. In the second part of this review, the molecular methods of study in pharmacogenetics, including microarray technology or DNA chips, are discussed. Among them we highlight the microarrays used to determine the gene expression that detect specific RNA sequences, and the microarrays employed to determine the genotype that detect specific DNA sequences, including polymorphisms, particularly single nucleotide polymorphisms (SNPs). The relationship between pharmacogenetics, bioinformatics and ethical concerns is reviewed.

  18. Economic evaluations of pharmacogenetic approaches in infectious diseases: a review of current approaches and evaluation of critical aspects affecting their quality

    Directory of Open Access Journals (Sweden)

    Paolo Meoni

    2013-11-01

    Full Text Available Pharmacogenetics holds great potential for improving the effectiveness of treatment modalities in infectious diseases by taking into account the genetic determinants of both the host and infectious agents’ individuality. Better utilization of resources and improved therapeutic efficiency are the expected outcomes of personalized medicine using pharmacogenetic and pharmacogenomics information made available by technological advances. However, there has been growing concern in the clinical community regarding the evaluation of the true benefits of these approaches. This perception is partly due to the limited number and perceived poor quality of economic evaluations in this field, and initiatives aimed at harmonizing and communicating strategies improving the quality of these studies and their acceptance by the clinical community are greatly needed. This paper reviews current literature of economic evaluations of pharmacogenetics interventions guiding pharmacotherapy in infectious diseases. PubMed and the NHS Centre for Reviews and Dissemination databases were searched using a combination of five broad research terms related to pharmacogenetic approaches, and papers relative to economic evaluations of pharmacogenetic interventions in infectious diseases retained for further analysis. Using these criteria, a total of 14 papers were included in this review. The area of economic evaluation of pharmacogenetic interventions in infectious diseases remains understudied and would benefit from greater harmonization. The main weaknesses of evaluations reviewed in this paper seem to be represented by poor evidence of pharmacogenetic marker validation, inconsistencies in the selection of costs and utility included in the economic models and the choice of sensitivity analysis. All these factors limit the overall transparency of the studies, greater acceptance of their results and applicability to diverse and possibly resourcelimited environments where these

  19. Trick or treat: The effect of placebo on the power of pharmacogenetic association studies

    Directory of Open Access Journals (Sweden)

    Singer Clara

    2005-03-01

    Full Text Available Abstract The genetic mapping of drug-response traits is often characterised by a poor signal-to-noise ratio that is placebo related and which distinguishes pharmacogenetic association studies from classical case-control studies for disease susceptibility. The goal of this study was to evaluate the statistical power of candidate gene association studies under different pharmacogenetic scenarios, with special emphasis on the placebo effect. Genotype/phenotype data were simulated, mimicking samples from clinical trials, and response to the drug was modelled as a binary trait. Association was evaluated by a logistic regression model. Statistical power was estimated as a function of the number of single nucleotide polymorphisms (SNPs genotyped, the frequency of the placebo 'response', the genotype relative risk (GRR of the response polymorphism, the strategy for selecting SNPs for genotyping, the number of individuals in the trial and the ratio of placebo-treated to drugtreated patients. We show that: (i the placebo 'response' strongly affects the statistical power of association studies -- even a highly penetrant drug-response allele requires at least a 500-patient trial in order to reach 80 per cent power, several-fold more than the value estimated by standard tools that are not calibrated to pharmacogenetics; (ii the power of a pharmacogenetic association study depends primarily on the penetrance of the response genotype and, when this penetrance is fixed, power decreases for larger placebo effects; (iii power is dramatically increased when adding markers; (iv an optimal study design includes a similar number of placebo- and drugtreated patients; and (v in this setting, straightforward haplotype analysis does not seem to have an advantage over single marker analysis.

  20. Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation.

    Science.gov (United States)

    Pink, J; Pirmohamed, M; Lane, S; Hughes, D A

    2014-02-01

    Pharmacogenetics-guided warfarin dosing is an alternative to standard clinical algorithms and new oral anticoagulants for patients with nonvalvular atrial fibrillation. However, clinical evidence for pharmacogenetics-guided warfarin dosing is limited to intermediary outcomes, and consequently, there is a lack of information on the cost-effectiveness of anticoagulation treatment options. A clinical trial simulation of S-warfarin was used to predict times within therapeutic range for different dosing algorithms. Relative risks of clinical events, obtained from a meta-analysis of trials linking times within therapeutic range with outcomes, served as inputs to an economic analysis. Neither dabigatran nor rivaroxaban were cost-effective options. Along the cost-effectiveness frontier, in relation to clinically dosed warfarin, pharmacogenetics-guided warfarin and apixaban had incremental cost-effectiveness ratios of £13,226 and £20,671 per quality-adjusted life year gained, respectively. On the basis of our simulations, apixaban appears to be the most cost-effective treatment.

  1. Haplotype-based case-control study between human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 gene and cerebral infarction.

    Science.gov (United States)

    Naganuma, Takahiro; Nakayama, Tomohiro; Sato, Naoyuki; Fu, Zhenyan; Yamaguchi, Mai; Soma, Masayoshi; Aoi, Noriko; Usami, Ron; Doba, Nobutaka; Hinohara, Shigeaki

    2009-10-01

    The aim of this study was to investigate the relationship between cerebral infarction (CI) and the human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) gene using single-nucleotide polymorphisms (SNPs) and a haplotype-based case-control study. We selected 5 SNPs in the human APE1/REF1 gene (rs1760944, rs3136814, rs17111967, rs3136817 and rs1130409), and performed case-control studies in 177 CI patients and 309 control subjects. rs17111967 was found to have no heterogeneity in Japanese. The overall distribution of the haplotype-based case-control study constructed by rs1760944, rs3136814 and rs1130409 showed a significant difference. The frequency of the G-C-T haplotype was significantly higher in the CI group than in the control group (2.5% vs. 0.0%, p>0.001). Based on the results of the haplotype-based case-control-study, the G-C-T haplotype may be a genetic marker of CI, and the APE1/REF-1 gene may be a CI susceptibility gene.

  2. Measuring pharmacogenetics in special groups: geriatrics.

    Science.gov (United States)

    Seripa, Davide; Panza, Francesco; Daragjati, Julia; Paroni, Giulia; Pilotto, Alberto

    2015-07-01

    The cytochrome P450 (CYP) enzymes oxidize about 80% of the most commonly used drugs. Older patients form a very interesting clinical group in which an increased prevalence of adverse drug reactions (ADRs) and therapeutic failures (TFs) is observed. Might CYP drug metabolism change with age, and justify the differences in drug response observed in a geriatric setting? A complete overview of the CYP pharmacogenetics with a focus on the epigenetic CYP gene regulation by DNA methylation in the context of advancing age, in which DNA methylation might change. Responder phenotypes consist of a continuum spanning from ADRs to TFs, with the best responders at the midpoint. CYP genetics is the basis of this continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice. Physiological age-related changes in DNA methylation, the main epigenetic mechanisms regulating gene expression in humans, results in a physiological decrease in CYP gene expression with advancing age. This may be one of the physiological changes that, together with increased drug use, contributed to the higher prevalence of ADRs and TFs observed in the geriatric setting, thus, making geriatrics a special group for pharmacogenetics.

  3. Clinical pharmacogenetics implementation: approaches, successes, and challenges.

    Science.gov (United States)

    Weitzel, Kristin W; Elsey, Amanda R; Langaee, Taimour Y; Burkley, Benjamin; Nessl, David R; Obeng, Aniwaa Owusu; Staley, Benjamin J; Dong, Hui-Jia; Allan, Robert W; Liu, J Felix; Cooper-Dehoff, Rhonda M; Anderson, R David; Conlon, Michael; Clare-Salzler, Michael J; Nelson, David R; Johnson, Julie A

    2014-03-01

    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. Herein we describe the processes for development of the program, the challenges that were encountered and the clinical acceptance by clinicians of the genomic medicine implementation. The initial clinical implementation of the UF PMP began in June 2012 and targeted clopidogrel use and the CYP2C19 genotype in patients undergoing left heart catheterization and percutaneous-coronary intervention (PCI). After 1 year, 1,097 patients undergoing left heart catheterization were genotyped preemptively, and 291 of those underwent subsequent PCI. Genotype results were reported to the medical record for 100% of genotyped patients. Eighty patients who underwent PCI had an actionable genotype, with drug therapy changes implemented in 56 individuals. Average turnaround time from blood draw to genotype result entry in the medical record was 3.5 business days. Seven different third party payors, including Medicare, reimbursed for the test during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month. These data highlight multiple levels of success in clinical implementation of genomic medicine. © 2014 Wiley Periodicals, Inc.

  4. Advances and challenges in hereditary cancer pharmacogenetics.

    Science.gov (United States)

    Cascorbi, Ingolf; Werk, Anneke Nina

    2017-01-01

    Cancer pharmacogenetics usually considers tumor-specific targets. However, hereditary genetic variants may interfere with the pharmacokinetics of antimetabolites and other anti-cancer drugs, which may lead to severe adverse events. Areas covered: Here, the impact of hereditary genes considered in drug labels such as thiopurine S-methyltransferase (TPMT), UDP-glucuronosyltransferase 1A1 (UTG1A1) and dihydropyrimidine dehydrogenase (DPYD) are discussed with respect to guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Moreover, the association between genetic variants of drug transporters with the clinical outcome is comprehensively discussed. Expert opinion: Precision therapy in the field of oncology is developing tremendously. There are a number of somatic tumor genetic markers that are indicative for treatment with anti-cancer drugs. By contrast, for some hereditary variants, recommendations have been developed. Although we have vast knowledge on the association between drug transporter variants and clinical outcome, the overall data is inconsistent and the predictability of the related phenotype is low. Further developments in research may lead to the discovery of rare, but functionally relevant single nucleotide polymorphisms and a better understanding of multiple genomic, epigenomic as well as phenotypic factors, contributing to drug response in malignancies.

  5. Progress in pharmacogenetics: consortiums and new strategies.

    Science.gov (United States)

    Maroñas, Olalla; Latorre, Ana; Dopazo, Joaquín; Pirmohamed, Munir; Rodríguez-Antona, Cristina; Siest, Gérard; Carracedo, Ángel; LLerena, Adrián

    2016-03-01

    Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach.

  6. Automating data acquisition into ontologies from pharmacogenetics relational data sources using declarative object definitions and XML.

    Science.gov (United States)

    Rubin, Daniel L; Hewett, Micheal; Oliver, Diane E; Klein, Teri E; Altman, Russ B

    2002-01-01

    Ontologies are useful for organizing large numbers of concepts having complex relationships, such as the breadth of genetic and clinical knowledge in pharmacogenomics. But because ontologies change and knowledge evolves, it is time consuming to maintain stable mappings to external data sources that are in relational format. We propose a method for interfacing ontology models with data acquisition from external relational data sources. This method uses a declarative interface between the ontology and the data source, and this interface is modeled in the ontology and implemented using XML schema. Data is imported from the relational source into the ontology using XML, and data integrity is checked by validating the XML submission with an XML schema. We have implemented this approach in PharmGKB (http://www.pharmgkb.org/), a pharmacogenetics knowledge base. Our goals were to (1) import genetic sequence data, collected in relational format, into the pharmacogenetics ontology, and (2) automate the process of updating the links between the ontology and data acquisition when the ontology changes. We tested our approach by linking PharmGKB with data acquisition from a relational model of genetic sequence information. The ontology subsequently evolved, and we were able to rapidly update our interface with the external data and continue acquiring the data. Similar approaches may be helpful for integrating other heterogeneous information sources in order make the diversity of pharmacogenetics data amenable to computational analysis.

  7. A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics

    Science.gov (United States)

    Claudio-Campos, Karla; Rivera-Miranda, Giselle; Bermúdez-Bosch, Luis; Renta, Jessicca Y.; Cadilla, Carmen L.; Cruz, Iadelisse; Feliu, Juan F.; Vergara, Cunegundo; Ruaño, Gualberto

    2016-01-01

    Aim This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. Patients & Methods A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. Results The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (pwarfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias). Conclusions Results supported our rationale to incorporate individual’s genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. Trial Registration ClinicalTrials.gov NCT01318057 PMID:26745506

  8. The diffusion of innovation: factors influencing the uptake of pharmacogenetics

    DEFF Research Database (Denmark)

    Nielsen, Louise Fuks; Møldrup, Claus

    2007-01-01

    BACKGROUND: Inspired by diffusion research, this paper examines how perceived need, health status, experiences with medicine and testing, consumption of mass media and sociodemography influence the public's familiarity, knowledge, attitudes and intentions regarding pharmacogenetics. The objective...

  9. [Pharmacogenetics in primary health care: implementation and future expectations].

    Science.gov (United States)

    Houwink, Elisa J F; Rigter, Tessel; Swen, Jesse J; Cornel, Martina C; Kienhuis, Anne; Rodenburg, Wendy; Weda, Marjolein

    2015-01-01

    Personalised medicine is a targeted approach to the prevention, diagnosis and treatment of disorders on the basis of the specific genetic profile of the patient. Pharmacogenetics research shows that differences in the genetic profile of patients explain the interindividual differences in efficacy and side effects of medicines. Although there are high expectations of personalised medicine and pharmacogenetics in healthcare, both are only used to a limited extent to date. Pharmacogenetics seems particularly important in diseases with a poor prognosis and treatments with potentially serious side effects. Pharmacogenetics testing is reimbursed in the case of serious side effects or unexpected ineffectiveness. 95% of patients in the Netherlands have at least one abnormality in the panel of genes for which guidance is available. The KNMP (Royal Dutch Pharmacists' Association) provides dosing advice based on genotype for 80 medicines, 27 of which are regularly prescribed in primary health care.

  10. Pharmacogenetics of antidepressant drugs: State of the art and clinical implementation - recommendations from the French National Network of Pharmacogenetics.

    Science.gov (United States)

    Quaranta, Sylvie; Dupouey, Julien; Colle, Romain; Verstuyft, Céline

    2017-04-01

    Tailoring antidepressant drug therapy to each individual patient is a complex process because these drugs have adverse effects leading to discontinuation. Pharmacogenetics may provide useful information in routine practice for optimizing antidepressant treatment by helping limit toxic effects while maintaining efficacy. This review presents the usefulness of pharmacogenetic tests for P450 cytochromes CYP2C19 and CYP2D6 in psychiatric patients taking antidepressants. Depending on the level of evidence, the French National Network of Pharmacogenetics (RNPGx) has issued recommendations stating that pharmacogenetic tests for CYP2D6 and CYP2C19 genes are potentially useful in psychiatric patients treated with antidepressant drugs. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  11. [Epilepsy pharmacogenetics : science or fiction?].

    Science.gov (United States)

    Depondt, Chantal

    2013-02-01

    Pharmacogenetics (PGX) is the study of how genetic variants influence individual responses to drugs. Although numerous candidate gene studies in epilepsy PGX have been published, to date only two validated associations exist: the association of the *2 and *3 alleles of CYP2C9 with phenytoin metabolism and the association of HLA-B*1502 with serious hypersensitivity reactions to carbamazepine. The advent of novel technologies such as genomewide association studies and next generation sequencing will likely lead to the identification of additional genetic biomarkers. The potential benefits of epilepsy PGX are multiple: epilepsy treatment in individual patients would become more rationalized, clinical trials could be stratified according to patients' genetic profiles and novel therapeutic pathways may be uncovered. Ultimately, it is hoped that PGX will improve the quality of life for people suffering from epilepsy worldwide. © 2013 médecine/sciences – Inserm / SRMS.

  12. [MODERN VIEWS ON THE PHARMACOGENETICS OF PAIN.

    Science.gov (United States)

    Makharin, O A; Zhenilo, V M; Patyuchenko, O Yu

    2017-09-01

    Quality anesthesia during surgery and in the postoperative period remains a topical problem of modern anesthesiology. The study of genetic characteristics of a patient is a goal that may be allow us to develop a personalized approach to solve this problem. The purpose of the review is a synthesis of literature data about the influence of genetic factors on pain perception and its treatment. The review included information obtained from SCOPUS, MedLine, EMBASE. The search keywords were: pain, pharmacogenetics, polymorphism, analgesics.Describe the effect ofgene polymorphisms of OPRM, 5HTRIA, 5HTR2A, COMT GCHI, SCN9A, KCNSI, CACNA2D3, CACNG2, PTGSI, PTGS2, MDRJ/ABCB] on the perception of pain, and CYP2D6, CYP2C9, CYP3A4 on the pharmacokinetics and pharmacodynamics of medi- cations used in the treatment of pain.

  13. Databases in the Area of Pharmacogenetics

    Science.gov (United States)

    Sim, Sarah C.; Altman, Russ B.; Ingelman-Sundberg, Magnus

    2012-01-01

    In the area of pharmacogenetics and personalized health care it is obvious that databases, providing important information of the occurrence and consequences of variant genes encoding drug metabolizing enzymes, drug transporters, drug targets, and other proteins of importance for drug response or toxicity, are of critical value for scientists, physicians, and industry. The primary outcome of the pharmacogenomic field is the identification of biomarkers that can predict drug toxicity and drug response, thereby individualizing and improving drug treatment of patients. The drug in question and the polymorphic gene exerting the impact are the main issues to be searched for in the databases. Here, we review the databases that provide useful information in this respect, of benefit for the development of the pharmacogenomic field. PMID:21309040

  14. Pharmacogenetics in drug regulation: promise, potential and pitfalls

    Science.gov (United States)

    Shah, Rashmi R

    2005-01-01

    Pharmacogenetic factors operate at pharmacokinetic as well as pharmacodynamic levels—the two components of the dose–response curve of a drug. Polymorphisms in drug metabolizing enzymes, transporters and/or pharmacological targets of drugs may profoundly influence the dose–response relationship between individuals. For some drugs, although retrospective data from case studies suggests that these polymorphisms are frequently associated with adverse drug reactions or failure of efficacy, the clinical utility of such data remains unproven. There is, therefore, an urgent need for prospective data to determine whether pre-treatment genotyping can improve therapy. Various regulatory guidelines already recommend exploration of the role of genetic factors when investigating a drug for its pharmacokinetics, pharmacodynamics, dose–response relationship and drug interaction potential. Arising from the global heterogeneity in the frequency of variant alleles, regulatory guidelines also require the sponsors to provide additional information, usually pharmacogenetic bridging data, to determine whether data from one ethnic population can be extrapolated to another. At present, sponsors explore pharmacogenetic influences in early clinical pharmacokinetic studies but rarely do they carry the findings forward when designing dose–response studies or pivotal studies. When appropriate, regulatory authorities include genotype-specific recommendations in the prescribing information. Sometimes, this may include the need to adjust a dose in some genotypes under specific circumstances. Detailed references to pharmacogenetics in prescribing information and pharmacogenetically based prescribing in routine therapeutics will require robust prospective data from well-designed studies. With greater integration of pharmacogenetics in drug development, regulatory authorities expect to receive more detailed genetic data. This is likely to complicate the drug evaluation process as well as

  15. Pharmacogenetics of healthy volunteers in Puerto Rico.

    Science.gov (United States)

    Claudio-Campos, Karla; Orengo-Mercado, Carmelo; Renta, Jessicca Y; Peguero, Muriel; García, Ricardo; Hernández, Gabriel; Corey, Susan; Cadilla, Carmen L; Duconge, Jorge

    2015-12-01

    Puerto Ricans are a unique Hispanic population with European, Native American (Taino), and higher West African ancestral contributions than other non-Caribbean Hispanics. In admixed populations, such as Puerto Ricans, genetic variants can be found at different frequencies when compared to parental populations and uniquely combined and distributed. Therefore, in this review, we aimed to collect data from studies conducted in healthy Puerto Ricans and to report the frequencies of genetic polymorphisms with major relevance in drug response. Filtering for healthy volunteers or individuals, we performed a search of pharmacogenetic studies in academic literature databases without limiting the period of the results. The search was limited to Puerto Ricans living in the island, excluding those studies performed in mainland (United States). We found that the genetic markers impacting pharmacological therapy in the areas of cardiovascular, oncology, and neurology are the most frequently investigated. Coincidently, the top causes of mortality in the island are cardiovascular diseases, cancer, diabetes, Alzheimer's disease, and stroke. In addition, polymorphisms in genes that encode for members of the CYP450 family (CYP2C9, CYP2C19, and CYP2D6) are also available due to their relevance in the metabolism of drugs. The complex genetic background of Puerto Ricans is responsible for the divergence in the reported allele frequencies when compared to parental populations (Africans, East Asians, and Europeans). The importance of reporting the findings of pharmacogenetic studies conducted in Puerto Ricans is to identify genetic variants with potential utility among this genetically complex population and eventually move forward the adoption of personalized medicine in the island.

  16. Pharmacogenetics of healthy volunteers in Puerto Rico

    Science.gov (United States)

    Claudio-Campos, Karla; Orengo-Mercado, Carmelo; Renta, Jessicca Y.; Peguero, Muriel; García, Ricardo; Hernández, Gabriel; Corey, Susan; Cadilla, Carmen L.; Duconge, Jorge

    2016-01-01

    Puerto Ricans are a unique Hispanic population with European, Native American (Taino), and higher West African ancestral contributions than other non-Caribbean Hispanics. In admixed populations, such as Puerto Ricans, genetic variants can be found at different frequencies when compared to parental populations and uniquely combined and distributed. Therefore, in this review, we aimed to collect data from studies conducted in healthy Puerto Ricans and to report the frequencies of genetic polymorphisms with major relevance in drug response. Filtering for healthy volunteers or individuals, we performed a search of pharmacogenetic studies in academic literature databases without limiting the period of the results. The search was limited to Puerto Ricans living in the island, excluding those studies performed in mainland (United States). We found that the genetic markers impacting pharmacological therapy in the areas of cardiovascular, oncology, and neurology are the most frequently investigated. Coincidently, the top causes of mortality in the island are cardiovascular diseases, cancer, diabetes, Alzheimer’s disease, and stroke. In addition, polymorphisms in genes that encode for members of the CYP450 family (CYP2C9, CYP2C19, and CYP2D6) are also available due to their relevance in the metabolism of drugs. The complex genetic background of Puerto Ricans is responsible for the divergence in the reported allele frequencies when compared to parental populations (Africans, East Asians, and Europeans). The importance of reporting the findings of pharmacogenetic studies conducted in Puerto Ricans is to identify genetic variants with potential utility among this genetically complex population and eventually move forward the adoption of personalized medicine in the island. PMID:26501165

  17. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update.

    Science.gov (United States)

    Johnson, J A; Caudle, K E; Gong, L; Whirl-Carrillo, M; Stein, C M; Scott, S A; Lee, M T; Gage, B F; Kimmel, S E; Perera, M A; Anderson, J L; Pirmohamed, M; Klein, T E; Limdi, N A; Cavallari, L H; Wadelius, M

    2017-09-01

    This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  18. Pharmacogenetics in dermatology: a patient-centered update.

    Science.gov (United States)

    Comfere, Nneka I; Ikediobi, Ogechi N; Peters, Margot S; el-Azhary, Rokea A; Gibson, Lawrence E

    2013-08-01

    The term pharmacogenetics is used to describe an evolving field that aims to understand the relationship between individual variations in genetic sequence and differences in the therapeutic and toxic response to medications. The promise of pharmacogenetics is empowerment of clinicians with information that will enable them to personalize drug therapy - to prescribe the right medication at the right dose for each patient, while minimizing adverse effects. Despite dramatic advances, wide application of pharmacogenetics to clinical practice has been slow for a number of reasons, including lack of evidence-based therapeutic guidelines as well as ethical concerns and cost. To illustrate applications to dermatology practice, we present three clinical scenarios that serve as a springboard for discussion of the principles of pharmacogenetics and how they can be used to guide treatment with azathioprine, 5-fluorouracil, and trastuzumab. The therapeutic and toxic effects of a given medication ultimately depend on its combined pharmacokinetic, pharmacodynamic, and pharmacogenetic properties in a given individual. Pharmacodynamic properties of individual medications must be correlated with single nucleotide polymorphisms. Test recommendations and standardization of therapy for specific disorders can then be established. © 2013 The International Society of Dermatology.

  19. Pharmacogenetics and pharmacogenomics as tools in cancer therapy.

    Science.gov (United States)

    Rodríguez-Vicente, Ana E; Lumbreras, Eva; Hernández, Jesus M; Martín, Miguel; Calles, Antonio; Otín, Carlos López; Algarra, Salvador Martín; Páez, David; Taron, Miquel

    2016-03-01

    Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments. Specifically, we present recent progress in breast cancer molecular classifiers, cell-free circulating DNA as a prognostic and predictive biomarker in cancer, patient-derived tumor xenograft models, chronic lymphocytic leukemia genomic landscape, and current pharmacogenetic advances in colorectal cancer. This review is based on the lectures presented by the speakers of the symposium "Pharmacogenetics and Pharmacogenomics as Tools in Cancer Therapy" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF), held in Madrid (Spain) on April 21, 2015.

  20. The Potential Utility of Pharmacogenetic Testing in Psychiatry

    Directory of Open Access Journals (Sweden)

    Kathryn R. Gardner

    2014-01-01

    Full Text Available Over the last decade, pharmacogenetics has become increasingly significant to clinical practice. Psychiatric patients, in particular, may benefit from pharmacogenetic testing as many of the psychotropic medications prescribed in practice lead to varied response rates and a wide range of side effects. The use of pharmacogenetic testing can help tailor psychotropic treatment and inform personalized treatment plans with the highest likelihood of success. Recently, many studies have been published demonstrating improved patient outcomes and decreased healthcare costs for psychiatric patients who utilize genetic testing. This review will describe evidence supporting the clinical utility of genetic testing in psychiatry, present several case studies to demonstrate use in everyday practice, and explore current patient and clinician opinions of genetic testing.

  1. Optogenetics and pharmacogenetics: principles and applications.

    Science.gov (United States)

    Jiang, Jingwei; Cui, Huxing; Rahmouni, Kamal

    2017-12-01

    Remote and selective spatiotemporal control of the activity of neurons to regulate behavior and physiological functions has been a long-sought goal in system neuroscience. Identification and subsequent bioengineering of light-sensitive ion channels (e.g., channelrhodopsins, halorhodopsin, and archaerhodopsins) from the bacteria have made it possible to use light to artificially modulate neuronal activity, namely optogenetics. Recent advance in genetics has also allowed development of novel pharmacological tools to selectively and remotely control neuronal activity using engineered G protein-coupled receptors, which can be activated by otherwise inert drug-like small molecules such as the designer receptors exclusively activated by designer drug, a form of chemogenetics. The cutting-edge optogenetics and pharmacogenetics are powerful tools in neuroscience that allow selective and bidirectional modulation of the activity of defined populations of neurons with unprecedented specificity. These novel toolboxes are enabling significant advances in deciphering how the nervous system works and its influence on various physiological processes in health and disease. Here, we discuss the fundamental elements of optogenetics and chemogenetics approaches and some of the applications that yielded significant advances in various areas of neuroscience and beyond. Copyright © 2017 the American Physiological Society.

  2. Pharmacogenetics of warfarin: challenges and opportunities

    Science.gov (United States)

    Ta Michael Lee, Ming; Klein, Teri E

    2014-01-01

    Since the introduction in the 1950s, warfarin has become the commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation or prosthetic heart valve replacement. Warfarin is highly efficacious; however, achieving the desired anticoagulation is difficult because of its narrow therapeutic window and highly variable dose response among individuals. Bleeding is often associated with overdose of warfarin. There is overwhelming evidence that an individual's warfarin maintenance is associated with clinical factors and genetic variations, most notably polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase subunit 1. Numerous dose-prediction algorithms incorporating both genetic and clinical factors have been developed and tested clinically. However, results from major clinical trials are not available yet. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges for the clinical implementation of warfarin pharmacogenetics. PMID:23657428

  3. Pharmacogenetics-based personalized therapy: Levels of evidence and recommendations from the French Network of Pharmacogenetics (RNPGx).

    Science.gov (United States)

    Picard, Nicolas; Boyer, Jean-Christophe; Etienne-Grimaldi, Marie-Christine; Barin-Le Guellec, Chantal; Thomas, Fabienne; Loriot, Marie-Anne

    2017-04-01

    More than 50 laboratories offer pharmacogenetic testing in France. These tests are restricted to a limited number of indications: prevention of serious adverse drug reactions; choice of most appropriate therapeutic option; dose adjustment for a specific drug. A very small proportion of these tests are mentioned in drug information labeling and the data provided (if any) are generally insufficient to ascertain whether a test is required and if it is useful. This article discusses the rationale for evaluating the performance and clinical usefulness of pharmacogenetics and provides, on behalf of the French national network of pharmacogenetics (RNPGx), three levels of recommendation for testing: essential, advisable, and possibly helpful. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  4. Lithium Pharmacogenetics: Where Do We Stand?

    Science.gov (United States)

    Pisanu, Claudia; Melis, Carla; Squassina, Alessio

    2016-11-01

    Preclinical Research Bipolar disorder (BPD) is a chronic and disabling psychiatric disorder with a prevalence of 0.8-1.2% in the general population. Although lithium is considered the first-line treatment, a large percentage of patients do not respond sufficiently. Moreover, lithium can induce severe side effects and has poor tolerance and a narrow therapeutic index. The genetics of lithium response has been largely investigated, but findings have so far failed to identify reliable biomarkers to predict clinical response. This has been largely determined by the highly complex phenotipic and genetic architecture of lithium response. To this regard, collaborative initiatives hold the promise to provide robust and standardized methods to disantenagle this complexity, as well as the capacity to collect large samples of patietnts, a crucial requirement to study the genetics of complex phenotypes. The International Consortium on Lithium Genetics (ConLiGen) has recently published the largest study so far on lithium response reporting significant associations for two long noncoding RNAs (lncRNAs). This result provides relevant insights into the pharmacogenetics of lithium supporting the involvement of the noncoding portion of the genome in modulating clinical response. Although a vast body of research is engaged in dissecting the genetic bases of response to lithium, the several drawbacks of lithium therapy have also stimulated multiple efforts to identify new safer treatments. A drug repurposing approach identified ebselen as a potential lithium mimetic, as it shares with lithium the ability to inhibit inositol monophosphatase. Ebselen, an antioxidant glutathione peroxidase mimetic, represents a valid and promising example of new potential therapeutic interventions for BD, but the paucity of data warrant further investigation to elucidate its potential efficacy and safety in the management of BPD. Nevertheless, findings provided by the growing field of pharmacogenomic

  5. Clinical Application of Pharmacogenetics: Where are We Now?

    Science.gov (United States)

    2014-01-01

    Pharmacogenetic (PGx) testing has the potential to improve drug therapy in an individual by informing appropriate drug dosing or drug selection in order to maximize efficacy and safety. Although multiple studies have illustrated the potential benefits of such testing when applied to specific drugs across a broad range of therapy areas, the uptake of PGx testing in routine clinical practice has been relatively limited. Implementation appears to be hampered by the absence of sufficiently strong evidence linking the results of testing with actionable benefits in terms of clinical outcomes. Meanwhile, there are now adequate data to allow dosing recommendations as have been developed by bodies including the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) in several settings, including TPMT/thiopurines, CYP2C19/clopidogrel, CYP2D6/codeine, VKORC1-CYP2C9/warfarin, HLA-B*5701/abacavir, SLCO1B1/simvastatin and HLAB*5801/allopurinol. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) have also recently initiated surveys in order to better understand the extent of, and the role played by, PGx testing in clinical practice. This should help identify where further training and education may be beneficial. To this end, in collaboration with ESPT, the IFCC Pharmacogenetic Laboratory Network has now been formed, with the aim of improving the uptake and quality of PGx testing. PMID:27683445

  6. Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?

    Science.gov (United States)

    Florez, Jose C

    2017-05-01

    In recent years, technological and analytical advances have led to an explosion in the discovery of genetic loci associated with type 2 diabetes. However, their ability to improve prediction of disease outcomes beyond standard clinical risk factors has been limited. On the other hand, genetic effects on drug response may be stronger than those commonly seen for disease incidence. Pharmacogenetic findings may aid in identifying new drug targets, elucidate pathophysiology, unravel disease heterogeneity, help prioritise specific genes in regions of genetic association, and contribute to personalised or precision treatment. In diabetes, precedent for the successful application of pharmacogenetic concepts exists in its monogenic subtypes, such as MODY or neonatal diabetes. Whether similar insights will emerge for the much more common entity of type 2 diabetes remains to be seen. As genetic approaches advance, the progressive deployment of candidate gene, large-scale genotyping and genome-wide association studies has begun to produce suggestive results that may transform clinical practice. However, many barriers to the translation of diabetes pharmacogenetic discoveries to the clinic still remain. This perspective offers a contemporary overview of the field with a focus on sulfonylureas and metformin, identifies the major uses of pharmacogenetics, and highlights potential limitations and future directions.

  7. Pharmacogenetics of the Neurodevelopmental Impact of Anticancer Chemotherapy

    Science.gov (United States)

    Robaey, Philippe; Krajinovic, Maja; Marcoux, Sophie; Moghrabi, Albert

    2008-01-01

    Pharmacogenetics holds the promise of minimizing adverse neurodevelopmental outcomes of cancer patients by identifying patients at risk, enabling the individualization of treatment and the planning of close follow-up and early remediation. This review focuses first on methotrexate, a drug often implicated in neurotoxicity, especially when used in…

  8. Progress and Promise of Attention-Deficit Hyperactivity Disorder Pharmacogenetics

    Science.gov (United States)

    Froehlich, Tanya E.; McGough, James J.; Stein, Mark A.

    2010-01-01

    One strategy for understanding variability in attention-deficit hyperactivity disorder (ADHD) medication response, and therefore redressing the current trial-and-error approach to ADHD medication management, is to identify genetic moderators of treatment. This article summarizes ADHD pharmacogenetic investigative efforts to date, which have primarily focused on short-term response to methylphenidate and largely been limited by modest sample sizes. The most well studied genes include the dopamine transporter and dopamine D4 receptor, with additional genes that have been significantly associated with stimulant medication response including the adrenergic α2A-receptor, catechol-O-methyltransferase, D5 receptor, noradrenaline (norepinephrine) transporter protein 1 and synaptosomal-associated protein 25 kDa. Unfortunately, results of current ADHD pharmacogenetic studies have not been entirely consistent, possibly due to differences in study design, medication dosing regimens and outcome measures. Future directions for ADHD pharmacogenetics investigations may include examination of drug-metabolizing enzymes and a wider range of stimulant and non-stimulant medications. In addition, researchers are increasingly interested in going beyond the individual candidate gene approach to investigate gene-gene interactions or pathways, effect modification by additional environmental exposures and whole genome approaches. Advancements in ADHD pharmacogenetics will be facilitated by multi-site collaborations to obtain larger sample sizes using standardized protocols. Although ADHD pharmacogenetic efforts are still in a relatively early stage, their potential clinical applications may include the development of treatment efficacy and adverse effect prediction algorithms that incorporate the interplay of genetic and environmental factors, as well as the development of novel ADHD treatments. PMID:20088618

  9. Feasibility of implementing a comprehensive warfarin pharmacogenetics service.

    Science.gov (United States)

    Nutescu, Edith A; Drozda, Katarzyna; Bress, Adam P; Galanter, William L; Stevenson, James; Stamos, Thomas D; Desai, Ankit A; Duarte, Julio D; Gordeuk, Victor; Peace, David; Kadkol, Shrihari S; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A; Garcia, Joe G N; Cavallari, Larisa H

    2013-11-01

    To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Prospective observational study. A 438-bed tertiary care hospital affiliated with a large academic institution. Eighty patients who started warfarin therapy and were managed by a newly implemented pharmacogenetics service. All patients received routine warfarin genotyping and clinical pharmacogenetics consultation. The primary outcomes were percentage of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders placed during the first 6 months of the service, 190 (44%) were deemed appropriate. For the 80 patients on the service who consented to data collection, 76% of the genotypes were available prior to the second warfarin dose. The median (range) time from genotype order to genotype result was 26 hours (7-80 hrs), and the time to genotype-guided dose recommendation was 30 hours (7-80 hrs). A total of 73% of warfarin doses ordered by the medical staff were within 0.5 mg of the daily dose recommended by the pharmacogenetics consult service. Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with most genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. © 2013 Pharmacotherapy Publications, Inc.

  10. The perceptions of pharmacists in Victoria, Australia on pharmacogenetics and its implications

    Directory of Open Access Journals (Sweden)

    McMahon T

    2011-09-01

    Full Text Available Objectives: This study aimed to explore how well Victorian pharmacists perceived they understood pharmacogenetics, their perceived capacity to counsel a patient about such testing, how they believed pharmacogenetics would impact upon their profession, and to investigate the ways in which Victorian pharmacists would like to be educated about pharmacogenetics.Methods: A cross-sectional survey was dispatched to 800 Victorian pharmacists. The participants were randomly selected and the survey was anonymous. The survey contained questions about where the pharmacists worked, the pharmacists’ perceived knowledge of pharmacogenetics, how well they believed they would be able to counsel patients about pharmacogenetic testing, how they thought pharmacists should be educated on the topic and how they believed pharmacogenetics would impact upon their profession.Results: 291 surveys were returned (36% response rate. Results suggest that Victorian pharmacists generally perceived they had a poor understanding of pharmacogenetics and that those who have more recently graduated from tertiary education had a better perceived understanding than those who have been in the workforce for longer. Most pharmacists indicated that they did not believe that they could counsel a patient adequately about the results of a pharmacogenetic test. Regarding education about pharmacogenetics, participants suggested that this would be best delivered during tertiary studies, and as seminars and workshops forming part of their continuing professional development. Although some pharmacists were unsure how pharmacogenetics would affect their profession, many believed it would have a major impact upon their role as a pharmacist and lead to improved patient care. Some concerns about the implementation of pharmacogenetics were noted, including economic and ethical issues.Conclusion: This study highlights the need for further research across the pharmacy profession in Australia on the

  11. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Overcoming Challenges of Real-World Implementation

    Science.gov (United States)

    Shuldiner, AR; Relling, MV; Peterson, JF; Hicks, JK; Freimuth, RR; Sadee, W; Pereira, NL; Roden, DM; Johnson, JA; Klein, TE

    2013-01-01

    The pace of discovery of potentially actionable pharmacogenetic variants has increased dramatically in recent years. However, the implementation of this new knowledge for individualized patient care has been slow. The Pharmacogenomics Research Network (PGRN) Translational Pharmacogenetics Program seeks to identify barriers and develop real-world solutions to implementation of evidence-based pharmacogenetic tests in diverse health-care settings. Dissemination of the resulting toolbox of “implementation best practices” will prove useful to a broad audience. PMID:23588301

  12. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

    Science.gov (United States)

    Despotovic, Jenny M.; Mortier, Nicole A.; Flanagan, Jonathan M.; He, Jin; Smeltzer, Matthew P.; Kimble, Amy C.; Aygun, Banu; Wu, Song; Howard, Thad; Sparreboom, Alex

    2011-01-01

    Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal. PMID:21876119

  13. Do guidelines recommending pharmacogenetic testing of psychiatric patients affect treatment costs and the use of healthcare services?

    DEFF Research Database (Denmark)

    Herbild, Louise; Bech, Mickael; Gyrd-Hansen, Dorte

    2011-01-01

    To identify the effects of local recommendations of pharmacogenetic testing in psychiatry with respect to treatment costs.......To identify the effects of local recommendations of pharmacogenetic testing in psychiatry with respect to treatment costs....

  14. Knowledge of Pharmacogenetics among Healthcare Professionals and Faculty Members of Health Training Institutions in Ghana.

    Science.gov (United States)

    Kudzi, W; Addy, B S; Dzudzor, B

    2015-03-01

    Pharmacogenetics has a potential for optimizing drug response and identifying risk of toxicity for patients. Pharmacogenetics knowledge of healthcare professionals and the unmet need for pharmacogenetics education in health training institutions are some of the challenges of integrating pharmacogenetics into routine medical practice. To assess pharmacogenetics knowledge among healthcare professionals and faculty members of health training institutions in Ghana. Semi-structured questionnaires were used to interview healthcare professionals from selected public and private hospitals. Faculty members from health training institutions were also interviewed. The respondents were Medical doctors 42 (46.7%), Pharmacists 29 (32.2%) and Nurses 19 (21.1%). Healthcare professionals rated their knowledge of Pharmacogenetics as Excellent 5 (5.6%), Very Good 10 (11.2%), Good 53 (60%) and Poor 19 (21.4%). Thirty-two faculty members from health training institutions were also interviewed. Faculty members rated their knowledge of pharmacogenetics as Excellent 2 (6.3%), Very Good 3 (9.4%), Good 9 (28.1%), Fair 12 (37.5%) and Poor 6 (18.8%). Thirty seven percent (12) of these faculty members said pharmacogenetics was not part of their institutions' curriculum, 7 (22%) did not know if pharmacogenetics was part of their curriculum and only 13 (40.6%) said it was part of their curriculum. Few healthcare professionals and faculty members of training institutions are aware of the discipline of pharmacogenetics. There is the need for continuous professional education on pharmacogenetics and development of competency standards for all healthcare professionals in Ghana.

  15. Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?

    Directory of Open Access Journals (Sweden)

    Juan Pablo Cayún Pellizaris

    2014-11-01

    Full Text Available In recent times, several investigations have been seeking an explanation for the great variability in both outcome and toxicity in cisplatin-based therapy through pharmacogenetic studies. These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular and esophageal cancer. In this review, we seek to update the reader in this area of investigation, focusing primarily on DNA reparation enzymes and cisplatin metabolism through Glutathione S-Transferases (GST genes. Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes where cisplatin is the cornerstone of these treatments. Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinic utility.

  16. P450 Pharmacogenetics in Indigenous North American Populations

    Directory of Open Access Journals (Sweden)

    Lindsay M. Henderson

    2018-02-01

    Full Text Available Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Métis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without adequate representation in pharmacogenetic studies establishing genotype-phenotype relationships, Indigenous populations may not benefit fully from new innovations in precision medicine testing to tailor and improve the safety and efficacy of drug treatment, resulting in health care disparities. The purpose of this review is to summarize and evaluate what is currently known about cytochrome P450 genetic variation in Indigenous populations in North America and to highlight the importance of including these groups in future pharmacogenetic studies for implementation of personalized drug therapy.

  17. Pharmacogenetics of ribavirin-induced anemia in hepatitis C.

    Science.gov (United States)

    Ampuero, Javier; Romero-Gómez, Manuel

    2016-09-01

    Pharmacogenetics assesses inherited genetic differences in drug metabolic pathways and its role in medicine is growing. Ribavirin (RBV) and peginterferon were the standard of care therapy in hepatitis C virus infection during 15 years, with the addition of first-generation protease inhibitors at the beginning of 2010s. New direct-acting agents are the new standard of care, but RBV remains important in some scenarios. The main adverse effect of RBV is anemia, which requires dose reduction and even stopping treatment in some patients. Pharmacogenetics has identified ITPA and SLC28/29 genes to be closely related to RBV-induced anemia. The routine evaluation of these genes could help to identify those patients at risk of developing anemia during the hepatitis C virus treatment.

  18. Hot Topics in Pharmacogenetics of Age-Related Macular Degeneration.

    Science.gov (United States)

    Schwartz, Stephen G; Brantley, Milam A; Kovach, Jaclyn L; Grzybowski, Andrzej

    2017-01-01

    Age-related macular degeneration (AMD) is a leading cause of irreversible visual loss and is primarily treated with nutritional supplementation as well as with anti-vascular endothelial growth factor (VEGF) agents for certain patients with neovascular disease. AMD is a complex disease with both genetic and environmental risk factors. In addition, treatment outcomes from nutritional supplementation and anti-VEGF agents vary considerably. Therefore, it is reasonable to suspect that there may be pharmacogenetic influences on these treatments. Many series have reported individual associations with variants in complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and other loci. However, at this time there are no validated associations. With respect to AMD, pharmacogenetics remains an intriguing area of research but is not helpful for routine clinical management. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Significance of Pharmacogenetics and Pharmacogenomics Research in Current Medical Practice.

    Science.gov (United States)

    Prakash, Swayam; Agrawal, Suraksha

    2016-01-01

    Human genome sequencing highlights the involvement of genetic variation towards differential risk of human diseases, presence of different phenotypes, and response to pharmacological elements. This brings the field of personalized medicine to forefront in the era of modern health care. Numerous recent approaches have shown that how variation in the genome at single nucleotide level can be used in pharmacological research. The two broad aspects that deal with pharmacological research are pharmacogenetics and pharmacogenomics. This review encompasses how these variations have created the basis of pharmacogenetics and pharmacogenomics research and important milestones accomplished in these two fields in different diseases. It further discusses at length their importance in disease diagnosis, response of drugs, and various treatment modalities on the basis of genetic determinants.

  20. Pharmacogenetics and Predictive Testing of Drug Hypersensitivity Reactions.

    Science.gov (United States)

    Böhm, Ruwen; Cascorbi, Ingolf

    2016-01-01

    Adverse drug reactions adverse drug reaction (ADR) occur in approximately 17% of patients. Avoiding ADR is thus mandatory from both an ethical and an economic point of view. Whereas, pharmacogenetics changes of the pharmacokinetics may contribute to the explanation of some type A reactions, strong relationships of genetic markers has also been shown for drug hypersensitivity belonging to type B reactions. We present the classifications of ADR, discuss genetic influences and focus on delayed-onset hypersensitivity reactions, i.e., drug-induced liver injury, drug-induced agranulocytosis, and severe cutaneous ADR. A guidance how to read and interpret the contingency table is provided as well as an algorithm whether and how a test for a pharmacogenetic biomarker should be conducted.

  1. Warfarin and vitamin K intake in the era of pharmacogenetics

    OpenAIRE

    Lurie, Yael; Loebstein, Ronen; Kurnik, Daniel; Almog, Shlomo; Halkin, Hillel

    2010-01-01

    The considerable variability in the warfarin dose–response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability...

  2. Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

    Science.gov (United States)

    Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan C.; Cacabelos, Pablo; Teijido, Óscar

    2018-01-01

    Alzheimer’s disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders. PMID:29301387

  3. Pharmacogenetics of the β2-Adrenergic Receptor Gene

    Science.gov (United States)

    Ortega, Victor E.; Hawkins, Gregory A.; Peters, Stephen P.; Bleecker, Eugene R.

    2009-01-01

    Asthma is a complex genetic disease with multiple genetic and environmental determinants contributing to the observed variability in response to common anti-asthma therapies. Asthma pharmacogenetic research has focused on multiple candidate genes including the β2-adrenergic receptor gene (ADRβ2) and its effect on individual responses to beta agonist therapy. At present, knowledge about the effects of ADRβ2 variation on therapeutic responses is evolving and should not alter current Asthma Guideline approaches consisting of the use of short acting beta agonists for as-needed symptom based therapy and the use of a regular long-acting beta agonist in combination with inhaled corticosteroid therapy for optimal control of asthma symptoms in those asthmatics who are not controlled on inhaled corticosteroid alone. This approach is based upon studies showing a consistent pharmacogenetic response to regular use of short acting beta agonists (SABA) and less consistent findings in studies evaluating long acting beta agonist (LABA). While emerging pharmacogenetic studies are provocative and should lead to functional approaches, conflicting data with responses to LABA therapy may be caused by factors that include small sample sizes of study populations and differences in experimental design that may limit the conclusions that may be drawn from these clinical trials at the present time. PMID:17996583

  4. Neuroimaging in psychiatric pharmacogenetics research: the promise and pitfalls.

    Science.gov (United States)

    Falcone, Mary; Smith, Ryan M; Chenoweth, Meghan J; Bhattacharjee, Abesh Kumar; Kelsoe, John R; Tyndale, Rachel F; Lerman, Caryn

    2013-11-01

    The integration of research on neuroimaging and pharmacogenetics holds promise for improving treatment for neuropsychiatric conditions. Neuroimaging may provide a more sensitive early measure of treatment response in genetically defined patient groups, and could facilitate development of novel therapies based on an improved understanding of pathogenic mechanisms underlying pharmacogenetic associations. This review summarizes progress in efforts to incorporate neuroimaging into genetics and treatment research on major psychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, and addiction. Methodological challenges include: performing genetic analyses in small study populations used in imaging studies; inclusion of patients with psychiatric comorbidities; and the extensive variability across studies in neuroimaging protocols, neurobehavioral task probes, and analytic strategies. Moreover, few studies use pharmacogenetic designs that permit testing of genotype × drug effects. As a result of these limitations, few findings have been fully replicated. Future studies that pre-screen participants for genetic variants selected a priori based on drug metabolism and targets have the greatest potential to advance the science and practice of psychiatric treatment.

  5. Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials.

    Science.gov (United States)

    Tortelli, Rosanna; Seripa, Davide; Panza, Francesco; Solfrizzi, Vincenzo; Logroscino, Giancarlo

    2016-01-01

    Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases. Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted. The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification. © 2016 S. Karger AG, Basel.

  6. Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Ramón Cacabelos

    2018-01-01

    Full Text Available Alzheimer’s disease (AD is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM and/or ultra-rapid (UM geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM or intermediate (IM metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.

  7. ParaHaplo 3.0: A program package for imputation and a haplotype-based whole-genome association study using hybrid parallel computing

    Directory of Open Access Journals (Sweden)

    Kamatani Naoyuki

    2011-05-01

    Full Text Available Abstract Background Use of missing genotype imputations and haplotype reconstructions are valuable in genome-wide association studies (GWASs. By modeling the patterns of linkage disequilibrium in a reference panel, genotypes not directly measured in the study samples can be imputed and used for GWASs. Since millions of single nucleotide polymorphisms need to be imputed in a GWAS, faster methods for genotype imputation and haplotype reconstruction are required. Results We developed a program package for parallel computation of genotype imputation and haplotype reconstruction. Our program package, ParaHaplo 3.0, is intended for use in workstation clusters using the Intel Message Passing Interface. We compared the performance of ParaHaplo 3.0 on the Japanese in Tokyo, Japan and Han Chinese in Beijing, and Chinese in the HapMap dataset. A parallel version of ParaHaplo 3.0 can conduct genotype imputation 20 times faster than a non-parallel version of ParaHaplo. Conclusions ParaHaplo 3.0 is an invaluable tool for conducting haplotype-based GWASs. The need for faster genotype imputation and haplotype reconstruction using parallel computing will become increasingly important as the data sizes of such projects continue to increase. ParaHaplo executable binaries and program sources are available at http://en.sourceforge.jp/projects/parallelgwas/releases/.

  8. The DAOA/G30 locus and affective disorders: haplotype based association study in a polydiagnostic approach

    Directory of Open Access Journals (Sweden)

    Knapp Michael

    2010-07-01

    Full Text Available Abstract Background The DAOA/G30 (D-amino acid oxidase activator gene complex at chromosomal region 13q32-33 is one of the most intriguing susceptibility loci for the major psychiatric disorders, although there is no consensus about the specific risk alleles or haplotypes across studies. Methods In a case-control sample of German descent (affective psychosis: n = 248; controls: n = 188 we examined seven single nucleotide polymorphisms (SNPs around DAOA/G30 (rs3916966, rs1935058, rs2391191, rs1935062, rs947267, rs3918342, and rs9558575 for genetic association in a polydiagnostic approach (ICD 10; Leonhard's classification. Results No single marker showed evidence of overall association with affective disorder neither in ICD10 nor Leonhard's classification. Haplotype analysis revealed no association with recurrent unipolar depression or bipolar disorder according to ICD10, within Leonhard's classification manic-depression was associated with a 3-locus haplotype (rs2391191, rs1935062, and rs3916966; P = 0.022 and monopolar depression with a 5-locus combination at the DAOA/G30 core region (P = 0.036. Conclusion Our data revealed potential evidence for partially overlapping risk haplotypes at the DAOA/G30 locus in Leonhard's affective psychoses, but do not support a common genetic contribution of the DAOA/G30 gene complex to the pathogenesis of affective disorders.

  9. Pharmacogenetics of drug-induced arrhythmias : a feasibility study using spontaneous adverse drug reactions reporting data

    NARCIS (Netherlands)

    De Bruin, Marie L; van Puijenbroek, Eugene P; Bracke, Madelon; Hoes, Arno W; Leufkens, Hubert G M

    PURPOSE: The bottleneck in pharmacogenetic research on rare adverse drug reactions (ADR) is retrieval of patients. Spontaneous reports of ADRs may form a useful source of patients. We investigated the feasibility of a pharmacogenetic study, in which cases were selected from the database of a

  10. What is needed to incorporate clinical pharmacogenetic tests into the practice of psychopharmacotherapy?

    Science.gov (United States)

    de Leon, Jose; Spina, Edoardo

    2016-01-01

    This editorial considers two questions in psychopharmacotherapy: 1) What is needed to market pharmacogenetic tests in the US, since the US appears to lead other countries? and 2) What is needed for US-marketed pharmacogenetic tests to be incorporated by prescribers into long-term practice? US marketing of pharmacogenetic tests requires 1) understanding the pharmacological complexity of drug response, 2) modifying the oversight of non-FDA regulatory agencies, 3) clarifying the FDA's role and 4) promoting innovative marketing. The incorporation of pharmacogenetic tests into long-term practice requires 1) not jeopardizing pharmacogenetic testing by short-sighted marketing of non-validated tests, 2) educating prescribers about benefits, 3) educating patients about limitations and 4) considering the differences between isolated testing and generalized testing incorporating big data.

  11. Pharmacogenetics of anti-cancer drugs: State of the art and implementation - recommendations of the French National Network of Pharmacogenetics.

    Science.gov (United States)

    Quaranta, Sylvie; Thomas, Fabienne

    2017-04-01

    Individualized treatment is of special importance in oncology because the drugs used for chemotherapy have a very narrow therapeutic index. Pharmacogenetics may contribute substantially to clinical routine for optimizing cancer treatment to limit toxic effects while maintaining efficacy. This review presents the usefulness of pharmacogenetic tests for some key applications: dihydropyrimidine dehydrogenase (DPYD) genotyping for fluoropyrimidine (5-fluorouracil, capecitabine), UDP glucuronosylstransferase (UGT1A1) for irinotecan and thiopurine S-methyltransferase (TPMT) for thiopurine drugs. Depending on the level of evidence, the French National Network of Pharmacogenetics (RNPGx) has issued three levels of recommendations for these pharmacogenetic tests: essential, advisable, and potentially useful. Other applications, for which the level of evidence is still discussed, will be evoked in the final section of this review. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  12. Development and Implementation of a Pharmacist-Managed Clinical Pharmacogenetics Service

    Science.gov (United States)

    Crews, Kristine R.; Cross, Shane J.; McCormick, John N.; Baker, Donald K.; Molinelli, Alejandro R.; Mullins, Richard; Relling, Mary V.; Hoffman, James M.

    2011-01-01

    Purpose The development and implementation of a pharmacist-managed Clinical Pharmacogenetics service is described. Summary Therapeutic drug monitoring (TDM) is a well-accepted role of the pharmacist. Pharmacogenetics, the study of genetic factors that influence the variability in drug response among patients, is a rapidly evolving discipline that integrates knowledge of pharmacokinetics and pharmacodynamics with modern advances in genetic testing. There is growing evidence for the clinical utility of pharmacogenetics, and pharmacists can play an essential role in the thoughtful application of pharmacogenetics to patient care. A pharmacist-managed Clinical Pharmacogenetics service was designed and implemented. The goal of the service is to provide clinical pharmacogenetic testing for gene products important to the pharmacodynamics of medications used in our patients. The service is modeled after and integrated with an already established Clinical Pharmacokinetics service. All clinical pharmacogenetic test results are first reported to one of the pharmacists, who reviews the result and provides a written consult. The consult includes an interpretation of the result and recommendations for any indicated changes to therapy. In 2009, 136 clinical pharmacogenetic tests were performed, consisting of 66 TPMT tests, 65 CYP2D6 tests, and 5 UGT1A1 tests. Our service has been met with positive clinician feedback. Conclusion Our experience demonstrates the feasibility of the design and function of a pharmacist-managed Clinical Pharmacogenetics service at an academic specialty hospital. The successful implementation of this service highlights the leadership role that pharmacists can take in moving pharmacogenetics from research to patient care, thereby potentially improving patient outcomes. PMID:21200062

  13. Pharmacoeconomic evaluations of pharmacogenetic and genomic screening programmes: a systematic review on content and adherence to guidelines.

    Science.gov (United States)

    Vegter, Stefan; Boersma, Cornelis; Rozenbaum, Mark; Wilffert, Bob; Navis, Gerjan; Postma, Maarten J

    2008-01-01

    The fields of pharmacogenetics and pharmacogenomics have become important practical tools to progress goals in medical and pharmaceutical research and development. As more screening tests are being developed, with some already used in clinical practice, consideration of cost-effectiveness implications is important. A systematic review was performed on the content of and adherence to pharmacoeconomic guidelines of recent pharmacoeconomic analyses performed in the field of pharmacogenetics and pharmacogenomics. Economic analyses of screening strategies for genetic variations, which were evidence-based and assumed to be associated with drug efficacy or safety, were included in the review. The 20 papers included cover a variety of healthcare issues, including screening tests on several cytochrome P450 (CYP) enzyme genes, thiopurine S-methyltransferase (TMPT) and angiotensin-converting enzyme (ACE) insertion deletion (ACE I/D) polymorphisms. Most economic analyses reported that genetic screening was cost effective and often even clearly dominated existing non-screening strategies. However, we found a lack of standardization regarding aspects such as the perspective of the analysis, factors included in the sensitivity analysis and the applied discount rates. In particular, an important limitation of several studies related to the failure to provide a sufficient evidence-based rationale for an association between genotype and phenotype. Future economic analyses should be conducted utilizing correct methods, with adherence to guidelines and including extensive sensitivity analyses. Most importantly, genetic screening strategies should be based on good evidence-based rationales. For these goals, we provide a list of recommendations for good pharmacoeconomic practice deemed useful in the fields of pharmacogenetics and pharmacogenomics, regardless of country and origin of the economic analysis.

  14. Pharmacogenetic effects of angiotensin-converting enzyme inhibitors over age-related urea andcreatinine variations in patients with dementia due to Alzheimer disease

    OpenAIRE

    Ferreira de Oliveira, Fabricio; Berretta, Juliana Marília; Suchi Chen, Elizabeth; Cardoso Smith, Marilia; Ferreira Bertolucci, Paulo Henrique

    2016-01-01

    Background: Renal function declines according to age and vascular risk factors, whereas few data are available regarding geneticallymediated effects of anti-hypertensives over renal function. Objective: To estimate urea and creatinine variations in dementia due to Alzheimer disease (AD) by way of a pharmacogenetic analysis of the anti-hypertensive effects of angiotensin-converting enzyme inhibitors (ACEis). Methods: Consecutive outpatients older than 60 years-old with AD and no history of kid...

  15. Development of a Post-Graduate Year 2 Pharmacy Residency in Clinical Pharmacogenetics

    Science.gov (United States)

    Hoffman, James M.; Gammal, Roseann S.; Relling, Mary V.; Crews, Kristine R.

    2017-01-01

    Purpose The structure and development of an innovative clinical pharmacogenetics post-graduate year 2 (PGY2) ASHP-accredited residency program is described. Summary The advent of the era of genomics has left practitioners wondering how to interpret the data obtained from sequencing and genotyping patients. In order to train the next leaders in the area of implementing pharmacogenetics, St. Jude Children’s Research Hospital established the first accredited residency program in clinical pharmacogenetics. The 12-month long PGY2 residency was created in accordance with the ASHP standards for advanced practice residencies. The resident learns to optimize patient outcomes through the expert provision of evidence-based, patient-centered precision medicine as an integral part of an interdisciplinary team. The resident gains hands-on experience in a dynamic environment regarding all aspects of running a clinical pharmacogenetics service. Since the first resident graduated in 2012, the program has graduated one resident each year. Conclusion To fill a need for pharmacists trained in pharmacogenetics, an innovative PGY2 residency in clinical pharmacogenetics was successfully developed. Upon completion of the program, residents are equipped with the clinical skills and necessary experience to drive precision medicine forward and lead the implementation of pharmacogenetics in various healthcare settings. PMID:28274984

  16. Pharmacogenetics in Latin American populations: regulatory aspects, application to herbal medicine, cardiovascular and psychiatric disorders.

    Science.gov (United States)

    Rodeiro, Idania; Remírez-Figueredo, Diadelis; García-Mesa, Milagros; Dorado, Pedro; LLerena, Adrián

    2012-01-01

    Meeting report of the "Second Symposium on Pharmacology of Cytochrome P450 and Transporters" organized by the Cuban Society of Pharmacology in collaboration with the European Society of Pharmacogenetics and Theranostics (ESPT) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (www.ribef.com). The Symposium covered different topics on pharmacogenetics and its clinical implications, focusing on Latin-American populations. The activities of the ESPT were also presented and discussed. The topics addressed were regulatory aspects, the use of pharmacogenetics in pre-clinical research, herbal medicine, and natural products, ending with a discussion about translation into clinical practice, specifically for cardiovascular disorders and psychiatry. Finally, the implication for population diversity in Latin America was also discussed. The RIBEF initiative represents a promising step towards the inclusion of Latin American populations among those to benefit from the implementation of pharmacogenetics in clinical practice. Among current RIBEF activities, the CEIBA.FP Consortium aims to study the variability of pheno- and genotypes in Hispanics that are relevant to pharmacogenetics. For this purpose, populations from Mexico, Cuba, Nicaragua, Costa Rica, Ecuador, Colombia, Brasil, Perú, Chile, Uruguay, Argentina, Portugal, and Spain are currently being studied. The meeting's main conclusion was that population pharmacogenetic studies as well as academic clinical trials might need to be conducted in the different geographic locations/countries. This is important in order to improve drug safety, dosage recommendations, and pharmacovigilance programs, because environmental and ethnic factors vary across locations.

  17. Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing.

    Science.gov (United States)

    Linares, Oscar A; Fudin, Jeffrey; Daly, Annemarie L; Boston, Raymond C

    2015-12-01

    (1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety. In silico clinical trial simulation. Healthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg). CYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC. PMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC's apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM's therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects. Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.

  18. Pharmacogenetic testing through the direct-to-consumer genetic testing company 23andMe.

    Science.gov (United States)

    Lu, Mengfei; Lewis, Cathryn M; Traylor, Matthew

    2017-06-19

    Rapid advances in scientific research have led to an increase in public awareness of genetic testing and pharmacogenetics. Direct-to-consumer (DTC) genetic testing companies, such as 23andMe, allow consumers to access their genetic information directly through an online service without the involvement of healthcare professionals. Here, we evaluate the clinical relevance of pharmacogenetic tests reported by 23andMe in their UK tests. The research papers listed under each 23andMe report were evaluated, extracting information on effect size, sample size and ethnicity. A wider literature search was performed to provide a fuller assessment of the pharmacogenetic test and variants were matched to FDA recommendations. Additional evidence from CPIC guidelines, PharmGKB, and Dutch Pharmacogenetics Working Group was reviewed to determine current clinical practice. The value of the tests across ethnic groups was determined, including information on linkage disequilibrium between the tested SNP and causal pharmacogenetic variant, where relevant. 23andMe offers 12 pharmacogenetic tests to their UK customers, some of which are in standard clinical practice, and others which are less widely applied. The clinical validity and clinical utility varies extensively between tests. The variants tested are likely to have different degrees of sensitivity due to different risk allele frequencies and linkage disequilibrium patterns across populations. The clinical relevance depends on the ethnicity of the individual and variability of pharmacogenetic markers. Further research is required to determine causal variants and provide more complete assessment of drug response and side effects. 23andMe reports provide some useful pharmacogenetics information, mirroring clinical tests that are in standard use. Other tests are unspecific, providing limited guidance and may not be useful for patients without professional interpretation. Nevertheless, DTC companies like 23andMe act as a powerful

  19. Pharmacogenetic guidance: individualized medicine promotes enhanced pain outcomes

    Directory of Open Access Journals (Sweden)

    Dragic LL

    2017-12-01

    Full Text Available Lisa Lynn Dragic,1 Erica L Wegrzyn,2 Michael E Schatman,3–5 Jeffrey Fudin2,6 1Central Arkansas Veterans Healthcare System, Little Rock, AR, USA; 2Department of Pharmacy, Albany Stratton VA Medical Center, Albany, NY, USA; 3Research and Network Development, Boston Pain Care, Waltham, MA, USA; 4Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA; 5Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA; 6Scientific and Clinical Affairs, Remitigate, LLC, Delmar, NY, USA Abstract: The use of pharmacogenomics has become more prevalent over the past several years in treating many disease states. Several cytochrome P450 enzymes play a role in the metabolism of many pain medications including opioids and antidepressants. Noncytochrome P450 enzymes such as methylenetetrahydrofolate reductase (MTHFR and catechol-O-methyl transferase (COMT also play a role in the explanation of opioid dosage requirements as well as in response to certain antidepressants. We present the case of a patient with reduced COMT and MTHFR expression treated with leucovorin 10 mg daily for the management of chronic pain. The use of leucovorin in this patient decreased pain scores, which were clinically significant and increased functionality. This case demonstrates the importance of pharmacogenetics testing in patients, as this can help direct providers to better therapeutic options for their patients. Keywords: pharmacogenetic, depression, pain, MTHFR, COMT, methyl tetrahydrofolate reductase, catechol-O-methyltransferase

  20. Pharmacogenetic approaches to the prediction of drug response

    International Nuclear Information System (INIS)

    Vesell, E.S.

    1986-01-01

    The following review of pharmacogenetic progress and methodology is offered to stimulate and suggest analogous studies on drugs of abuse. It is readily acknowledged that formidable methodological problems are posed by adapting to drugs of abuse these pharmacogenetic approaches based on the administration of single safe doses of various prescription drugs to normal subjects under carefully controlled environmental conditions. Results of similarly designed studies on drugs of abuse in addicts might be uninterpretable because of confounding by numerous environmental perturbations, including the smoking of cigarettes and/or marijuana, nutritional variations, and intake of other drugs such as ethanol. Ethical considerations render objectionable the administration to unaddicted subjects of drugs at dosage levels usually ingested by drug abusers. Other approaches would have to be taken in such normal subjects. Possibilities include administration of tracer doses of /sup 14/C- or /sup 13/C- labeled drugs or growth of normal cells in culture to investigate their pharmacokinetic and/or pharmacodynamic responses to various drugs of abuse

  1. Pharmacogenetics and Cardiovascular Disease—Implications for Personalized Medicine

    Science.gov (United States)

    Cavallari, Larisa H.

    2013-01-01

    The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients. There are many challenges in moving from research data to translation to practice; we discuss some of these barriers and the approaches some health systems are taking to overcome them. The body of literature that has led to the clinical implementation of CYP2C19 genotyping for clopidogrel, VKORC1, CYP2C9; and CYP4F2 for warfarin; and SLCO1B1 for statins is comprehensively described. We also provide clarity for other genes that have been extensively studied relative to these drugs, but for which the data are conflicting. Finally, we comment briefly on pharmacogenetics of other cardiovascular drugs and highlight β-blockers as the drug class with strong data that has not yet seen clinical implementation. It is anticipated that genetic information will increasingly be available on patients, and it is important to identify those examples where the evidence is sufficiently robust and predictive to use genetic information to guide clinical decisions. The review herein provides several examples of the accumulation of evidence and eventual clinical translation in cardiovascular pharmacogenetics. PMID:23686351

  2. From evidence based medicine to mechanism based medicine : Reviewing the role of pharmacogenetics

    NARCIS (Netherlands)

    Wilffert, Bob; Swen, Jesse; Mulder, Hans; Touw, Daan; Maitland-Van der Zee, Anke-Hilse; Deneer, Vera

    Aim of the review The translation of evidence based medicine to a specific patient presents a considerable challenge. We present by means of the examples nortriptyline, tramadol, clopidogrel, coumarins, abacavir and antipsychotics the discrepancy between available pharmacogenetic information and its

  3. From evidence based medicine to mechanism based medicine. Reviewing the role of pharmacogenetics

    NARCIS (Netherlands)

    Wilffert, Bob; Swen, Jesse; Mulder, Hans; Touw, Daan; Maitland-Van der Zee, Anke-Hilse; Deneer, Vera

    Aim of the review The translation of evidence based medicine to a specific patient presents a considerable challenge. We present by means of the examples nortriptyline, tramadol, clopidogrel, coumarins, abacavir and antipsychotics the discrepancy between available pharmacogenetic information and its

  4. Pharmacogenetics of drug-induced birth defects : What is known so far?

    NARCIS (Netherlands)

    Wilffert, Bob; Altena, Judith; Tijink, Laurien; van Gelder, Marleen M. H. J.; de Jong-van den Berg, Lolkje T. W.

    A literature review was performed to collect information on the role of pharmacogenetics in six proposed teratogenic mechanisms associated with drug use during pregnancy: folate antagonism, oxidative stress, angiotensin-converting enzyme inhibition and angiotensin II receptor antagonism,

  5. Clinical implementation of pharmacogenetics in kidney transplantation: calcineurin inhibitors in the starting blocks.

    Science.gov (United States)

    Elens, Laure; Bouamar, Rachida; Shuker, Nauras; Hesselink, Dennis A; van Gelder, Teun; van Schaik, Ron H N

    2014-04-01

    Pharmacogenetics has generated many expectations for its potential to individualize therapy proactively and improve medical care. However, despite the huge amount of reported genetic associations with either pharmacokinetics or pharmacodynamics of drugs, the translation into patient care is still slow. In fact, strong evidence for a substantial clinical benefit of pharmacogenetic testing is still limited, with a few exceptions. In kidney transplantation, established pharmacogenetic discoveries are being investigated for application in the clinic to improve efficacy and to limit toxicity associated with the use of immunosuppressive drugs, especially the frequently used calcineurin inhibitors (CNIs) tacrolimus and ciclosporin. The purpose of the present review is to picture the current status of CNI pharmacogenetics and to discuss the most promising leads that have been followed so far. © 2013 The British Pharmacological Society.

  6. Pharmacogenetic Risk Stratification in Angiotensin-Converting Enzyme Inhibitor-Treated Patients with Congestive Heart Failure

    DEFF Research Database (Denmark)

    Nelveg-Kristensen, Karl Emil; Busk Madsen, Majbritt; Torp-Pedersen, Christian

    2015-01-01

    BACKGROUND: Evidence for pharmacogenetic risk stratification of angiotensin-converting enzyme inhibitor (ACEI) treatment is limited. Therefore, in a cohort of ACEI-treated patients with congestive heart failure (CHF), we investigated the predictive value of two pharmacogenetic scores...... SNPs of the angiotensin-converting enzyme gene (rs4343) and ABO blood group genes (rs495828 and rs8176746). METHODS: Danish patients with CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were included. Subjects were genotyped and categorized according to pharmacogenetic.......05 [95% CI 0.79-1.40]), respectively. CONCLUSIONS: We found no association between either of the analyzed pharmacogenetic scores and fatal outcomes in ACEI-treated patients with CHF....

  7. Partnership with the Confederated Salish and Kootenai Tribes: Establishing an Advisory Committee for Pharmacogenetic Research.

    Science.gov (United States)

    Morales, Chelsea T; Muzquiz, LeeAnna I; Howlett, Kevin; Azure, Bernie; Bodnar, Brenda; Finley, Vernon; Incashola, Tony; Mathias, Cheryl; Laukes, Cindi; Beatty, Patrick; Burke, Wylie; Pershouse, Mark A; Putnam, Elizabeth A; Trinidad, Susan Brown; James, Rosalina; Woodahl, Erica L

    2016-01-01

    Inclusion of American Indian and Alaska Native (AI/AN) populations in pharmacogenetic research is key if the benefits of pharmacogenetic testing are to reach these communities. Community-based participatory research (CBPR) offers a model to engage these communities in pharmacogenetics. An academic-community partnership between the University of Montana (UM) and the Confederated Salish and Kootenai Tribes (CSKT) was established to engage the community as partners and advisors in pharmacogenetic research. A community advisory committee, the Community Pharmacogenetics Advisory Council (CPAC), was established to ensure community involvement in the research process. To promote bidirectional learning, researchers gave workshops and presentations about pharmacogenetic research to increase research capacity and CPAC members trained researchers in cultural competencies. As part of our commitment to a sustainable relationship, we conducted a self-assessment of the partnership, which included surveys and interviews with CPAC members and researchers. Academic and community participants agree that the partnership has promoted a bidirectional exchange of knowledge. Interviews showed positive feedback from the perspectives of both the CPAC and researchers. CPAC members discussed their trust in and support of the partnership, as well as having learned more about research processes and pharmacogenetics. Researchers discussed their appreciation of CPAC involvement in the project and guidance the group provided in understanding the CSKT community and culture. We have created an academic-community partnership to ensure CSKT community input and to share decision making about pharmacogenetic research. Our CBPR approach may be a model for engaging AI/AN people, and other underserved populations, in genetic research.

  8. A nationwide survey of pharmacists' perception of pharmacogenetics in the context of a clinical decision support system containing pharmacogenetics dosing recommendations.

    Science.gov (United States)

    Bank, Paul Cd; Swen, Jesse J; Guchelaar, Henk-Jan

    2017-02-01

    To benchmark Dutch pharmacists knowledge, experience and attitudes toward pharmacogenetics (PGx) with a specific focus on the effects of awareness of the Dutch Pharmacogenetics Working Group guidelines. A web-based survey containing 41 questions was sent to all certified Dutch pharmacists. A total of 667 pharmacists completed the survey (18.8%). Virtually all responders believed in the concept of PGx (99.7%). However, only 14.7% recently ordered a PGx test (≤6 months), 14.1% felt adequately informed and 88.8% would like to receive additional training on PGx. Being aware of the Dutch Pharmacogenetics Working Group guidelines did not have any significant effect on knowledge or adoption of PGx. Dutch pharmacists are very positive toward PGx. However, test adoption is low and additional training is warranted.

  9. Routine pharmacogenetic testing in clinical practice: dream or reality?

    Science.gov (United States)

    Grossman, Iris

    2007-10-01

    Pharmacogenetics (PGx) has become progressively popular in recent years, thanks to growing anticipation among scientists, healthcare providers and the general public for the incorporation of genetic tests into the diagnostic arsenal at the physician's disposal. Indeed, much research has been dedicated to elucidation of genetic determinants underlying interindividual variability in pharmacokinetic parameters, as well as drug safety and efficacy. However, few PGx applications have thus far been realized in healthcare management. This review uses examples from PGx research of psychiatric drugs to illustrate why the current published findings are inadequate and insufficient for utilization as routine clinical predictors of treatment safety, efficacy or dosing. I therefore suggest the necessary steps to demonstrate the validity, utility and cost-effectiveness of PGx. These recommendations include a whole range of aspects, starting from standardization of criteria and assessment of the technical quality of genotyping assays, up to design of prospective PGx studies, providing the basis for reimbursement programs to be recognized in routine clinical practice.

  10. Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals

    Directory of Open Access Journals (Sweden)

    Jacinta Nwamaka Nwogu

    2016-01-01

    Full Text Available Neurological complications associated with the human immunodeficiency virus (HIV are a matter of great concern. While antiretroviral (ARV drugs are the cornerstone of HIV treatment and typically produce neurological benefit, some ARV drugs have limited CNS penetration while others have been associated with neurotoxicity. CNS penetration is a function of several factors including sieving role of blood-brain and blood-CSF barriers and activity of innate drug transporters. Other factors are related to pharmacokinetics and pharmacogenetics of the specific ARV agent or mediated by drug interactions, local inflammation, and blood flow. In this review, we provide an overview of the various factors influencing CNS penetration of ARV drugs with an emphasis on those commonly used in sub-Saharan Africa. We also summarize some key associations between ARV drug penetration, CNS efficacy, and neurotoxicity.

  11. Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

    Science.gov (United States)

    Brown, Jacob T; Bishop, Jeffrey R

    2015-01-01

    Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

  12. The future of pharmacogenetics in the treatment of heart failure.

    Science.gov (United States)

    Anwar, Mohamed Subhan; Iskandar, Muhammad Zaid; Parry, Helen M; Doney, Alex S; Palmer, Colin N; Lang, Chim C

    2015-11-01

    Heart failure is a common disease with high levels of morbidity and mortality. Current treatment comprises β-blockers, ACE inhibitors, aldosterone antagonists and diuretics. Variation in clinical response seen in patients begs the question of whether there is a pharmacogenetic component yet to be identified. To date, the genes most studied involve the β-1, β-2, α-2 adrenergic receptors and the renin-angiotensin-aldosterone pathway, mainly focusing on SNPs. However results have been inconsistent. Genome-wide association studies and next-generation sequencing are seen as alternative approaches to discovering genetic variations influencing drug response. Hopefully future research will lay the foundations for genotype-led drug management in these patients with the ultimate aim of improving their clinical outcome.

  13. Primary Care Clinicians Attitudes and Knowledge of Pharmacogenetics in a Large, Multi-state, Healthcare System

    Directory of Open Access Journals (Sweden)

    Megan Olander

    2018-04-01

    Full Text Available   Background: Considerable progress has been made in the way of pharmacogenetic research and the development of clinical recommendations; however, its implementation into clinical practice has been slower than anticipated. We sought to better understand its lack of clinical uptake within primary care. Aim: The primary objective of this survey was to ascertain primary care clinicians’ perceptions of pharmacogenetic use and implementation in an integrated health system of metropolitan and rural settings across several states. Methods: Primary care clinicians (including MDs, DOs, NPs, and PAs were invited to participate in a survey via email. Questions about pharmacogenetics knowledge and perceptions were presented to assess current understanding and usage of pharmacogenetics in practice. Results: The rate of response for the survey was 17%. Of the 90 respondents, 58% were female, 69% were MDs/DOs, 20% were NPs, and 11% were PAs. Fifty-eight percent of respondents received their clinical degree in or after 2000. Ninety percent of respondents noted that they were uncomfortable ordering a pharmacogenetics test, with 76% stating they were uncomfortable applying the results of a pharmacogenetic test. Notably, 78% of respondents were interested in having pharmacogenetic testing available through Medication Therapy Management (MTM services, although PAs were significantly less interested as compared to NPs and MD/DOs. Ninety-five percent of respondents were interested in a clinical decision support tool relevant to pharmacogenetic results. Conclusions: As a whole, prescribing clinicians in primary care clinics are uncomfortable in the ordering, interpreting, and applying pharmacogenetic results to individual patients. However, favorable attitudes towards providing pharmacogenetic testing through existing MTM clinics provides the opportunity for pharmacists to advance existing practices. Conflict of Interest: We declare no conflicts of interest or

  14. Pharmacogenetics: progress, pitfalls and clinical potential for coronary heart disease.

    Science.gov (United States)

    Humphries, Steve E; Hingorani, Aroon

    2006-02-01

    Much has been written about the potential of pharmacogenetic testing to inform therapy based on an individual's genetic makeup, and to decide the most effective choice of available drugs, or to avoid dangerous side effects. Currently, there is little hard data for either in the field of cardiovascular disease. The usual approach has been opportunistic use of drug trials in unrelated patients, and to look for differences in response or outcome by "candidate gene" genotype, for example genes coding for drug metabolising enzymes (activators and metabolisers), and enzymes and receptors involved in lipid metabolism, adrenergic response, etc. As with all association studies, initially promising results have often failed the test of replication in larger studies, and the relationship between the CETP Taq-I variant and response to statins has now been disproved. The strongest data to date is the report [Chasman, D.I., Posada, D., Subrahmanyan, L., Cook, N.R., Stanton Jr., V.P., Ridker, P.M., 2004. Pharmacogenetic study of statin therapy and cholesterol reduction. J. Am. Med. Assoc. 291, 2821-2827] of a poorer cholesterol-lowering response to Pravastatin in the 7% of patients carrying a certain haplotype of the HMG CoA reductase gene (14% fall versus 19%), but if this is overcome simply by a higher dose, it is of little clinical relevance. Currently, the best example of avoiding side effects is determining genotype at the CYP2C9 locus with respect of warfarin treatment, since carriers for functional variants (>20% of the population) require lower doses for optimal anticoagulation, and homozygotes, although rare, may well experience serious bleeding if given a usual dose. The full potential of this field will only be realised with much further work.

  15. Review of Opioid Pharmacogenetics and Considerations for Pain Management.

    Science.gov (United States)

    Owusu Obeng, Aniwaa; Hamadeh, Issam; Smith, Michael

    2017-09-01

    Opioid analgesics are the standards of care for the treatment of moderate to severe nociceptive pain, particularly in the setting of cancer and surgery. Their analgesic properties mainly emanate from stimulation of the μ receptors, which are encoded by the OPRM1 gene. Hepatic metabolism represents the major route of elimination, which, for some opioids, namely codeine and tramadol, is necessary for their bioactivation into more potent analgesics. The highly polymorphic nature of the genes coding for phase I and phase II enzymes (pharmacokinetics genes) that are involved in the metabolism and bioactivation of opioids suggests a potential interindividual variation in their disposition and, most likely, response. In fact, such an association has been substantiated in several pharmacokinetic studies described in this review, in which drug exposure and/or metabolism differed significantly based on the presence of polymorphisms in these pharmacokinetics genes. Furthermore, in some studies, the observed variability in drug exposure translated into differences in the incidence of opioid-related adverse effects, particularly nausea, vomiting, constipation, and respiratory depression. Although the influence of polymorphisms in pharmacokinetics genes, as well as pharmacodynamics genes (OPRM1 and COMT) on response to opioids has been a subject of intense research, the results have been somehow conflicting, with some evidence insinuating for a potential role for OPRM1. The Clinical Pharmacogenetics Implementation Consortium guidelines provide CYP2D6-guided therapeutic recommendations to individualize treatment with tramadol and codeine. However, implementation guidelines for other opioids, which are more commonly used in real-world settings for pain management, are currently lacking. Hence, further studies are warranted to bridge this gap in our knowledge base and ultimately ascertain the role of pharmacogenetic markers as predictors of response to opioid analgesics. © 2017

  16. Pharmacogenetics in cardiovascular diseases: State of the art and implementation-recommendations of the French National Network of Pharmacogenetics (RNPGx).

    Science.gov (United States)

    Lamoureux, Fabien; Duflot, Thomas

    2017-04-01

    The use of genomic markers to predict drug response and effectiveness has the potential to improve healthcare by increasing drug efficacy and minimizing adverse effects. Polymorphisms associated with inter-individual variability in drug metabolism, transport, or pharmacodynamics of major cardiovascular drugs have been identified. These include single nucleotide polymorphisms (SNP) affecting clinical outcomes in patients receiving antiplatelet agents, oral anticoagulants and statins. Based on clinical evidence supporting genetic testing in the management of cardiovascular diseases using these drug classes, this short review presents clinical guidance regarding current pharmacogenetics implementation in routine medical practice. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  17. Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmacogenetic analyses

    Directory of Open Access Journals (Sweden)

    Stott David J

    2011-10-01

    Full Text Available Abstract Background The PHArmacogenetic study of Statins in the Elderly at risk (PHASE is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly. Methods The genome wide association study (GWAS was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification. Results Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5. The top SNP (rs445925, chromosome 19 with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19 with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results. Conclusion With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof

  18. A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury.

    Science.gov (United States)

    Zhang, Haili; Zheng, Ming; Wu, Manhong; Xu, Dan; Nishimura, Toshihiko; Nishimura, Yuki; Giffard, Rona; Xiong, Xiaoxing; Xu, Li Jun; Clark, J David; Sahbaie, Peyman; Dill, David L; Peltz, Gary

    2016-05-01

    Haloperidol is an effective antipsychotic agent, but it causes Parkinsonian-like extrapyramidal symptoms in the majority of treated subjects. To address this treatment-limiting toxicity, we analyzed a murine genetic model of haloperidol-induced toxicity (HIT). Analysis of a panel of consomic strains indicated that a genetic factor on chromosome 10 had a significant effect on susceptibility to HIT. We analyzed a whole-genome SNP database to identify allelic variants that were uniquely present on chromosome 10 in the strain that was previously shown to exhibit the highest level of susceptibility to HIT. This analysis implicated allelic variation within pantetheinase genes (Vnn1 and Vnn3), which we propose impaired the biosynthesis of cysteamine, could affect susceptibility to HIT. We demonstrate that administration of cystamine, which is rapidly metabolized to cysteamine, could completely prevent HIT in the murine model. Many of the haloperidol-induced gene expression changes in the striatum of the susceptible strain were reversed by cystamine coadministration. Since cystamine administration has previously been shown to have other neuroprotective actions, we investigated whether cystamine administration could have a broader neuroprotective effect. Cystamine administration caused a 23% reduction in infarct volume after experimentally induced cerebral ischemia. Characterization of this novel pharmacogenetic factor for HIT has identified a new approach for preventing the treatment-limiting toxicity of an antipsychotic agent, which could also be used to reduce the extent of brain damage after stroke. Copyright © 2016 by the Genetics Society of America.

  19. Pharmacogenetics of tyrosine kinase inhibitors in gastrointestinal stromal tumor and chronic myeloid leukemia.

    Science.gov (United States)

    Ravegnini, Gloria; Sammarini, Giulia; Angelini, Sabrina; Hrelia, Patrizia

    2016-07-01

    Gastrointestinal stromal tumors (GIST) and chronic myeloid leukemia (CML) are two tumor types deeply different from each other. Despite the differences, these disorders share treatment with tyrosine kinase inhibitor imatinib. Despite the success of imatinib, the response rates vary among different individuals and pharmacogenetics may play an important role in the final clinical outcome. In this review, the authors provide an overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST and CML treatment efficacy and toxicity. So far, several polymorphisms influencing the pharmacokinetic determinants of imatinib have been identified. However, the data are not yet conclusive enough to translate pharmacogenetic tests in clinical practice. In this context, the major obstacles to pharmacogenetic test validation are represented by the small sample size of most studies, ethnicity and population admixture as confounding source, and uncertainty related to genetic variants analyzed. In conclusion, a combination of different theoretical approaches, experimental model systems and statistical methods is clearly needed, in order to appreciate pharmacogenetics applied to clinical practice in the near future.

  20. From evidence based medicine to mechanism based medicine. Reviewing the role of pharmacogenetics.

    Science.gov (United States)

    Wilffert, Bob; Swen, Jesse; Mulder, Hans; Touw, Daan; Maitland-Van der Zee, Anke-Hilse; Deneer, Vera

    2013-06-01

    The translation of evidence based medicine to a specific patient presents a considerable challenge. We present by means of the examples nortriptyline, tramadol, clopidogrel, coumarins, abacavir and antipsychotics the discrepancy between available pharmacogenetic information and its implementation in daily clinical practice. Literature review. A mechanism based approach may be helpful to personalize medicine for the individual patient to which pharmacogenetics may contribute significantly. The lack of consistency in what we accept in bioequivalence and in pharmacogenetics of drug metabolising enzymes is discussed and illustrated with the example of nortriptyline. The impact of pharmacogenetics on examples like tramadol, clopidogrel, coumarins and abacavir is described. Also the present status of the polymorphisms of 5-HT2A and C receptors in antipsychotic-induced weight gain is presented as a pharmacodynamic example with until now a greater distance to clinical implementation. The contribution of pharmacogenetics to tailor-made pharmacotherapy, which especially might be of value for patients deviating from the average, has not yet reached the position it seems to deserve.

  1. Pharmacogenetic analysis of the effects of polymorphisms in APOE, IDE and IL1B on a ketone body based therapeutic on cognition in mild to moderate Alzheimer's disease; a randomized, double-blind, placebo-controlled study

    Directory of Open Access Journals (Sweden)

    Poirier Judes

    2011-10-01

    Full Text Available Abstract Background To examine the effect of genetic variation in APOE, IDE and IL1B on the response to induced ketosis in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog in subjects with mild to moderate Alzheimer's disease (AD. Methods Genotype effects on ADAS-Cog scores from a randomized, double-blind, placebo-controlled study in mild to moderate AD were examined by an overall two way analysis of variance. In addition, interactions with the carriage status of the epsilon 4 allele of the APOE gene (APOE4 were examined. Results Significant differences in response to induced ketosis were found among non-carriers of putative gain-of-function polymorphisms in rs1143627 and rs16944 in the IL1B gene and among variants of the polymorphism rs2251101 in the IDE gene. Significant differences were found among non-carriers of the APOE4 gene, with notable improvement among the E3/E3 genotype group. Conclusions Variants in APOE, IL1B and IDE may influence the cognitive response to induced ketosis in patients with mild to moderate AD. Trial registration This trial was registered with ClinicalTrials.gov, registry number NCT00142805.

  2. Pharmacogenetic analysis of the effects of polymorphisms in APOE, IDE and IL1B on a ketone body based therapeutic on cognition in mild to moderate Alzheimer's disease; a randomized, double-blind, placebo-controlled study

    Science.gov (United States)

    2011-01-01

    Background To examine the effect of genetic variation in APOE, IDE and IL1B on the response to induced ketosis in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) in subjects with mild to moderate Alzheimer's disease (AD). Methods Genotype effects on ADAS-Cog scores from a randomized, double-blind, placebo-controlled study in mild to moderate AD were examined by an overall two way analysis of variance. In addition, interactions with the carriage status of the epsilon 4 allele of the APOE gene (APOE4) were examined. Results Significant differences in response to induced ketosis were found among non-carriers of putative gain-of-function polymorphisms in rs1143627 and rs16944 in the IL1B gene and among variants of the polymorphism rs2251101 in the IDE gene. Significant differences were found among non-carriers of the APOE4 gene, with notable improvement among the E3/E3 genotype group. Conclusions Variants in APOE, IL1B and IDE may influence the cognitive response to induced ketosis in patients with mild to moderate AD. Trial registration This trial was registered with ClinicalTrials.gov, registry number NCT00142805. PMID:21992747

  3. Pharmacogenetics of cerebrovascular metabolism modulators in dementia due to Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Fabricio Ferreira de Oliveira

    2015-03-01

    Full Text Available The aims of this study were to investigate risk factors for cognitive and functional decline among 193 patients with Alzheimer’s disease dementia (AD, and to conduct pharmacogenetic analysis on cerebrovascular metabolism modulators, taking into account APOE haplotypes and the genotypes of ACE, CETP, LDLR and the LXR-β gene. For all patients, later age at AD onset was the most important risk factor for faster cognitive and functional decline, while the late-life coronary heart disease risk was inversely related to cognitive decline only for carriers of APOE4+ haplotypes. Schooling was protective against cognitive decline only for women and carriers of APOE4+ haplotypes, while higher body mass index in late life was protective against cognitive decline only for men. Carriers of the APOE-ε4/ε4 haplotype had earlier AD onset, whereas genotypes of CETP and LDLR that had traditionally been associated with higher risk of AD were associated with later onset of dementia. Angiotensin-converting enzyme inhibitors caused a 50% reduction in Mini-Mental State Examination score changes, and had better disease-modifying properties than did centrally-acting angiotensin-converting enzyme inhibitors alone. Angiotensin receptor blockers had genetically mediated effects that led to faster cognitive and functional decline, while patients with genetic tendencies towards faster cognitive and functional decline had maximum benefits when they used lipophilic statins, and vice versa.

  4. Pharmacogenetics of neurological and psychiatric diseases at older age: has the time come?

    Science.gov (United States)

    Lozupone, Madia; Panza, Francesco; Stella, Eleonora; La Montagna, Maddalena; Bisceglia, Paola; Miscio, Giuseppe; Galizia, Ilaria; Daniele, Antonio; di Mauro, Lazzaro; Bellomo, Antonello; Logroscino, Giancarlo; Greco, Antonio; Seripa, Davide

    2017-03-01

    In recent years, a number of pharmacological approaches for treating neuropsychiatric conditions at older age have proven to be inadequate. The resulting increased prevalence of therapeutic failures (TF) and a worsening of clinical symptoms often linked to adverse reactions (ADRs), are perhaps among the major causes of the increasing rate of hospitalizations and institutionalizations observed in these patients. Areas covered: This review underlines the importance of pharmacogenetic data to fingerprint the pharmacological treatment of neuropsychiatric late-life conditions throughout the analysis of metabolizing enzymes and transporters of psychotropic drugs, mainly those of the cytochrome P450 (CYP) family. Pharmacodynamic response measures as treatment effects mediated through targets (i.e., receptors in the brain) may also contribute to this image. Expert opinion: CYP genetics is the basis of a continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice with advancing age. Furthermore, other specific polymorphic genes influence drug response through differential effects of their functional genetic variants. The known genotypes associated with an altered metabolizer status and drug transporters may help clinical decision-making to avoid concomitant treatments, reduce therapeutic attempts and increase drug safety in neuropsychiatric conditions in older age, after controlling for other clinical variables.

  5. Cholinesterase inhibitors in Alzheimer's disease and Lewy body spectrum disorders: the emerging pharmacogenetic story

    Directory of Open Access Journals (Sweden)

    Lam Benjamin

    2009-12-01

    Full Text Available Abstract This review provides an update on the current state of pharmacogenetic research in the treatment of Alzheimer's disease (AD and Lewy body disease (LBD as it pertains to the use of cholinesterase inhibitors (ChEI. AD and LBD are first reviewed from clinical and pathophysiological perspectives. This is followed by a discussion of ChEIs used in the symptomatic treatment of these conditions, focusing on their unique and overlapping pharmacokinetic and pharmacodynamic profiles, which can be used to identify candidate genes for pharmacogenetics studies. The literature published to date is then reviewed and limitations are discussed. This is followed by a discussion of potential endophenotypes which may help to refine future pharmacogenetic studies of response and adverse effects to ChEIs.

  6. Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers.

    Science.gov (United States)

    Dunnenberger, Henry M; Crews, Kristine R; Hoffman, James M; Caudle, Kelly E; Broeckel, Ulrich; Howard, Scott C; Hunkler, Robert J; Klein, Teri E; Evans, William E; Relling, Mary V

    2015-01-01

    Although the field of pharmacogenetics has existed for decades, practioners have been slow to implement pharmacogenetic testing in clinical care. Numerous publications describe the barriers to clinical implementation of pharmacogenetics. Recently, several freely available resources have been developed to help address these barriers. In this review, we discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of patients. Array-based preemptive testing includes a large number of relevant pharmacogenes that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to be available prior to any prescribing decision so that genomic variation may be considered as an inherent patient characteristic in the planning of therapy. This review describes the common elements among programs that have implemented preemptive genotyping and highlights key processes for implementation, including clinical decision support.

  7. Preemptive Clinical Pharmacogenetics Implementation: Current programs in five United States medical centers

    Science.gov (United States)

    Dunnenberger, Henry M.; Crews, Kristine R.; Hoffman, James M.; Caudle, Kelly E.; Broeckel, Ulrich; Howard, Scott C.; Hunkler, Robert J.; Klein, Teri E.; Evans, William E.; Relling, Mary V.

    2015-01-01

    Although the field of pharmacogenetics has existed for decades, the implementation of, pharmacogenetic testing in clinical care has been slow. There are numerous publications, describing the barriers to clinical implementation of pharmacogenetics. Recently, several freely, available resources have been developed to help address these barriers. In this review we, discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of, patients. Array-based preemptive testing includes a large number of relevant pharmacogenes, that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to, be available prior to any prescribing decision so that genomic variation may be considered as, an inherent patient characteristic in the planning of therapy. This review describes the common, elements among programs that have implemented preemptive genotyping and highlights key, processes for implementation, including clinical decision support. PMID:25292429

  8. Pharmacogenetics: has the time come for pharmacists to embrace and implement the science?

    Science.gov (United States)

    Beier, Manju T; Panchapagesan, Madhumitha; Carman, Ladd E

    2013-11-01

    Pharmacogenetics--the study of interindividual differences in medication response as a result of genetic variations--has emerged as a potentially useful tool for individualizing medication regimens for patients. Genetic variations can affect drug disposition inseveral ways, from modifying receptor sensitivities to impacting drug metabolism. Over the last several years, the Food and Drug Administration has been steadily including pharmacogenetic information in drug labeling for several commonly prescribed drugs. Several organizations are attempting to provide evidence-based guidelines for widespread implementation and interpretation. Pharmacists, armed with knowledge of drug metabolism pathways and drug-gene interactions, are uniquely positioned to play an active role in the education, provision, and clinical implementation of pharmacogenetics.

  9. Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy.

    Science.gov (United States)

    Mei, Lin; Ontiveros, Evelena P; Griffiths, Elizabeth A; Thompson, James E; Wang, Eunice S; Wetzler, Meir

    2015-07-01

    Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20-40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including l-asparaginase, glucocorticoids, 6-mercaptopurine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Molecular actions and clinical pharmacogenetics of lithium therapy

    Science.gov (United States)

    Can, Adem; Schulze, Thomas G.; Gould, Todd D.

    2014-01-01

    Mood disorders, including bipolar disorder and depression, are relatively common human diseases for which pharmacological treatment options are often not optimal. Among existing pharmacological agents and mood stabilizers used for the treatment of mood disorders, lithium has a unique clinical profile. Lithium has efficacy in the treatment of bipolar disorder generally, and in particular mania, while also being useful in the adjunct treatment of refractory depression. In addition to antimanic and adjunct antidepressant efficacy, lithium is also proven effective in the reduction of suicide and suicidal behaviors. However, only a subset of patients manifests beneficial responses to lithium therapy and the underlying genetic factors of response are not exactly known. Here we discuss preclinical research suggesting mechanisms likely to underlie lithium’s therapeutic actions including direct targets inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) among others, as well as indirect actions including modulation of neurotrophic and neurotransmitter systems and circadian function. We follow with a discussion of current knowledge related to the pharmacogenetic underpinnings of effective lithium therapy in patients within this context. Progress in elucidation of genetic factors that may be involved in human response to lithium pharmacology has been slow, and there is still limited conclusive evidence for the role of a particular genetic factor. However, the development of new approaches such as genome-wide association studies (GWAS), and increased use of genetic testing and improved identification of mood disorder patients sub-groups will lead to improved elucidation of relevant genetic factors in the future. PMID:24534415

  11. Pharmacogenetics and breast cancer management: current status and perspectives.

    Science.gov (United States)

    Ciccolini, Joseph; Fanciullino, Raphaelle; Serdjebi, Cindy; Milano, Gérard

    2015-05-01

    Breast cancer has benefited from a number of innovative therapeutics over the last decade. Cytotoxics, hormone therapy, targeted therapies and biologics can now be given to ensure optimal management of patients. As life expectancy of breast cancer patients has been significantly stretched and that several lines of treatment are now made available, determining the best drug or drug combinations to be primarily given and the best dosing and scheduling for each patient is critical for ensuring an optimal toxicity/efficacy balance. Defining patient's characteristics at the tumor level (pharmacogenomics) and the constitutional level (pharmacogenetics) is a rising trend in oncology. This review covers the latest strategies based upon the search of relevant biomarkers for efficacy, resistance and toxicity to be undertaken at the bedside to shift towards precision medicine in breast cancer patients. In the expanding era of bioguided medicine, identifying relevant and clinically validated biomarkers from the plethora of published material remains an uneasy task. Sorting the variety of genetic and molecular markers that have been investigated over the last decade on their level of evidence and addressing the issue of drug exposure should help to improve the management of breast cancer therapy.

  12. Undetected Toxicity Risk in Pharmacogenetic Testing for Dihydropyrimidine Dehydrogenase

    Directory of Open Access Journals (Sweden)

    Felicia Stefania Falvella

    2015-04-01

    Full Text Available Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD, a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T, fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C, conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.

  13. Pharmacogenetics of immunosuppressants: State of the art and clinical implementation - recommendations from the French National Network of Pharmacogenetics (RNPGx).

    Science.gov (United States)

    Woillard, Jean-Baptiste; Chouchana, Laurent; Picard, Nicolas; Loriot, Marie-Anne

    2017-04-01

    Therapeutic drug monitoring is already widely used for immunosuppressive drugs due to their narrow therapeutic index. This article summarizes evidence reported in the literature regarding the pharmacogenetics of (i) immunosuppressive drugs used in transplantation and (ii) azathioprine used in chronic inflammatory bowel disease. The conditions of use of currently available major pharmacogenetic tests are detailed and recommendations are provided based on a scale established by the RNPGx scoring tests as "essential", "advisable" and "potentially useful". Other applications for which the level of evidence is still debated are also discussed. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  14. Introducing Pharmacogenetics and Personalized Medicine via a Weblog

    Directory of Open Access Journals (Sweden)

    Kaitlin Bova

    2014-01-01

    Full Text Available Objectives: To evaluate a weblog (blog-based course introducing pharmacogenetics (PGt and personalized medicine (PM relative to freshmen pharmacy students' knowledge base. Methods: Incoming freshmen pharmacy students were invited by email to enroll in a one semester-hour, elective, on-line blog-based course entitled "Personal Genome Evaluation". The course was offered during the students' first semester in college. A topic list related to PGt and PM was developed by a group of faculty with topics being presented via the blog once or twice weekly through week 14 of the 15 week semester. A pre-course and post-course survey was sent to the students to compare their knowledge base relative to general information, drug response related to PGt, and PM. Results: Fifty-one freshmen pharmacy students enrolled in the course and completed the pre-course survey and 49 of the 51 students completed the post-course survey. There was an increase in the students' general, PGt and PM knowledge base as evidenced by a statistically significant higher number of correct responses for 17 of 21 questions on the post-course survey as compared to the pre-course survey. Notably, following the course, students had an increased knowledge base relative to "genetic privacy", drug dosing based on metabolizer phenotype, and the breadth of PM, among other specific points. Conclusions: The study indicated that introducing PGt and PM via a blog format was feasible, increasing the students' knowledge of these emerging areas. The blog format is easily transferable and can be adopted by colleges/schools to introduce PGt and PM.   Type: Case Study

  15. OX1 and OX2 orexin/hypocretin receptor pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Miles Douglas Thompson

    2014-05-01

    Full Text Available Orexin/hypocretin peptide mutations are rare in humans. Even though human narcolepsy is associated with orexin deficiency, this is only extremely rarely due to mutations in the gene coding prepro-orexin, the precursor for both orexin peptides. In contrast, coding and non-coding variants of the OX1 and OX2 orexin receptors have been identified in many human populations; sometimes, these have been associated with disease phenotype, although most confer a relatively low risk. In most cases, these studies have been based on a candidate gene hypothesis that predicts involvement of orexins in the relevant pathophysiological processes. In the current review, the known human OX1/HCRTR1 and OX2/HCRTR2 genetic variants/polymorphisms as well as studies concerning their involvement in disorders such as narcolepsy, excessive daytime sleepiness, cluster headache, polydipsia-hyponatremia in schizophrenia, and affective disorders are presented. In most cases, the functional cellular or pharmacological correlates of orexin variants have not been investigated  with the exception of the possible impact of an amino acid 10 Pro/Ser variant of OX2 on orexin potency  leaving conclusions on the nature of the receptor variant effects speculative. Nevertheless, we present perspectives that could shape the basis for further studies. The pharmacology and other properties of the orexin receptor variants are discussed in the context of GPCR signaling. Since orexinergic therapeutics are emerging, the impact of receptor variants on the affinity or potency of ligands deserves consideration. This perspective (pharmacogenetics is also discussed in the review.

  16. Added value of pharmacogenetic testing in predicting statin response: Results from the REGRESS trial

    NARCIS (Netherlands)

    Van Der Baan, F.H.; Knol, M.J.; Maitland-Van Der Zee, A.H.; Regieli, J.J.; Van Iperen, E.P.A.; Egberts, A.C.G.; Klungel, O.H.; Grobbee, D.E.; Jukema, J.W.

    2013-01-01

    It was investigated whether pharmacogenetic factors, both as single polymorphism and as gene-gene interactions, have an added value over non-genetic factors in predicting statin response. Five common polymorphisms were selected in apolipoprotein E, angiotensin-converting enzyme, hepatic lipase and

  17. Asthma pharmacogenetics and the development of genetic profiles for personalized medicine

    Directory of Open Access Journals (Sweden)

    Ortega VE

    2015-01-01

    Full Text Available Victor E Ortega, Deborah A Meyers, Eugene R Bleecker Center for Genomics and Personalized Medicine Research, Pulmonary Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA Abstract: Human genetics research will be critical to the development of genetic profiles for personalized or precision medicine in asthma. Genetic profiles will consist of gene variants that predict individual disease susceptibility and risk for progression, predict which pharmacologic therapies will result in a maximal therapeutic benefit, and predict whether a therapy will result in an adverse response and should be avoided in a given individual. Pharmacogenetic studies of the glucocorticoid, leukotriene, and β2-adrenergic receptor pathways have focused on candidate genes within these pathways and, in addition to a small number of genome-wide association studies, have identified genetic loci associated with therapeutic responsiveness. This review summarizes these pharmacogenetic discoveries and the future of genetic profiles for personalized medicine in asthma. The benefit of a personalized, tailored approach to health care delivery is needed in the development of expensive biologic drugs directed at a specific biologic pathway. Prior pharmacogenetic discoveries, in combination with additional variants identified in future studies, will form the basis for future genetic profiles for personalized tailored approaches to maximize therapeutic benefit for an individual asthmatic while minimizing the risk for adverse events. Keywords: asthma, pharmacogenetics, response heterogeneity, single nucleotide polymorphism, genome-wide association study

  18. Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics

    NARCIS (Netherlands)

    Becquemont, Laurent; Alfirevic, Ana; Amstutz, Ursula; Brauch, Hiltrud; Jacqz-Aigrain, Evelyne; Laurent-Puig, Pierre; Molina, Miguel A.; Niemi, Mikko; Schwab, Matthias; Somogyi, Andrew A.; Thervet, Eric; Maitland-van der Zee, Anke-Hilse; van Kuilenburg, André B. P.; van Schaik, Ron H. N.; Verstuyft, Céline; Wadelius, Mia; Daly, Ann K.

    2011-01-01

    The present article summarizes the discussions of the 3rd European Science Foundation University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We

  19. Genome-wide pharmacogenetics of antidepressant response in the GENDEP project

    DEFF Research Database (Denmark)

    Uher, Rudolf; Perroud, Nader; Ng, Mandy Y.M.

    2010-01-01

    . A set of 72 a priori-selected candidate genes did not show pharmacogenetic associations above a chance level, but an association with response to escitalopram was detected in the interleukin-6 gene, which is a close homologue of IL11. Conclusions: While limited statistical power means that a number...

  20. The role of pharmacogenetics in the treatment of chronic hepatitis C infection.

    Science.gov (United States)

    Kawaguchi-Suzuki, Marina; Frye, Reginald F

    2014-02-01

    Hepatitis C virus (HCV) chronically infects 170 million people worldwide. Until recently, combination therapy with peginterferon-α (pegIFN) and ribavirin (RBV) has been the standard of care. However, for many patients, especially those infected with the most common HCV genotype 1 (HCV-1), this treatment has resulted in unsatisfactory treatment response rates. Many clinical factors, including pharmacogenetics, influence the treatment response rate. Genetic variation in the interleukin 28B (IL28B) gene is the major determinant of treatment response, a finding that has been replicated in multiple independent cohorts. This review focuses on the association between pharmacogenetics and conventional pegIFN/RBV therapy in patients infected with HCV non-genotype 1; patients reinfected with HCV after liver transplantation; and patients coinfected with HCV and human immunodeficiency virus. We also review the pharmacogenetic data for boceprevir and telaprevir triple therapy in patients with HCV-1 infection, as well as viral genomic polymorphisms and genetic variants that may protect against anemia. Pharmacogenetic information offers a personalized medicine approach to help clinicians and patients make better informed decisions to maximize response and minimize toxicity for the treatment of chronic HCV infection. © 2013 Pharmacotherapy Publications, Inc.

  1. APPLICATIONS OF PHARMACOGENETIC TESTING FOR PERSONALIZATION OF THERAPY WITH ORAL ANTICOAGULANTS IN RUSSIA

    Directory of Open Access Journals (Sweden)

    D. A. Sychev

    2013-01-01

    Full Text Available The clinical significance of the patient genetic characteristics in the individual pharmacological response to oral anticoagulants is considered. Possible tactics of warfarin dosing and new oral anticoagulants choice on the basis of pharmacogenetic testing as well as indications for this approach in clinical practice are discussed. It should increase efficacy and safety of anticoagulant therapy.

  2. Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update.

    Science.gov (United States)

    Sriretnakumar, Venuja; Huang, Eric; Müller, Daniel J

    2015-01-01

    Clozapine (CLZ) is the most effective treatment for treatment-resistant schizophrenia (SCZ) patients, with potential added benefits of reduction in suicide risk and aggression. However, CLZ is also mainly underused due to its high risk for the potentially lethal side-effect of agranulocytosis as well as weight gain and related metabolic dysregulation. Pharmacogenetics promises to enable the prediction of patient treatment response and risk of adverse effects based on patients' genetics, paving the way toward individualized treatment. This article reviews pharmacogenetics studies of CLZ response and side-effects with a focus on articles from January 2012 to February 2015, as an update to the previous reviews. Pharmacokinetic genes explored primarily include CYP1A2, while pharmacodynamic genes consisted of traditional pharmacogenetic targets such as brain-derived neurotrophic factor as well novel mitochondrial genes, NDUFS-1 and translocator protein. Pharmacogenetics is a promising avenue for individualized medication of CLZ in SCZ, with several consistently replicated gene variants predicting CLZ response and side-effects. However, a large proportion of studies have yielded mixed results. Large-scale Genome-wide association studies (e.g., CRESTAR) and targeted gene studies with standardized designs (response measurements, treatment durations, plasma level monitoring) are required for further progress toward clinical translation. Additionally, in order to improve study quality, we recommend accounting for important confounders, including polypharmacy, baseline measurements, treatment duration, gender, and age at onset.

  3. Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden

    NARCIS (Netherlands)

    Verhoef, T. I.; Redekop, W. K.; Langenskiold, S.; Kamali, F.; Wadelius, M.; Burnside, G.; Maitland-van der Zee, A.-H.; Hughes, D. A.; Pirmohamed, M.

    2016-01-01

    We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per

  4. Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature.

    Directory of Open Access Journals (Sweden)

    Elizabeth J J Berm

    Full Text Available Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx tests it is important to assess whether they provide good value for money. This review provides an update of the literature.A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies' overall quality was assessed with the Quality of Health Economic Studies (QHES instrument.We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost-utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated favorable cost-effectiveness. Majority of evaluations did not provide information regarding the intrinsic value of the PGx test. There were considerable differences in the costs for PGx testing. Reporting of the direction and magnitude of bias on the cost-effectiveness estimates as well as motivation for the chosen economic model and perspective were frequently missing.Application of PGx tests was mostly found to be a cost-effective or cost-saving strategy. We found that only the minority of recent pharmacoeconomic evaluations assessed the intrinsic value of the PGx tests. There was an increase in the number of studies and in the reporting of quality associated characteristics. To improve future evaluations, scenario analysis including a broad range of PGx tests costs and equal costs of comparator drugs to assess the intrinsic value of the PGx tests, are recommended. In addition, robust clinical evidence regarding PGx tests' efficacy remains of utmost importance.

  5. Development of COS-SNP and HRM markers for high-throughput and reliable haplotype-based detection of Lr14a in durum wheat (Triticum durum Desf.)

    Czech Academy of Sciences Publication Activity Database

    Terracciano, I.; Maccaferri, M.; Bassi, F.; Mantovani, P.; Šimková, Hana; Doležel, Jaroslav; Tuberosa, R.

    2013-01-01

    Roč. 126, č. 4 (2013), s. 1077-1101 ISSN 0040-5752 Institutional research plan: CEZ:AV0Z50380511 Keywords : LEAF RUST RESISTANCE * RESOLUTION MELTING ANALYSIS * GENETIC-LINKAGE MAP Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.507, year: 2013

  6. Development of COS-SNP and HRM markers for high-throughput and reliable haplotype-based detection of Lr14a in durum wheat (Triticum durum Desf.).

    Science.gov (United States)

    Terracciano, Irma; Maccaferri, Marco; Bassi, Filippo; Mantovani, Paola; Sanguineti, Maria C; Salvi, Silvio; Simková, Hana; Doležel, Jaroslav; Massi, Andrea; Ammar, Karim; Kolmer, James; Tuberosa, Roberto

    2013-04-01

    Leaf rust (Puccinia triticina Eriks. & Henn.) is a major disease affecting durum wheat production. The Lr14a-resistant gene present in the durum wheat cv. Creso and its derivative cv. Colosseo is one of the best characterized leaf-rust resistance sources deployed in durum wheat breeding. Lr14a has been mapped close to the simple sequence repeat markers gwm146, gwm344 and wmc10 in the distal portion of the chromosome arm 7BL, a gene-dense region. The objectives of this study were: (1) to enrich the Lr14a region with single nucleotide polymorphisms (SNPs) and high-resolution melting (HRM)-based markers developed from conserved ortholog set (COS) genes and from sequenced Diversity Array Technology (DArT(®)) markers; (2) to further investigate the gene content and colinearity of this region with the Brachypodium and rice genomes. Ten new COS-SNP and five HRM markers were mapped within an 8.0 cM interval spanning Lr14a. Two HRM markers pinpointed the locus in an interval of HRM designed for agarose gel electrophoresis/KASPar(®) assays and high-resolution melting analysis, respectively, as well as the double-marker combinations ubw14/ubw18, ubw14/ubw35 and wPt-4038-HRM-ubw35 will be useful for germplasm haplotyping and for molecular-assisted breeding.

  7. Association between SLC19A1 Gene Polymorphism and High Dose Methotrexate Toxicity in Childhood Acute Lymphoblastic Leukaemia and Non Hodgkin Malignant Lymphoma: Introducing a Haplotype based Approach

    Science.gov (United States)

    Kotnik, Barbara Faganel; Jazbec, Janez; Grabar, Petra Bohanec; Rodriguez-Antona, Cristina

    2017-01-01

    Abstract Background We investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX) related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL) and non Hodgkin malignant lymphoma (NHML). Patients and methods Eighty-eight children and adolescents with ALL/NHML were investigated for the influence of SLC 19A1 single nucleotide polymorphisms (SNPs) and haplotypes on HD-MTX induced toxicities. Results Patients with rs2838958 TT genotype had higher probability for mucositis development as compared to carriers of at least one rs2838958 C allele (OR 0.226 (0.071–0.725), p < 0.009). Haplotype TGTTCCG (H4) statistically significantly reduced the risk for the occurrence of adverse events during treatment with HD-MTX (OR 0.143 (0.023–0.852), p = 0.030). Conclusions SLC 19A1 SNP and haplotype analysis could provide additional information in a personalized HD-MTX therapy for children with ALL/NHML in order to achieve better treatment outcome. However further studies are needed to validate the results. PMID:29333125

  8. [Use of pharmacogenetic testing to prevent adverse drug reactions during statin therapy].

    Science.gov (United States)

    Rumyantsev, N A; Kukes, V G; Kazakov, R E; Rumyantsev, A A; Sychev, D A

    The number of patients receiving statins increases every year and due to the fact that they should take statins during their lives, the problem of their safety use comes to the forefront. The paper analyzes the safety of using the medications of this group and discusses the diagnosis of myopathies induced by statins and the occurrence of immune-mediated statin myopathies. It considers a personalized approach to prescribing statins, analyzes Russian and foreign experience in using pharmacogenetics to reduce the risk of myopathies, publishes the results of the authors' experience in clinically introducing pharmacogenetic testing at hospitals, and analyzes the long-term results of determining the polymorphism of the SLCO1B1 gene for the prediction of the risk of adverse events when using statins and estimating patient compliance to prescribed treatment.

  9. Pharmacogenetics Informed Decision Making in Adolescent Psychiatric Treatment: A Clinical Case Report

    Directory of Open Access Journals (Sweden)

    Teri Smith

    2015-02-01

    Full Text Available Advances made in genetic testing and tools applied to pharmacogenetics are increasingly being used to inform clinicians in fields such as oncology, hematology, diabetes (endocrinology, cardiology and expanding into psychiatry by examining the influences of genetics on drug efficacy and metabolism. We present a clinical case example of an adolescent male with anxiety, attention deficit hyperactivity disorder (ADHD and autism spectrum disorder who did not tolerate numerous medications and dosages over several years in attempts to manage his symptoms. Pharmacogenetics testing was performed and DNA results on this individual elucidated the potential pitfalls in medication use because of specific pharmacodynamic and pharmacokinetic differences specifically involving polymorphisms of genes in the cytochrome p450 enzyme system. Future studies and reports are needed to further illustrate and determine the type of individualized medicine approach required to treat individuals based on their specific gene patterns. Growing evidence supports this biological approach for standard of care in psychiatry.

  10. Using local multiplicity to improve effect estimation from a hypothesis-generating pharmacogenetics study.

    Science.gov (United States)

    Zou, W; Ouyang, H

    2016-02-01

    We propose a multiple estimation adjustment (MEA) method to correct effect overestimation due to selection bias from a hypothesis-generating study (HGS) in pharmacogenetics. MEA uses a hierarchical Bayesian approach to model individual effect estimates from maximal likelihood estimation (MLE) in a region jointly and shrinks them toward the regional effect. Unlike many methods that model a fixed selection scheme, MEA capitalizes on local multiplicity independent of selection. We compared mean square errors (MSEs) in simulated HGSs from naive MLE, MEA and a conditional likelihood adjustment (CLA) method that model threshold selection bias. We observed that MEA effectively reduced MSE from MLE on null effects with or without selection, and had a clear advantage over CLA on extreme MLE estimates from null effects under lenient threshold selection in small samples, which are common among 'top' associations from a pharmacogenetics HGS.

  11. Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

    Science.gov (United States)

    Campbell, Jared M; Bateman, Emma; Peters, Micah Dj; Bowen, Joanne M; Keefe, Dorothy M; Stephenson, Matthew D

    2016-03-01

    Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps.

  12. Pharmacogenetics in clinical practice: how far have we come and where are we going?

    Science.gov (United States)

    Johnson, Julie A

    2013-01-01

    Recent years have seen great advances in our understanding of genetic contributors to drug response. Drug discovery and development around targeted genetic (somatic) mutations has led to a number of new drugs with genetic indications, particularly for the treatment of cancers. Our knowledge of genetic contributors to variable drug response for existing drugs has also expanded dramatically, such that the evidence now supports clinical use of genetic data to guide treatment in some situations, and across a variety of therapeutic areas. Clinical implementation of pharmacogenetics has seen substantial growth in recent years and groups are working to identify the barriers and best practices for pharmacogenetic-guided treatment. The advances and challenges in these areas are described and predictions about future use of genetics in drug therapy are discussed. PMID:23651030

  13. Exploring a Laboratory Model of Pharmacogenetics as Applied to Clinical Decision Making

    Directory of Open Access Journals (Sweden)

    Angela Smith, PharmD Candidate

    2013-01-01

    Full Text Available Objective: To evaluate a pilot of a laboratory model for relating pharmacogenetics to clinical decision making. Case Study: This pilot was undertaken and evaluated to help determine if a pharmacogenetics laboratory should be included in the core Doctor of Pharmacy curriculum. The placement of the laboratory exercise in the curriculum was determined by identifying the point in the curriculum where the students had been introduced to the chemistry of deoxyribonucleic acid (DNA as well as instructed on the chemistry of genetic variation. The laboratory included cytochrome P450 2C19 genotyping relative to the *2 variant. Twenty-four students served as the pilot group. Students provided buccal swabs as the source of DNA. Students stabilized the samples and were then provided instructions related to sample preparation, polymerase chain reaction, and gel electrophoresis. The results were reported as images of gels. Students used a reference gel image to compare their results to. Students then applied a dosing algorithm to make a “clinical decision” relative to clopidogrel use. Students were offered a post laboratory survey regarding attitudes toward the laboratory. Twenty-four students completed the laboratory with genotyping results being provided for 22 students (91.7%. Sixteen students were wild-type (*1/*1, while six students were heterozygous (*1/*2. Twenty-three students (96% completed the post laboratory survey. All 23 agreed (6, 26.1% or strongly agreed (17, 73.9% that the laboratory “had relevance and value in the pharmacy curriculum”. Conclusion: The post pilot study survey exploring a laboratory model for pharmacogenetics related to clinical decision making indicated that such a laboratory would be viewed positively by students. This model may be adopted by colleges to expand pharmacogenetics education.

  14. Exploring a Laboratory Model of Pharmacogenetics as Applied to Clinical Decision Making

    Directory of Open Access Journals (Sweden)

    David F. Kisor

    2013-01-01

    Full Text Available Objective: To evaluate a pilot of a laboratory model for relating pharmacogenetics to clinical decision making. Case Study: This pilot was undertaken and evaluated to help determine if a pharmacogenetics laboratory should be included in the core Doctor of Pharmacy curriculum. The placement of the laboratory exercise in the curriculum was determined by identifying the point in the curriculum where the students had been introduced to the chemistry of deoxyribonucleic acid (DNA as well as instructed on the chemistry of genetic variation. The laboratory included cytochrome P450 2C19 genotyping relative to the *2 variant. Twenty-four students served as the pilot group. Students provided buccal swabs as the source of DNA. Students stabilized the samples and were then provided instructions related to sample preparation, polymerase chain reaction, and gel electrophoresis. The results were reported as images of gels. Students used a reference gel image to compare their results to. Students then applied a dosing algorithm to make a "clinical decision" relative to clopidogrel use. Students were offered a post laboratory survey regarding attitudes toward the laboratory. Twenty-four students completed the laboratory with genotyping results being provided for 22 students (91.7%. Sixteen students were wild-type (*1/*1, while six students were heterozygous (*1/*2. Twenty-three students (96% completed the post laboratory survey. All 23 agreed (6, 26.1% or strongly agreed (17, 73.9% that the laboratory "had relevance and value in the pharmacy curriculum" Conclusion: The post pilot study survey exploring a laboratory model for pharmacogenetics related to clinical decision making indicated that such a laboratory would be viewed positively by students. This model may be adopted by colleges to expand pharmacogenetics education.   Type: Case Study

  15. Gender-specific genetic determinants of blood pressure and organ weight: pharmacogenetic approach

    Czech Academy of Sciences Publication Activity Database

    Ueno, T.; Tremblay, J.; Kuneš, Jaroslav; Zicha, Josef; Dobešová, Zdenka; Pausova, Z.; Deng, A. Y.; Sun, Y.; Jacob, H. J.; Hamet, P.

    2003-01-01

    Roč. 52, č. 6 (2003), s. 689-700 ISSN 0862-8408 R&D Projects: GA MŠk LN00A069; GA AV ČR IAA7011711; GA ČR GA305/03/0769 Institutional research plan: CEZ:AV0Z5011922 Keywords : Prague hypertriglyceridemic rat * quantitative trait loci ů hypertension * pharmacogenetics Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 0.939, year: 2003

  16. DNA cards: determinants of DNA yield and quality in collecting genetic samples for pharmacogenetic studies.

    Science.gov (United States)

    Mas, Sergi; Crescenti, Anna; Gassó, Patricia; Vidal-Taboada, Jose M; Lafuente, Amalia

    2007-08-01

    As pharmacogenetic studies frequently require establishment of DNA banks containing large cohorts with multi-centric designs, inexpensive methods for collecting and storing high-quality DNA are needed. The aims of this study were two-fold: to compare the amount and quality of DNA obtained from two different DNA cards (IsoCode Cards or FTA Classic Cards, Whatman plc, Brentford, Middlesex, UK); and to evaluate the effects of time and storage temperature, as well as the influence of anticoagulant ethylenediaminetetraacetic acid on the DNA elution procedure. The samples were genotyped by several methods typically used in pharmacogenetic studies: multiplex PCR, PCR-restriction fragment length polymorphism, single nucleotide primer extension, and allelic discrimination assay. In addition, they were amplified by whole genome amplification to increase genomic DNA mass. Time, storage temperature and ethylenediaminetetraacetic acid had no significant effects on either DNA card. This study reveals the importance of drying blood spots prior to isolation to avoid haemoglobin interference. Moreover, our results demonstrate that re-isolation protocols could be applied to increase the amount of DNA recovered. The samples analysed were accurately genotyped with all the methods examined herein. In conclusion, our study shows that both DNA cards, IsoCode Cards and FTA Classic Cards, facilitate genetic and pharmacogenetic testing for routine clinical practice.

  17. Importance of pharmacogenetics in the treatment of children with attention deficit hyperactive disorder: a case report.

    Science.gov (United States)

    Tan-Kam, Teerarat; Suthisisang, Chutamanee; Pavasuthipaisit, Chosita; Limsila, Penkhae; Puangpetch, Apichaya; Sukasem, Chonlaphat

    2013-01-01

    This case report highlights the importance of pharmacogenetic testing in the treatment of attention deficit hyperactive disorder (ADHD). A 6-year-old boy diagnosed with ADHD was prescribed methylphenidate 5 mg twice daily (7 am and noon) and the family was compliant with administration of this medication. On the first day of treatment, the patient had an adverse reaction, becoming disobedient, more mischievous, erratic, resistant to discipline, would not go to sleep until midnight, and had a poor appetite. The All-In-One PGX (All-In-One Pharmacogenetics for Antipsychotics test for CYP2D6, CYP2C19, and CYP2C9) was performed using microarray-based and real-time polymerase chain reaction techniques. The genotype of our patient was identified to be CYP2D6*2/*10, with isoforms of the enzyme consistent with a predicted cytochrome P450 2D6 intermediate metabolizer phenotype. Consequently, the physician adjusted the methylphenidate dose to 2.5 mg once daily in the morning. At this dosage, the patient had a good response without any further adverse reactions. Pharmacogenetic testing should be included in the management plan for ADHD. In this case, cooperation between the medical team and the patients' relatives was key to successful treatment.

  18. Haplotype-based stratification of Huntington's disease.

    Science.gov (United States)

    Chao, Michael J; Gillis, Tammy; Atwal, Ranjit S; Mysore, Jayalakshmi Srinidhi; Arjomand, Jamshid; Harold, Denise; Holmans, Peter; Jones, Lesley; Orth, Michael; Myers, Richard H; Kwak, Seung; Wheeler, Vanessa C; MacDonald, Marcy E; Gusella, James F; Lee, Jong-Min

    2017-11-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes. We have used the large collection of 4078 heterozygous HD subjects analyzed in our recent genome-wide association study of HD age at onset to estimate the frequency of these haplotypes in European subjects, finding that common genetic variation at HTT can distinguish the normal and CAG-expanded chromosomes for more than 95% of European HD individuals. As a resource for the HD research community, we have also determined the haplotypes present in a series of publicly available HD subject-derived fibroblasts, induced pluripotent cells, and embryonic stem cells in order to facilitate efforts to develop inclusive methods of allele-specific HTT silencing applicable to most HD patients. Our data providing genetic guidance for therapeutic gene-based targeting will significantly contribute to the developments of rational treatments and implementation of precision medicine in HD.

  19. Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

    LENUS (Irish Health Repository)

    Trompet, Stella

    2011-10-06

    Abstract Background The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER\\/PHASE project and second show that the PROSPER\\/PHASE study can be used to study pharmacogenetics in the elderly. Methods The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer\\'s instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification. Results Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE\\/APOC1; LDLR; FADS2\\/FEN1; HMGCR; PSRC1\\/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results. Conclusion With the GWAS in the PROSPER\\/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof

  20. Anticoagulation Endpoints with Clinical Implementation of Warfarin Pharmacogenetic Dosing in a Real-World Setting – A Proposal for a New Pharmacogenetic Dosing Approach

    Science.gov (United States)

    Arwood, Meghan J.; Deng, Jiexin; Drozda, Katarzyna; Pugach, Oksana; Nutescu, Edith A.; Schmidt, Stephan; Duarte, Julio D.; Cavallari, Larisa H.

    2016-01-01

    Achieving therapeutic anticoagulation efficiently with warfarin is important to reduce thrombotic and bleeding risks and is influenced by genotype. Utilizing data from a diverse population of 257 patients who received VKORC1 and CYP2C9 genotype-guided warfarin dosing, we aimed to examine genotype-associated differences in anticoagulation endpoints and derive a novel pharmacogenetic nomogram to more optimally dose warfarin. We observed significant differences across patients with 0, 1, or ≥2 reduced-function VKORC1 or CYP2C9 alleles, respectively, in time to achieve therapeutic international normalized ratio (INR) (7.8±5.8, 7.2±4.7, and 5.4±4.6 days, P=0.0004) and mean percentage of time in therapeutic range in the first 28 days (22.2, 27.8, and 32.2%, P=0.0127) with use of existing pharmacogenetic algorithms. These data suggest that more aggressive dosing is necessary for patients with 0 to 1 VKORC1/CYP2C9 variants to more efficiently achieve therapeutic anticoagulation. Herein, we provide a novel kinetic/pharmacodynamic-derived dosing nomogram optimized for a heterogeneous patient population. PMID:28032893

  1. Pharmacogenetics of efficacy and safety of HCV treatment in HCV-HIV coinfected patients: significant associations with IL28B and SOCS3 gene variants.

    Directory of Open Access Journals (Sweden)

    Francesc Vidal

    Full Text Available This was a safety and efficacy pharmacogenetic study of a previously performed randomized trial which compared the effectiveness of treatment of hepatitis C virus infection with pegylated interferon alpha (pegIFNα 2a vs. 2b, both with ribavirin, for 48 weeks, in HCV-HIV coinfected patients.The study groups were made of 99 patients (efficacy pharmacogenetic substudy and of 114 patients (safety pharmacogenetic substudy. Polymorphisms in the following candidate genes IL28B, IL6, IL10, TNFα, IFNγ, CCL5, MxA, OAS1, SOCS3, CTLA4 and ITPA were assessed. Genotyping was carried out using Sequenom iPLEX-Gold, a single-base extension polymerase chain reaction. Efficacy end-points assessed were: rapid, early and sustained virological response (RVR, EVR and SVR, respectively. Safety end-points assessed were: anemia, neutropenia, thrombocytopenia, flu-like syndrome, gastrointestinal disturbances and depression. Chi square test, Student's T test, Mann-Whitney U test and logistic regression were used for statistic analyses.As efficacy is concerned, IL28B and CTLA4 gene polymorphisms were associated with RVR (p<0.05 for both comparisons. Nevertheless, only polymorphism in the IL28B gene was associated with SVR (p = 0.004. In the multivariate analysis, the only gene independently associated with SVR was IL28B (OR 2.61, 95%CI 1.2-5.6, p = 0.01. With respect to safety, there were no significant associations between flu-like syndrome or depression and the genetic variants studied. Gastrointestinal disturbances were associated with ITPA gene polymorphism (p = 0.04. Anemia was associated with OAS1 and CTLA4 gene polymorphisms (p = 0.049 and p = 0.045, respectively, neutropenia and thromobocytopenia were associated with SOCS3 gene polymorphism (p = 0.02 and p = 0.002, respectively. In the multivariate analysis, the associations of the SOCS3 gene polymorphism with neutropenia (OR 0.26, 95%CI 0.09-0.75, p = 0.01 and thrombocytopenia (OR

  2. Pharmacogenetic & pharmacokinetic biomarker for efavirenz based ARV and rifampicin based anti-TB drug induced liver injury in TB-HIV infected patients.

    Directory of Open Access Journals (Sweden)

    Getnet Yimer

    Full Text Available BACKGROUND: Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI in HIV and tuberculosis (TB co-infected patients. METHODS AND FINDINGS: Newly diagnosed treatment naïve TB-HIV co-infected patients (n = 353 were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001, higher plasma efavirenz level (p = 0.009, efavirenz/8-hydroxyefavirenz ratio (p = 0.036, baseline AST (p = 0.022, ALT (p = 0.014, lower hemoglobin (p = 0.008, and serum albumin (p = 0.007, NAT2 slow-acetylator genotype (p = 0.039 and ABCB1 3435TT genotype (p = 0.001. CONCLUSION: We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification

  3. Importance of pharmacogenetics in the treatment of children with attention deficit hyperactive disorder: a case report

    Directory of Open Access Journals (Sweden)

    Tan-kam T

    2013-01-01

    Full Text Available Teerarat Tan-kam,1 Chutamanee Suthisisang,2 Chosita Pavasuthipaisit,1 Penkhae Limsila,1 Apichaya Puangpetch,3 Chonlaphat Sukasem31Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public Health, 2Department of Pharmacology, Faculty of Pharmacy, Mahidol University, 3Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandAbstract: This case report highlights the importance of pharmacogenetic testing in the treatment of attention deficit hyperactive disorder (ADHD. A 6-year-old boy diagnosed with ADHD was prescribed methylphenidate 5 mg twice daily (7 am and noon and the family was compliant with administration of this medication. On the first day of treatment, the patient had an adverse reaction, becoming disobedient, more mischievous, erratic, resistant to discipline, would not go to sleep until midnight, and had a poor appetite. The All-In-One PGX (All-In-One Pharmacogenetics for Antipsychotics test for CYP2D6, CYP2C19, and CYP2C9 was performed using microarray-based and real-time polymerase chain reaction techniques. The genotype of our patient was identified to be CYP2D6*2/*10, with isoforms of the enzyme consistent with a predicted cytochrome P450 2D6 intermediate metabolizer phenotype. Consequently, the physician adjusted the methylphenidate dose to 2.5 mg once daily in the morning. At this dosage, the patient had a good response without any further adverse reactions. Pharmacogenetic testing should be included in the management plan for ADHD. In this case, cooperation between the medical team and the patients' relatives was key to successful treatment.Keywords: attention deficit hyperactive disorder, pharmacogenomics, CYP2D6, adverse drug reactions, dose adjustment, intermediate metabolizer

  4. Pharmacogenomics and pharmacogenetics for the intensive care unit: a narrative review.

    Science.gov (United States)

    MacKenzie, Meghan; Hall, Richard

    2017-01-01

    Knowledge of how alterations in pharmacogenomics and pharmacogenetics may affect drug therapy in the intensive care unit (ICU) has received little study. We review the clinically relevant application of pharmacogenetics and pharmacogenomics to drugs and conditions encountered in the ICU. We selected relevant literature to illustrate the important concepts contained within. Two main approaches have been used to identify genetic abnormalities - the candidate gene approach and the genome-wide approach. Genetic variability in response to drugs may occur as a result of alterations of drug-metabolizing (cytochrome P [CYP]) enzymes, receptors, and transport proteins leading to enhancement or delay in the therapeutic response. Of relevance to the ICU, genetic variation in CYP-450 isoenzymes results in altered effects of midazolam, fentanyl, morphine, codeine, phenytoin, clopidogrel, warfarin, carvedilol, metoprolol, HMG-CoA reductase inhibitors, calcineurin inhibitors, non-steroidal anti-inflammatory agents, proton pump inhibitors, and ondansetron. Changes in cholinesterase enzyme function may affect the disposition of succinylcholine, benzylisoquinoline muscle relaxants, remifentanil, and hydralazine. Genetic variation in transport proteins leads to differences in the response to opioids and clopidogrel. Polymorphisms in drug receptors result in altered effects of β-blockers, catecholamines, antipsychotic agents, and opioids. Genetic variation also contributes to the diversity and incidence of diseases and conditions such as sepsis, malignant hyperthermia, drug-induced hypersensitivity reactions, cardiac channelopathies, thromboembolic disease, and congestive heart failure. Application of pharmacogenetics and pharmacogenomics has seen improvements in drug therapy. Ongoing study and incorporation of these concepts into clinical decision making in the ICU has the potential to affect patient outcomes.

  5. Fulfilling the promise of personalized medicine? Systematic review and field synopsis of pharmacogenetic studies.

    Directory of Open Access Journals (Sweden)

    Michael V Holmes

    2009-12-01

    Full Text Available Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics.We conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research.Original research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTION CRITERIA: We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans.Study characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study.From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive. A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25 ratio 1. The majority of studies (81.8% were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40-222] with no trend to an increase over time, generated a high proportion (74.5% of nominally significant (por=4 studies, only 31 meta-analyses were identified. The majority (69.4% of end-points were continuous and likely surrogate rather than hard (binary clinical end-points.The high expectation but limited translation of pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research

  6. Does Pharmacogenetic Testing for CYP450 2D6 and 2C19 among Patients with Diagnoses within the Schizophrenic Spectrum Reduce Treatment Costs?

    DEFF Research Database (Denmark)

    Herbild, Louise; Andersen, Stig Ejdrup; Werge, Thomas

    2013-01-01

    The effect of pharmacogenetic testing for CYP450 2D6 and 2C19 on treatment costs have not yet been documented. This study used Danish patient registers to calculate health care costs of treating patients with diagnoses within the schizophrenic spectrum for one year with or without pharmacogenetic...... testing for polymorphisms in the genes for the CYP2D6 and CYP2C19 enzymes. In a randomized, controlled trial, stratified with respect to metabolizer genotype, 104 patients were assigned to treatment based on pharmacogenetic testing and 103 patients to treatment as usual. Random exclusion of extensive...

  7. Novel Use of Pharmacogenetic Testing in the Identification of CYP2C9 Polymorphisms Related to NSAID-Induced Gastropathy.

    Science.gov (United States)

    Gupta, Anita; Zheng, Lu; Ramanujam, Vendhan; Gallagher, John

    2015-05-01

    To illustrate the potential value of pharmacogenetic testing to identify patients at risk for nonsteroidal anti-inflammatory drug-induced gastropathy. Case report. We report a case encountered in an outpatient setting for pain management. We present a case of a patient treated with celecoxib who developed severe nonsteroidal anti-inflammatory drug-induced gastropathy. Suspecting a relation between this adverse event and altered drug metabolism, pharmacogenetic testing was performed to assess the role of the cytochrome P450 (CP450) enzyme profile. Pharmacogenetic testing revealed a relation between this adverse event and an allelic variant of cytochrome P450, CYP2C9, subsequently leading to discontinuation of the drug along with counseling to caution the patient to avoid the use of celecoxib and other drugs metabolized by the same enzyme. Although pharmacogenetic testing is not routinely used in clinical decision making, pain physicians must be aware of the potential benefits of this testing for managing patients with pain, and to improve drug efficacy and safety profile. Wiley Periodicals, Inc.

  8. Pharmacogenetics in cancer therapy - 8 years of experience at the Institute for Oncology and Radiology of Serbia.

    Science.gov (United States)

    Cavic, Milena; Krivokuca, Ana; Boljevic, Ivana; Brotto, Ksenija; Jovanovic, Katarina; Tanic, Miljana; Filipovic, Lana; Zec, Manja; Malisic, Emina; Jankovic, Radmila; Radulovic, Sinisa

    2016-01-01

    Pharmacogenetics is a study of possible mechanism by which an individual's response to drugs is genetically determined by variations in their DNA sequence. The aim of pharmacogenetics is to identify the optimal drug and dose for each individual based on their genetic constitution, i.e. to individualize drug treatment. This leads to achieving the maximal therapeutic response for each patient, while reducing adverse side effects of therapy and the cost of treatment. A centralized pharmacogenetics service was formed at the Institute for Oncology and Radiology of Serbia (IORS) with the aim to provide a personalized approach to cancer treatment of Serbian patients. Analyses of KRAS mutations in metastatic colorectal cancer, EGFR mutations in advanced non-small cell lung cancer, CYP2D6 polymorphism in breast cancer, DPD polymorphism in colorectal cancer and MTHFR polymorphism in osteosarcoma have been performed by real time polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). Mutation testing analyses were successful for 1694 KRAS samples and 1821 EGFR samples, while polymorphism testing was successful for 9 CYP2D6 samples, 65 DPD samples and 35 MTHFR samples. Pharmacogenetic methods presented in this paper provide cancer patients in Serbia the best possible choice of treatment at the moment.

  9. Cases of Adverse Reaction to Psychotropic Drugs and Possible Association with Pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Irina Piatkov

    2012-10-01

    Full Text Available Thousands of samples for pharmacogenetic tests have been analysed in our laboratory since its establishment. In this article we describe some of the most interesting cases of CYP poor metabolisers associated with adverse reactions to psychotropic drugs. Prevention of disease/illness, including Adverse Drug Reaction (ADR, is an aim of modern medicine. Scientific data supports the fact that evaluation of drug toxicology includes several factors, one of which is genetic variations in pharmacodynamics and pharmacokinetics of drug pathways. These variations are only a part of toxicity evaluation, however, even if it would help to prevent only a small percentage of patients from suffering adverse drug reactions, especially life threatening ADRs, pharmacogenetic testing should play a significant role in any modern psychopharmacologic practice. Medical practitioners should also consider the use of other medications or alternative dosing strategies for drugs in patients identified as altered metabolisers. This will promise not only better and safer treatments for patients, but also potentially lowering overall healthcare costs.

  10. Privacy in Pharmacogenetics: An End-to-End Case Study of Personalized Warfarin Dosing.

    Science.gov (United States)

    Fredrikson, Matthew; Lantz, Eric; Jha, Somesh; Lin, Simon; Page, David; Ristenpart, Thomas

    2014-08-01

    We initiate the study of privacy in pharmacogenetics, wherein machine learning models are used to guide medical treatments based on a patient's genotype and background. Performing an in-depth case study on privacy in personalized warfarin dosing, we show that suggested models carry privacy risks, in particular because attackers can perform what we call model inversion : an attacker, given the model and some demographic information about a patient, can predict the patient's genetic markers. As differential privacy (DP) is an oft-proposed solution for medical settings such as this, we evaluate its effectiveness for building private versions of pharmacogenetic models. We show that DP mechanisms prevent our model inversion attacks when the privacy budget is carefully selected . We go on to analyze the impact on utility by performing simulated clinical trials with DP dosing models. We find that for privacy budgets effective at preventing attacks, patients would be exposed to increased risk of stroke, bleeding events, and mortality . We conclude that current DP mechanisms do not simultaneously improve genomic privacy while retaining desirable clinical efficacy, highlighting the need for new mechanisms that should be evaluated in situ using the general methodology introduced by our work.

  11. Pharmacogenetics and pharmacogenomics in psoriasis treatment: current challenges and future prospects.

    Science.gov (United States)

    Sutherland, Alison; Power, Rebecca J; Rahman, Proton; O'Rielly, Darren D

    2016-08-01

    Topical, systemic, oral disease modifying, and biologic agents are part of the armamentarium to manage psoriatic disease. The choice of therapy depends upon disease severity, relevant co-morbidities and patient preference. There is great variability in patient response with these agents, and there is still no clear method of selecting the preferred therapeutic agent for efficacy or lack of adverse events. This article will review the pharmacogenetic and pharmacogenomic targets that are currently known with respect to psoriasis vulgaris, and the most frequent co-morbidity of psoriasis, psoriatic arthritis. Presently, no clinically actionable biomarker exists for any therapeutic agent used to treat psoriasis or psoriatic arthritis. The lack of validated outcome measures and conflicting results of open-label studies conducted may be attributed to a multitude of issues that confound discovery. Consequently, studies have been underpowered to identify genes or genetic variants worth translating to clinical practice. In order to achieve a pharmacogenetic/pharmacogenomic signature, improvements in study design of future investigations are required, including carefully designed prospective studies. It is imperative to combine known clinical, serological, and molecular markers with consistent outcomes and an adequate health economic evaluation before they can be adopted widely in clinical practice.

  12. Pharmacogenetics and Metabolism from Science to Implementation in Clinical Practice: The Example of Dihydropyrimidine Dehydrogenase.

    Science.gov (United States)

    Del Re, Marzia; Restante, Giuliana; Di Paolo, Antonello; Crucitta, Stefania; Rofi, Eleonora; Danesi, Romano

    2017-01-01

    Fluoropyrimidines are widely used in the treatment of solid tumors and remain the backbone of many combination chemotherapy regimens. Despite their clinical benefit, they are associated with frequent gastrointestinal and hematological toxicities, which often lead to treatment discontinuation. Fluoropyrimidines undergo complex anabolic and catabolic biotransformation. Enzymes involved in this pathway include dihydropyrimidine dehydrogenase (DPD), which breaks down 5-FU and its prodrugs. Candidate gene approaches have demonstrated associations between 5-FU treatment outcomes and germline polymorphisms in DPD. The aim of this review is to report and discuss the latest results on fluoropyrimidine pharmacogenetics. Literature from PubMed databases and bibliography from retrieved publications have been analyzed according to terms such DPD, DPYD, fluoropyrimdines, polymorphisms, toxicity, pharmacogenetics. To date, many sequence variations have been identified within DPYD gene, although the majority of these have no functional consequences on enzymatic activity. Nowadays, there is a general agreement on the clinical significance of the importance of DPD deficiency in patients who suffer from severe, life-threatening drug toxicity although preemptive testing is not applied to all patients. Considering the published literature, clinicians are strongly encouraged to consider testing for DPD poor metabolizer variants as a rational pre-treatment screening for patients candidate to a fluoropyrimidine-based regimens, in order to prevent toxicities and personalise treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia.

    Science.gov (United States)

    Maxwell, Whitney D; Ramsey, Laura B; Johnson, Samuel G; Moore, Kate G; Shtutman, Michael; Schoonover, John H; Kawaguchi-Suzuki, Marina

    2017-09-01

    Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes-based studies are available. We also summarize the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy. © 2017 Pharmacotherapy Publications, Inc.

  14. The Value of Evidence in the Decision-Making Process for Reimbursement of Pharmacogenetic Dosing of Warfarin.

    Science.gov (United States)

    Janzic, Andrej; Locatelli, Igor; Kos, Mitja

    2017-10-01

    After early clinical trials that evaluated pharmacogenetic (PG) algorithms, many healthcare payers were reluctant to cover this technology and, consequently, PG dosing of warfarin could not be translated into clinical practice. The aim of this study was to estimate the value of upgrading evidence relating to PG dosing of warfarin from the healthcare payer perspective. Randomized controlled trials (RCTs) that evaluated PG dosing of warfarin were identified through a systematic literature search, and their findings were combined by a cumulative meta-analysis. A health economic model was used to estimate economic outcomes and to calculate the expected value of perfect information (EVPI) as a measure of the value of clinical trials for decision makers. Nine RCTs were identified and included in our analysis. The estimated difference in the percentage of time in the therapeutic range was 5.6 percentage points in 2007, decreasing to 4.3 percentage points when all studies were included. At a reimbursement price of €160 per PG testing, the EVPI for the clinical benefit was estimated at €80 and €90 per patient in 2007 and 2014, respectively. A reduction in the price of PG testing to €40, which was observed in this period, resulted in an EVPI of €3 per patient. The estimated cumulative effect of PG dosing has remained similar since 2007, but additional evidence has contributed to a more precise estimation. While these variations should not affect the reimbursement decision, a large decline in the cost of PG testing in recent years calls for reconsideration.

  15. Verification of pharmacogenetics-based warfarin dosing algorithms in Han-Chinese patients undertaking mechanic heart valve replacement.

    Science.gov (United States)

    Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

    2014-01-01

    To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88-4.38 mg/day) than the low-dose range (pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement.

  16. Verification of Pharmacogenetics-Based Warfarin Dosing Algorithms in Han-Chinese Patients Undertaking Mechanic Heart Valve Replacement

    Science.gov (United States)

    Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

    2014-01-01

    Objective To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. Methods We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. Results A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88–4.38 mg/day) than the low-dose range (warfarin dose prediction and in the low-dose and the ideal-dose ranges. Conclusions All of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement. PMID:24728385

  17. Should pharmacogenetics be incorporated in major depression treatment? Economic evaluation in high- and middle-income European countries.

    Science.gov (United States)

    Olgiati, Paolo; Bajo, Emanuele; Bigelli, Marco; De Ronchi, Diana; Serretti, Alessandro

    2012-01-10

    The serotonin transporter 5-HTTLPR polymorphism moderates response to SSRIs and side-effect burden. The aim of this study is to quantify the cost-utility of incorporating 5-HTTLPR genotyping in drug treatment of major depressive disorder (MDD). We previously reported a theoretical model to simulate antidepressant treatment with citalopram or bupropion for 12 weeks. The drugs were alternatively selected according to an 'as usual' algorithm or based on response and tolerability predicted by 5-HTTLPR profile. Here we apply this model to conduct a cost-utility analysis in three European regions with high GDP (Euro A), middle GDP (Euro B) and middle-high GDP (Euro C). In addition we test a verification scenario in which citalopram+bupropion augmentation is administered to individuals with the least favorable 5-HTTLPR genotype. Treatment outcomes are remission and Quality Adjusted-Life Weeks (QALW). Cost data (international $, year 2009) are retrieved from the World Health Organization (WHO) and national official sources. In base-case scenario incremental cost-effectiveness ratio (ICER) values are $1147 (Euro A), $1185 (Euro B) and $1178 (Euro C). From cost-effectiveness acceptability curve (CEAC), the probability of having an ICER value below WHO recommended cost-utility threshold (3 GDP per capita=$1926) is >90% in high-income countries (Euro A). In middle- income regions, these probabilities are <30% (Euro B) and <55% (Euro C) respectively. All estimates are robust against variations in treatment parameters, but if genetic test cost decreases to $100, pharmacogenetic approach becomes cost-effective in middle-income countries (Euro B). This simulation using data from 27 European states suggests that choosing antidepressant treatment from the results of 5-HTTLPR might be a cost-effective solution in high income countries. Its feasibility in middle income countries needs further research. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. A pharmacogenetic study of CD4 recovery in response to HIV antiretroviral therapy in two South African population groups.

    Science.gov (United States)

    Parathyras, John; Gebhardt, Stefan; Hillermann-Rebello, Renate; Grobbelaar, Nelis; Venter, Mauritz; Warnich, Louise

    2009-05-01

    South Africa, like many other Southern African countries, has one of the highest HIV infection rates in the world and many individuals consequently receive antiretroviral therapy (ART). However, knowledge regarding (i) the prevalence of functional single nucleotide polymorphisms (SNPs) in pharmacologically relevant genes, and (ii) variance in pharmacotherapy both within and between different populations and ethnic groups is limited. The aim of this study was to determine whether selected polymorphisms in cytochrome P450 (CYP) genes (CYP2B6 and CYP3A4) and the multidrug-resistance 1 (ABCB1) gene underlie altered antiretroviral (ARV) drug response in two South African populations. DNA samples from 182 HIV-positive individuals of Mixed-Ancestry and Xhosa ethnicity on ART were genotyped for the A-392G SNP in CYP3A4, the G516T and A785G SNPs in CYP2B6, and the T-129C, C1236T, G2677T/A and C3435T SNPs in ABCB1. Univariate two-way analysis of variance (ANOVA) testing revealed no apparent effect of ethnicity on immune recovery (in terms of CD4-cell count) in response to ART. Univariate one-way ANOVA testing revealed a discernible effect of genotype on immune recovery in the cases of the T-129C (P=0.03) and G2677A (P<0.01) polymorphisms in the ABCB1 gene. This study serves as a basis for better understanding and possible prediction of pharmacogenetic risk profiles and drug response in individuals and ethnic groups in South Africa.

  19. The utility of pharmacogenetic testing to support the treatment of bipolar disorder

    Directory of Open Access Journals (Sweden)

    Ielmini M

    2018-03-01

    Full Text Available Marta Ielmini,1 Nicola Poloni,1 Ivano Caselli,1 Jordi Espadaler,2 Miquel Tuson,2 Alessandro Grecchi,3 Camilla Callegari1 1Department of Medicine and Surgery, Division of Psychiatry, University of Insubria, Varese, Italy; 2AB-BIOTICS S.A, R&D Unit, Sant Cugat del Valles, Barcelona, Spain; 3ASST Santi Paolo e Carlo Borromeo, Division of Psychiatry, Milan, Italy Background: Bipolar disorder (BD is a frequent cause of disability, health care costs, and risk of suicide. Pharmacogenetic tests (PGTs could help clinicians to identify those patients predisposed to the occurrence of adverse events (AEs improving the understanding of the correlation between genetic variants and drug response.Materials and methods: The study evaluated 30 patients affected by BD type I or II (according to Diagnostic and Statistical Manual of Mental Disorders, version 5 who underwent the PGT Neurofarmagen® (AB-BIOTICS SA, Barcelona, Spain between March 2016 and March 2017. The primary aim of this study was to identify if the treatment prescribed by the psychiatrists was consistent with the treatment suggested by the PGT at T0 (corresponding to the test report communication. As a secondary aim, we wanted to assess if clinicians had changed the treatment (in case of discordance at T1 (3-month follow-up visit according to the results of the PGT.Results: At T0, only 4 patients (13% had an optimal therapy in line with the PGT suggestions. At 3-month follow-up, 13 patients (40% had received a change of therapy consistent to the test, showing a significant statistical improvement in the Clinical Global Impression item Severity (CGI-S score over time compared to those not having changes consistent with the test. Regarding AEs, at baseline 9 out of 10 (90% of the patients who received a therapy modification according to the test presented AEs, and a significant within-group reduction was observed after 3 months (p = 0.031.Conclusion: Despite the small sample size, the study shows

  20. [Pharmacogenetics in anesthesia and intensive care medicine : Clinical and legal challenges exemplified by malignant hyperthermia].

    Science.gov (United States)

    Klingler, W; Pfenninger, E

    2016-05-01

    Pharmacotherapy is a key component of anesthesiology and intensive care medicine. The individual genetic profile influences not only the effect of pharmaceuticals but can also completely alter the mode of action. New technologies for genetic screening (e.g. next generation sequencing) and increasing knowledge of molecular pathways foster the disclosure of pharmacogenetic syndromes, which are classified as rare diseases. Taking into account the high genetic variability in humans and over 8000 known rare diseases, up to 20 % of the population may be affected. In summary, rare diseases are not rare. Most pharmacogenetic syndromes lead to a weakening or loss of pharmacological action. In contrast, malignant hyperthermia (MH), which is the most relevant pharmacogenetic syndrome for anesthesia, is characterized by a pharmacologically induced overactivation of calcium metabolism in skeletal muscle. Volatile anesthetic agents and succinylcholine trigger life-threatening hypermetabolic crises. Emergency treatment is based on inhibition of the calcium release channel of the sarcoplasmic reticulum by dantrolene. After an adverse pharmacological event patients must be informed and a clarification consultation must be carried out during which the hereditory character of MH is explained. The patient should be referred to a specialist MH center where a predisposition can be diagnosed by the functional in vitro contracture test from a muscle biopsy. Additional molecular genetic investigations can yield mutations in the genes for calcium-regulating proteins in skeletal muscle, e.g. ryanodine receptor 1 (RyR1) and calcium voltage-gated channel subunit alpha 1S (CACNA1S). Currently, an association to MH has only been shown for 35 mutations out of more than 400 known and probably hundreds of unknown genetic variations. Furthermore, MH predisposition is not excluded by negative mutation screening. For anesthesiological patient safety it is crucial to identify individuals at risk and

  1. Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients.

    Science.gov (United States)

    Ruzzo, A; Graziano, F; Galli, Fabio; Galli, Francesca; Rulli, E; Lonardi, S; Ronzoni, M; Massidda, B; Zagonel, V; Pella, N; Mucciarini, C; Labianca, R; Ionta, M T; Bagaloni, I; Veltri, E; Sozzi, P; Barni, S; Ricci, V; Foltran, L; Nicolini, M; Biondi, E; Bramati, A; Turci, D; Lazzarelli, S; Verusio, C; Bergamo, F; Sobrero, A; Frontini, L; Menghi, M; Magnani, M

    2017-10-24

    Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDRpharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

  2. Subjective response as a consideration in the pharmacogenetics of alcoholism treatment.

    Science.gov (United States)

    Roche, Daniel Jo; Ray, Lara A

    2015-01-01

    Currently available pharmacological treatments for alcoholism have modest efficacy and high individual variability in treatment outcomes, both of which have been partially attributed to genetic factors. One path to reducing the variability and improving the efficacy associated with these pharmacotherapies may be to identify overlapping genetic contributions to individual differences in both subjective responses to alcohol and alcoholism pharmacotherapy outcomes. As acute subjective response to alcohol is highly predictive of future alcohol related problems, identifying such shared genetic mechanisms may inform the development of personalized treatments that can effectively target converging pathophysiological mechanisms that convey risk for alcoholism. The focus of this review is to revisit the association between subjective response to alcohol and the etiology of alcoholism while also describing genetic contributions to this relationship, discuss potential pharmacogenetic approaches to target subjective response to alcohol in order to improve the treatment of alcoholism and examine conceptual and methodological issues associated with these topics, and outline future approaches to overcome these challenges.

  3. An RDF/OWL knowledge base for query answering and decision support in clinical pharmacogenetics.

    Science.gov (United States)

    Samwald, Matthias; Freimuth, Robert; Luciano, Joanne S; Lin, Simon; Powers, Robert L; Marshall, M Scott; Adlassnig, Klaus-Peter; Dumontier, Michel; Boyce, Richard D

    2013-01-01

    Genetic testing for personalizing pharmacotherapy is bound to become an important part of clinical routine. To address associated issues with data management and quality, we are creating a semantic knowledge base for clinical pharmacogenetics. The knowledge base is made up of three components: an expressive ontology formalized in the Web Ontology Language (OWL 2 DL), a Resource Description Framework (RDF) model for capturing detailed results of manual annotation of pharmacogenomic information in drug product labels, and an RDF conversion of relevant biomedical datasets. Our work goes beyond the state of the art in that it makes both automated reasoning as well as query answering as simple as possible, and the reasoning capabilities go beyond the capabilities of previously described ontologies.

  4. ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Barratt DT

    2012-04-01

    Full Text Available Daniel T Barratt1, Janet K Coller1, Richard Hallinan2, Andrew Byrne2, Jason M White1, David JR Foster3, Andrew A Somogyi1,41Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia; 2The Byrne Surgery, Specialist Drug and Alcohol Practice, Redfern, New South Wales; 3Division of Health Sciences, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia; 4Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, South Australia, AustraliaBackground: Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment.Methods: Opioid-dependent subjects (n = 119 maintained on methadone (15–300 mg/day were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T, as well as for the OPRM1 18A > G single nucleotide polymorphism. Subjects’ methadone doses and trough plasma (R-methadone concentrations (Ctrough were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype, and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype.Results: Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype had significantly lower doses (median ± standard

  5. The role of depression pharmacogenetic decision support tools in shared decision making.

    Science.gov (United States)

    Arandjelovic, Katarina; Eyre, Harris A; Lenze, Eric; Singh, Ajeet B; Berk, Michael; Bousman, Chad

    2017-10-29

    Patients discontinue antidepressant medications due to lack of knowledge, unrealistic expectations, and/or unacceptable side effects. Shared decision making (SDM) invites patients to play an active role in their treatment and may indirectly improve outcomes through enhanced engagement in care, adherence to treatment, and positive expectancy of medication outcomes. We believe decisional aids, such as pharmacogenetic decision support tools (PDSTs), facilitate SDM in the clinical setting. PDSTs may likewise predict drug tolerance and efficacy, and therefore adherence and effectiveness on an individual-patient level. There are several important ethical considerations to be navigated when integrating PDSTs into clinical practice. The field requires greater empirical research to demonstrate clinical utility, and the mechanisms thereof, as well as exploration of the ethical use of these technologies.

  6. Pharmacogenetics of ustekinumab in patients with moderate-to-severe plaque psoriasis.

    Science.gov (United States)

    Prieto-Pérez, Rocío; Llamas-Velasco, Mar; Cabaleiro, Teresa; Solano-López, Guillermo; Márquez, Beatriz; Román, Manuel; Ochoa, Dolores; Talegón, María; Daudén, Esteban; Abad-Santos, Francisco

    2017-01-01

    Aim/Materials & methods: Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with ustekinumab. We evaluated 121 polymorphisms to study a possible association between these SNPs and the response to ustekinumab (PASI75 at 4 months; n = 69). The adjusted results (false discovery rate) showed an association between five SNPs in TNFRSF1A, HTR2A, NFKBIA, ADAM33 and IL13 genes, and poor response to ustekinumab. Furthermore, six SNPs in CHUK, C17orf51, ZNF816A, STAT4, SLC22A4 and Corf72 genes were associated with better response to ustekinumab. However, there was no significant association between response to ustekinumab and SNPs in HLA-C as it has been recently described. Finally, a higher weight was obtained in nonresponders than responders (p = 0.018). Further studies would be necessary to be closer to personalized medicine.

  7. Automation of complex assays: pharmacogenetics of warfarin dosing.

    Science.gov (United States)

    Wu, Whei-Kuo; Hujsak, Paul G; Kureshy, Fareed

    2007-10-01

    AutoGenomics, Inc. (Carlsbad, CA, USA) have developed a multiplex microarray assay for genotyping both VKORC1 and CYP2C9 using the INFINITI(™) Analyzer. Multiple alleles in each DNA sample are analyzed by polymerase chain reaction amplification, followed by detection primer extension using the INFINITI Analyzer. The INFINITI Analyzer performs single-nucleotide polymorphism (SNP) analysis using universal oligonucleotides immobilized on the biochip. To genotype broader ethnic groups, genomic DNA from whole blood was tested for nine SNPs for VKORC1 and six for CYP2C9 genotypes. Information related to all 15 SNPs is needed to determine dosing of population of diverse ethnic origin. The INFINITI system provides genotyping information for same day dosing of warfarin.

  8. Genetics and Treatment Response in Parkinson's Disease: An Update on Pharmacogenetic Studies.

    Science.gov (United States)

    Politi, Cristina; Ciccacci, Cinzia; Novelli, Giuseppe; Borgiani, Paola

    2018-03-01

    Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopamine neurons of the central nervous system. The disease determines a significant disability due to a combination of motor symptoms such as bradykinesia, rigidity and rest tremor and non-motor symptoms such as sleep disorders, hallucinations, psychosis and compulsive behaviors. The current therapies consist in combination of drugs acting to control only the symptoms of the illness by the replacement of the dopamine lost. Although patients generally receive benefits from this symptomatic pharmacological management, they also show great variability in drug response in terms of both efficacy and adverse effects. Pharmacogenetic studies highlighted that genetic factors play a relevant influence in this drug response variability. In this review, we tried to give an overview of the recent progresses in the pharmacogenetics of PD, reporting the major genetic factors identified as involved in the response to drugs and highlighting the potential use of some of these genomic variants in the clinical practice. Many genes have been investigated and several associations have been reported especially with adverse drug reactions. However, only polymorphisms in few genes, including DRD2, COMT and SLC6A3, have been confirmed as associated in different populations and in large cohorts. The identification of genomic biomarkers involved in drug response variability represents an important step in PD treatment, opening the prospective of more personalized therapies in order to identify, for each person, the better therapy in terms of efficacy and toxicity and to improve the PD patients' quality of life.

  9. PG4KDS: a model for the clinical implementation of pre-emptive pharmacogenetics.

    Science.gov (United States)

    Hoffman, James M; Haidar, Cyrine E; Wilkinson, Mark R; Crews, Kristine R; Baker, Donald K; Kornegay, Nancy M; Yang, Wenjian; Pui, Ching-Hon; Reiss, Ulrike M; Gaur, Aditya H; Howard, Scott C; Evans, William E; Broeckel, Ulrich; Relling, Mary V

    2014-03-01

    Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Children's Research Hospital pre-emptively genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1,559 patients have been enrolled, and four gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high-risk drugs. Of the 1,016 patients with genotype test results available, 78% of them had at least one high-risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support-gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre-emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable. © 2014 Wiley Periodicals, Inc.

  10. Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

    Science.gov (United States)

    Campbell, Jared M; Bateman, Emma; Stephenson, Matthew D; Bowen, Joanne M; Keefe, Dorothy M; Peters, Micah D J

    2016-07-01

    Methotrexate chemotherapy is associated with various toxicities which can result in the interruption or discontinuation of treatment and a subsequently raised risk of relapse. This umbrella systematic review was conducted to synthesize the results of all existing systematic reviews that investigate the pharmacogenetics of methotrexate-induced toxicity, with the aim of developing a comprehensive reference for personalized medicine. Databases searched were PubMed, Embase, JBI Database of Systematic Reviews and Implementation Reports, DARE, and ProQuest. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool. Three systematic reviews on methotrexate-induced toxicity were included in the review. Meta-analyses were reported across Asian, Caucasian, pediatric and adult patients for the MTHFR C677T and A1298C polymorphisms. Toxicity outcomes included different forms of hematologic, ectodermal and hepatic toxicities. Results varied considerably depending on the patient groups and subgroups investigated in the different systematic reviews, as well as the genetic models utilized. However, significant associations were found between the MTHFR C677T allele and; hepatic toxicity, myelosuppression, oral mucositis, gastrointestinal toxicity, and skin toxicity. Additionally, limited evidence suggests that the MTHFR A1298C polymorphism may be associated with decreased risk of skin toxicity and leukopenia. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of methotrexate toxicity. The next step in making personalized medicine for methotrexate therapy a clinical reality is research on the effectiveness and cost-effectiveness of MTHFR genotype testing to enable the close monitoring of at-risk patients for the timely initiation of rescue therapies.

  11. Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases.

    Science.gov (United States)

    Giletti, Andrea; Vital, Marcelo; Lorenzo, Mariana; Cardozo, Patricia; Borelli, Gabriel; Gabus, Raúl; Martínez, Lem; Díaz, Lilian; Assar, Rodrigo; Rodriguez, María Noel; Esperón, Patricia

    2017-11-15

    Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. Genotype distribution and allele frequency were determined for SLC19A1 G 80 A, MTHFR C 677 T and A 1298 C, TYMS 28bp copy number variation, SLCO1B1 T 521 C, DHFR C -1610 G/T, DHFR C -680 A, DHFR A -317 G and DHFR 19bp indel. Multivariate analysis showed that DHFR -1610 G/T (OR=0.107, p=0.018) and MTHFR 677 T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR -1610 CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic.

    Science.gov (United States)

    Shaw, Paul B; Donovan, Jennifer L; Tran, Maichi T; Lemon, Stephenie C; Burgwinkle, Pamela; Gore, Joel

    2010-08-01

    The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199-1205, 2007), Gage et al. (J Clin Ther 84:326-331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753-764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R (2) from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as >or=2x or >or=2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin.

  13. ECOGENETICS AND PHARMACOGENETICS: THE IMPORTANCE OF GENETIC POLYMORPHISMS IN THE VARIABILITY OF ORGANISMS RESPONSE TO ENVIRONMENTAL FACTORS

    Directory of Open Access Journals (Sweden)

    Cristian Tudose

    2005-08-01

    protect confidentiality and privacy of individual genetic information may make such research infeasible. In the present paper we expose some general considerations about the importance of the borderline disciplines which are studying the cited aspects (ecogenetics, pharmacogenetics and pharmacogenomics, emphasising the importance of human populations genome polymorphisms affecting drug efficiency and producing adverse reactions; eventually we expose the most recent trends in pharmacogenomics related to the subject

  14. Warfarin Pharmacogenetics

    Science.gov (United States)

    Johnson, Julie A.; Cavallari, Larisa H.

    2014-01-01

    The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing. PMID:25282448

  15. The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study

    Science.gov (United States)

    Talarico, Anna; Fabbri, Matteo; Bertocco, Cesare; Vigliano, Marco; Moratelli, Stefano; Cuneo, Antonio; Serino, Maria Luisa; Avato, Francesco Maria

    2016-01-01

    Objectives Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3’-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis. Methods 133 OAT patients were recruited and assessed for warfarin/3’-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups Results In the whole OAT group both warfarin and 3’-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3’-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3’-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; pwarfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3’-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI

  16. Pharmacogenetics of hepatitis C: transition from interferon-based therapies to direct-acting antiviral agents

    Directory of Open Access Journals (Sweden)

    Kamal SM

    2014-06-01

    28B gene and natural clearance of HCV infection or after PEGylated interferon-alpha and ribavirin treatment with and without direct antiviral agents. This paper synthesizes the recent advances in the pharmacogenetics of HCV infection in the era of triple therapies.Keywords: hepatitis C virus, interleukin-28B polymorphisms, PEGylated interferon and ribavirin, direct-acting antiviral agents, pharmacogenetics, rational therapeutics

  17. Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women.

    Science.gov (United States)

    Mutagonda, Ritah F; Kamuhabwa, Appolinary A R; Minzi, Omary M S; Massawe, Siriel N; Asghar, Muhammad; Homann, Manijeh V; Färnert, Anna; Aklillu, Eleni

    2017-07-03

    Pregnancy has considerable effects on the pharmacokinetic properties of drugs used to treat uncomplicated Plasmodium falciparum malaria. The role of pharmacogenetic variation on anti-malarial drug disposition and efficacy during pregnancy is not well investigated. The study aimed to examine the effect of pharmacogenetics on lumefantrine (LF) pharmacokinetics and treatment outcome in pregnant women. Pregnant women with uncomplicated falciparum malaria were enrolled and treated with artemether-lumefantrine (ALu) at Mkuranga and Kisarawe district hospitals in Coast Region of Tanzania. Day-7 LF plasma concentration and genotyping forCYP2B6 (c.516G>T, c.983T>C), CYP3A4*1B, CYP3A5 (*3, *6, *7) and ABCB1 c.4036A4G were determined. Blood smear for parasite quantification by microscopy, and dried blood spot for parasite screening and genotyping using qPCR and nested PCR were collected at enrolment up to day 28 to differentiate between reinfection from recrudescence. Treatment response was recorded following the WHO protocol. In total, 92 pregnant women in their second and third trimester were included in the study and 424 samples were screened for presence of P. falciparum. Parasites were detected during the follow up period in 11 (12%) women between day 7 and 28 after treatment and PCR genotyping confirmed recrudescent infection in 7 (63.3%) women. The remaining four (36.4%) pregnant women had reinfection: one on day 14 and three on day 28. The overall PCR-corrected treatment failure rate was 9.0% (95% CI 4.4-17.4). Day 7 LF concentration was not significantly influenced by CYP2B6, CYP3A4*1B and ABCB1 c.4036A>G genotypes. Significant associations between CYP3A5 genotype and day 7 plasma LF concentrations was found, being higher in carriers of CYP3A5 defective variant alleles than CYP3A5*1/*1 genotype. No significant influence of CYP2B6, CYP3A5 and ABCB1 c.4036A>Genotypes on malaria treatment outcome were observed. However, CYP3A4*1B did affect malaria treatment outcome in

  18. DRD4 and DAT1 in ADHD: Functional neurobiology to pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Darko Turic

    2010-05-01

    Full Text Available Darko Turic1, James Swanson2, Edmund Sonuga-Barke1,31Institute for Disorders of Impulse and Attention, School of Psychology, University of Southampton, UK; 2Child Development Center, University of California, Irvine, California, US; 3Department of Experimental, Clinical and Health Psychology, Ghent University, BelgiumAbstract: Attention deficit/hyperactivity disorder (ADHD is a common and potentially very impairing neuropsychiatric disorder of childhood. Statistical genetic studies of twins have shown ADHD to be highly heritable, with the combination of genes and gene by environment interactions accounting for around 80% of phenotypic variance. The initial molecular genetic studies where candidates were selected because of the efficacy of dopaminergic compounds in the treatment of ADHD were remarkably successful and provided strong evidence for the role of DRD4 and DAT1 variants in the pathogenesis of ADHD. However, the recent application of noncandidate gene strategies (eg, genome-wide association scans has failed to identify additional genes with substantial genetic main effects, and the effects for DRD4 and DAT1 have not been replicated. This is the usual pattern observed for most other physical and mental disorders evaluated with current state-of-the-art methods. In this paper we discuss future strategies for genetic studies in ADHD, highlighting both the pitfalls and possible solutions relating to candidate gene studies, genome-wide studies, defining the phenotype, and statistical approaches.Keywords: dopamine, ADHD, pharmacogenetics, candidate gene

  19. Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity.

    Science.gov (United States)

    Jabir, Rafid Salim; Naidu, Rakesh; Annuar, Muhammad Azrif Bin Ahmad; Ho, Gwo Fuang; Munisamy, Murali; Stanslas, Johnson

    2012-12-01

    Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

  20. Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Maxwell, Rochelle R; Cole, Peter D

    2017-06-01

    The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

  1. Pharmacogenetics in diverse ethnic populations--implications for drug discovery and development.

    Science.gov (United States)

    McCarthy, Linda C; Davies, Kirstie J; Campbell, David A

    2002-07-01

    It is widely acknowledged that the vast quantities of data now publicly available as a result of the human genome initiative have the potential to revolutionize the pharmaceutical industry. More tangibly to the drug development business, the dawn of the pharmacogenetics era has the potential to impact not only the discovery of new medicines but also the safety and efficacy of pharmaceutical agents. Coincident with these scientific advances is the emergence of new markets for pharmaceutical agents. Japan, which represents the world's second biggest market, is a good example. With the ICH E5 agreement in 1998 and a rapid change in the drug registration process in Japan, there are increasing opportunities to improve access to more medicines in all parts of the world. However, it is increasingly clear that significant genetic variation still exists between populations, with a host of data on interethnic variation in drug metabolizing enzyme and drug transporter activity. Evidence suggesting that this genetic variation may play an important role in defining some of the interethnic variation in drug response to currently marketed compounds is reviewed here, and future possibilities of using such information to better streamline the drug development process are discussed.

  2. Pharmacogenetics of aldo-keto reductase 1C (AKR1C) enzymes.

    Science.gov (United States)

    Alshogran, Osama Y

    2017-10-01

    Genetic variation in metabolizing enzymes contributes to variable drug response and disease risk. Aldo-keto reductase type 1C (AKR1C) comprises a sub-family of reductase enzymes that play critical roles in the biotransformation of various drug substrates and endogenous compounds such as steroids. Several single nucleotide polymorphisms have been reported among AKR1C encoding genes, which may affect the functional expression of the enzymes. Areas covered: This review highlights and comprehensively discusses previous pharmacogenetic reports that have examined genetic variations in AKR1C and their association with disease development, drug disposition, and therapeutic outcomes. The article also provides information about the effect of AKR1C genetic variants on enzyme function in vitro. Expert opinion: The current evidence that links the effect of AKR1C gene polymorphisms to disease progression and development is inconsistent and needs further validation, despite of the tremendous knowledge available. Information about association of AKR1C genetic variants and drug efficacy, safety, and pharmacokinetics is limited, thus, future studies that advance our understanding about these relationships and their clinical relevance are needed. It is imperative to achieve consistent findings before the potential translation and adoption of AKR1C genetic variants in clinical practice.

  3. Clinical importance of pharmacogenetics in the treatment of hepatitis C virus infection.

    Science.gov (United States)

    Kamal, Adina Maria; MitruŢ, Paul; Kamal, Kamal Constantin; Tica, Oana Sorina; Niculescu, Mihaela; Alexandru, Dragoş Ovidiu; Tica, Andrei Adrian

    2016-01-01

    Globally, over 4% of the world population is affected by hepatitis C virus (HCV) infection. The current standard of care for hepatitis C infection is combination therapy with pegylated interferon and ribavirin for 48 weeks, which yield a sustained virological response in only a little over half of the patients with genotype 1 HCV. We investigated the clinical importance of pharmacogenetics in treatment efficacy and prediction of hematotoxicity. A total of 148 patients infected with HCV were enrolled. All patients were treated for a period of 48 weeks or less with pegylated interferon and ribavirin. Four genotypes were investigated: inosine triphosphatase (ITPA) rs1127354, C20orf194 rs6051702, interferon lambda (IFNL)3 rs8099917, IFNL3÷4 rs12979860 in the population from southwestern Romania. Genetic variants for rs129798660 and rs6051702 proved once more to represent an indisputable clinical tool for predicting sustained virological response (SVR) (69.23%, chi-square p=0.007846, ppharmacogenetics should play a constant role in treatment decisions for patients infected with hepatitis C virus.

  4. Psychiatry meets pharmacogenetics for the treatment of revolving door patients with psychiatric disorders.

    Science.gov (United States)

    Panza, Francesco; Lozupone, Madia; Stella, Eleonora; Lofano, Lucia; Gravina, Carolina; Urbano, Maria; Daniele, Antonio; Bellomo, Antonello; Logroscino, Giancarlo; Greco, Antonio; Seripa, Davide

    2016-12-01

    Therapeutic failures (TFs) and adverse drug reactions (ADRs), together with the recurring nature of the clinical course of psychiatric disorders, mainly bipolar disorders (BDs), strongly contributed to the prevalence and frequency of hospital readmissions observed in these patients. This is the revolving door (RD) condition, dramatically rising costs for the management of these patients in psychiatric settings. Areas covered: We searched in the medical literature until May 2016 to review the role of functional variants in the cytochrome P450 (CYP) 2D6 gene on observed ADRs and TFs in RD patients with BDs, conferring a different capacity to metabolize psychotropic drugs. Expert commentary: CYP2D6 functional polymorphisms might directly contributed to the prevalence and frequency of the RD condition, commonly observed in BD patients. Although several environmental and socio-demographic/diagnostic variables such as alcohol/drug abuse, and medication non-compliance accounted for a significant proportion of the ability to predict RD prevalence and frequency, the pharmacogenetics of CYP, particularly CYP2D6, may help to identify BD patients at risk for ADRs and TFs. These patients may be addressed towards alternative treatments, thus improving their quality of life, and reducing RD prevalence and frequency and the overall costs for their management.

  5. Orexin Receptor Multimerization versus Functional Interactions: Neuropharmacological Implications for Opioid and Cannabinoid Signalling and Pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Miles D. Thompson

    2017-10-01

    Full Text Available Orexins/hypocretins are neuropeptides formed by proteolytic cleavage of a precursor peptide, which are produced by neurons found in the lateral hypothalamus. The G protein-coupled receptors (GPCRs for these ligands, the OX1 and OX2 orexin receptors, are more widely expressed throughout the central nervous system. The orexin/hypocretin system has been implicated in many pathways, and its dysregulation is under investigation in a number of diseases. Disorders in which orexinergic mechanisms are being investigated include narcolepsy, idiopathic sleep disorders, cluster headache and migraine. Human narcolepsy has been associated with orexin deficiency; however, it has only rarely been attributed to mutations in the gene encoding the precursor peptide. While gene variations within the canine OX2 gene hcrtr2 have been directly linked with narcolepsy, the majority of human orexin receptor variants are weakly associated with diseases (the idiopathic sleep disorders, cluster headache and polydipsia-hyponatremia in schizophrenia or are of potential pharmacogenetic significance. Evidence for functional and/or heterodimerization between wild-type variant orexin receptors and opioid and cannabinoid receptors is discussed in the context of its relevance to depression and epilepsy.

  6. Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia.

    Science.gov (United States)

    Beam, Teresa A; Loudermilk, Emily F; Kisor, David F

    2017-02-01

    A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca 2+ homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace. Copyright © 2017 the American Physiological Society.

  7. Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine.

    Science.gov (United States)

    El Rouby, Nihal; Lima, John J; Johnson, Julie A

    2018-04-01

    Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism. Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy. Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs.

  8. Pharmacogenetic Variation at CYP2D6, CYP2C9, and CYP2C19: Population Genetic and Forensic Aspects

    OpenAIRE

    Sistonen, Johanna

    2008-01-01

    Pharmacogenetics deals with genetically determined variation in drug response. In this context, three phase I drug-metabolizing enzymes, CYP2D6, CYP2C9, and CYP2C19, have a central role, affecting the metabolism of about 20-30% of clinically used drugs. Since genes coding for these enzymes in human populations exhibit high genetic polymorphism, they are of major pharmacogenetic importance. The aims of this study were to develop new genotyping methods for CYP2D6, CYP2C9, and CYP2C19 that would...

  9. Influence of pre-hydration and pharmacogenetics on plasma methotrexate concentration and renal dysfunction following high-dose methotrexate therapy.

    Science.gov (United States)

    Yanagimachi, Masakatsu; Goto, Hiroaki; Kaneko, Tetsuji; Naruto, Takuya; Sasaki, Koji; Takeuchi, Masanobu; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Kajiwara, Ryosuke; Fujii, Hisaki; Tanaka, Fumiko; Goto, Shoko; Takahashi, Hiroyuki; Mori, Masaaki; Kai, Sumio; Yokota, Shumpei

    2013-12-01

    High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (p < 0.001, OR 6.40, 95 % CI 2.39-17.16) and renal dysfunction (p = 0.013, OR 3.15, 95 % CI 1.27-7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (p = 0.009, OR 5.54, 95 % CI 1.54-19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism on prolonged high MTX concentration. We reconfirmed the importance of adequate pre-hydration before HD-MTX to prevent prolonged high MTX concentration and MTX-related renal dysfunction.

  10. Pharmacogenetic testing prior to carbamazepine treatment of epilepsy: patients' and physicians' preferences for testing and service delivery.

    Science.gov (United States)

    Powell, Graham; Holmes, Emily A F; Plumpton, Catrin O; Ring, Adele; Baker, Gus A; Jacoby, Ann; Pirmohamed, Munir; Marson, Anthony G; Hughes, Dyfrig A

    2015-11-01

    Pharmacogenetic studies have identified the presence of the HLA-A*31:01 allele as a predictor of cutaneous adverse drugs reactions (ADRs) to carbamazepine. This study aimed to ascertain the preferences of patients and clinicians to inform carbamazepine pharmacogenetic testing services. Attributes of importance to people with epilepsy and neurologists were identified through interviews and from published sources. Discrete choice experiments (DCEs) were conducted in 82 people with epilepsy and 83 neurologists. Random-effects logit regression models were used to determine the importance of the attributes and direction of effect. In the patient DCE, all attributes (seizure remission, reduction in seizure frequency, memory problems, skin rash and rare, severe ADRs) were significant. The estimated utility of testing was greater, at 0.52 (95% CI 0.19, 1.00) than not testing at 0.33 (95% CI -0.07, 0.81). In the physician DCE, cost, inclusion in the British National Formulary, coverage, negative predictive value (NPV) and positive predictive value (PPV) were significant. Marginal rates of substitution indicated that neurologists were willing to pay £5.87 for a 1 percentage point increase in NPV and £3.99 for a 1 percentage point increase in PPV. The inclusion of both patients' and clinicians' perspectives represents an important contribution to the understanding of preferences towards pharmacogenetic testing prior to initiating carbamazepine. Both groups identified different attributes but had generally consistent preferences. Patients' acceptance of a decrease in treatment benefit for a reduced chance of severe ADRs adds support for the implementation of HLA-A*31:01 testing in routine practice. © 2015 The British Pharmacological Society.

  11. Potential of a Pharmacogenetic-Guided Algorithm to Predict Optimal Warfarin Dosing in a High-Risk Hispanic Patient

    Directory of Open Access Journals (Sweden)

    Dagmar F. Hernandez-Suarez MD

    2016-12-01

    Full Text Available Deep abdominal vein thrombosis is extremely rare among thrombotic events secondary to the use of contraceptives. A case to illustrate the clinical utility of ethno-specific pharmacogenetic testing in warfarin management of a Hispanic patient is reported. A 37-year-old Hispanic Puerto Rican, non-gravid female with past medical history of abnormal uterine bleeding on hormonal contraceptive therapy was evaluated for abdominal pain. Physical exam was remarkable for unspecific diffuse abdominal tenderness, and general initial laboratory results—including coagulation parameters—were unremarkable. A contrast-enhanced computed tomography showed a massive thrombosis of the main portal, splenic, and superior mesenteric veins. On admission the patient was started on oral anticoagulation therapy with warfarin at 5 mg/day and low-molecular-weight heparin. The prediction of an effective warfarin dose of 7.5 mg/day, estimated by using a recently developed pharmacogenetic-guided algorithm for Caribbean Hispanics, coincided with the actual patient’s warfarin dose to reach the international normalized ratio target. We speculate that the slow rise in patient’s international normalized ratio observed on the initiation of warfarin therapy, the resulting high risk for thromboembolic events, and the required warfarin dose of 7.5 mg/day are attributable in some part to the presence of the NQO1 *2 (g.559C>T, p.P187S polymorphism, which seems to be significantly associated with resistance to warfarin in Hispanics. By adding genotyping results of this novel variant, the predictive model can inform clinicians better about the optimal warfarin dose in Caribbean Hispanics. The results highlight the potential for pharmacogenetic testing of warfarin to improve patient care.

  12. Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines.

    Directory of Open Access Journals (Sweden)

    Barbara A Jennings

    Full Text Available The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic and drug metabolising (pharmacokinetic enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479 and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively. There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively. We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.

  13. Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice.

    Science.gov (United States)

    Matic, Maja; de Wildt, Saskia N; Tibboel, Dick; van Schaik, Ron H N

    2017-07-01

    The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 ( CYP2D6 ), cytochrome P450 family 3 subfamily A member 4 ( CYP3A4 ), cytochrome P450 family 3 subfamily A member 5 ( CYP3A5 ), UDP glucuronosyltransferase family 2 member B7 ( UGT2B7 ), ATP binding cassette subfamily B member 1 ( ABCB1 ), ATP binding cassette subfamily C member 3 ( ABCC3 ), solute carrier family 22 member 1 ( SLC22A1 ), opioid receptor kappa 1 ( OPRM1 ), catechol- O -methyltransferase ( COMT ), and potassium voltage-gated channel subfamily J member 6 ( KCNJ6 ). Treatment guidelines based on genotype are already available only for CYP2D6 . The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context. © 2016

  14. Optimizing trial design in pharmacogenetics research: comparing a fixed parallel group, group sequential, and adaptive selection design on sample size requirements.

    Science.gov (United States)

    Boessen, Ruud; van der Baan, Frederieke; Groenwold, Rolf; Egberts, Antoine; Klungel, Olaf; Grobbee, Diederick; Knol, Mirjam; Roes, Kit

    2013-01-01

    Two-stage clinical trial designs may be efficient in pharmacogenetics research when there is some but inconclusive evidence of effect modification by a genomic marker. Two-stage designs allow to stop early for efficacy or futility and can offer the additional opportunity to enrich the study population to a specific patient subgroup after an interim analysis. This study compared sample size requirements for fixed parallel group, group sequential, and adaptive selection designs with equal overall power and control of the family-wise type I error rate. The designs were evaluated across scenarios that defined the effect sizes in the marker positive and marker negative subgroups and the prevalence of marker positive patients in the overall study population. Effect sizes were chosen to reflect realistic planning scenarios, where at least some effect is present in the marker negative subgroup. In addition, scenarios were considered in which the assumed 'true' subgroup effects (i.e., the postulated effects) differed from those hypothesized at the planning stage. As expected, both two-stage designs generally required fewer patients than a fixed parallel group design, and the advantage increased as the difference between subgroups increased. The adaptive selection design added little further reduction in sample size, as compared with the group sequential design, when the postulated effect sizes were equal to those hypothesized at the planning stage. However, when the postulated effects deviated strongly in favor of enrichment, the comparative advantage of the adaptive selection design increased, which precisely reflects the adaptive nature of the design. Copyright © 2013 John Wiley & Sons, Ltd.

  15. Pharmacogenetic effects of angiotensin-converting enzyme inhibitors over age-related urea and creatinine variations in patients with dementia due to Alzheimer disease.

    Science.gov (United States)

    Ferreira de Oliveira, Fabricio; Berretta, Juliana Marília; Suchi Chen, Elizabeth; Cardoso Smith, Marilia; Ferreira Bertolucci, Paulo Henrique

    2016-06-30

    Renal function declines according to age and vascular risk factors, whereas few data are available regarding genetically-mediated effects of anti-hypertensives over renal function. To estimate urea and creatinine variations in dementia due to Alzheimer disease (AD) by way of a pharmacogenetic analysis of the anti-hypertensive effects of angiotensin-converting enzyme inhibitors (ACEis). Consecutive outpatients older than 60 years-old with AD and no history of kidney transplant or dialytic therapy were recruited for prospective correlations regarding variations in fasting blood levels of urea and creatinine in one year, considering ACE genotypes of rs1800764 and rs4291 and their respective haplotypes, and treatment with ACEis along with blood pressure variations. For 190 patients, 152 had arterial hypertension, and 122 used ACEis. Minor allele frequencies were 0.492 for rs1800764-C and 0.337 for rs4291-T, both in Hardy-Weinberg equilibrium. There were no overall significant yearly variations in levels of urea and creatinine, but their concurrent variations were positively correlated (ρ <0.0001). Each A allele of rs4291 led to an yearly urea increase of 3,074 mg/dL, and an yearly creatinine increase of 0.044 mg/dL, while the use of ACEis was protective regarding creatinine variations. The use of ACEis was also protective for carriers of rs1800764-CT/rs4291-AA, while carriers of rs1800764-CT/rs4291-AT had steeper reductions in creatinine levels, particularly when they were treated with ACEis. Effects of ACEis over creatinine variations are genetically mediated and independent of blood pressure variations in older people with AD.

  16. The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study.

    Science.gov (United States)

    Gemmati, Donato; Burini, Francesco; Talarico, Anna; Fabbri, Matteo; Bertocco, Cesare; Vigliano, Marco; Moratelli, Stefano; Cuneo, Antonio; Serino, Maria Luisa; Avato, Francesco Maria; Tisato, Veronica; Gaudio, Rosa Maria

    2016-01-01

    Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3'-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis. 133 OAT patients were recruited and assessed for warfarin/3'-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups. In the whole OAT group both warfarin and 3'-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3'-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3'-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; ppharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI) inversely related to the number variant alleles. Our results overall suggest that 3'-hydroxywarfarin monitoring could be of great advantage in INR monitoring respect to classical warfarin assessment showing significant contribution also in multivariate analysis. Therefore, additional active metabolites should be recognized and investigated as novel useful indicators.

  17. Optimizing clopidogrel dose response: a new clinical algorithm comprising CYP2C19 pharmacogenetics and drug interactions

    Directory of Open Access Journals (Sweden)

    Saab YB

    2015-09-01

    Full Text Available Yolande B Saab,1 Rony Zeenny,2 Wijdan H Ramadan2 1School of Pharmacy, Pharmaceutical Sciences Department, 2School of Pharmacy, Pharmacy Practice Department, Lebanese American University, Byblos, Lebanon Purpose: Response to clopidogrel varies widely with nonresponse rates ranging from 4% to 30%. A reduced function of the gene variant of the CYP2C19 has been associated with lower drug metabolite levels, and hence diminished platelet inhibition. Drugs that alter CYP2C19 activity may also mimic genetic variants. The aim of the study is to investigate the cumulative effect of CYP2C19 gene polymorphisms and drug interactions that affects clopidogrel dosing, and apply it into a new clinical-pharmacogenetic algorithm that can be used by clinicians in optimizing clopidogrel-based treatment. Method: Clopidogrel dose optimization was analyzed based on two main parameters that affect clopidogrel metabolite area under the curve: different CYP2C19 genotypes and concomitant drug intake. Clopidogrel adjusted dose was computed based on area under the curve ratios for different CYP2C19 genotypes when a drug interacting with CYP2C19 is added to clopidogrel treatment. A clinical-pharmacogenetic algorithm was developed based on whether clopidogrel shows 1 expected effect as per indication, 2 little or no effect, or 3 clinical features that patients experience and fit with clopidogrel adverse drug reactions. Results: The study results show that all patients under clopidogrel treatment, whose genotypes are different from *1*1, and concomitantly taking other drugs metabolized by CYP2C19 require clopidogrel dose adjustment. To get a therapeutic effect and avoid adverse drug reactions, therapeutic dose of 75 mg clopidogrel, for example, should be lowered to 6 mg or increased to 215 mg in patients with different genotypes. Conclusion: The implementation of clopidogrel new algorithm has the potential to maximize the benefit of clopidogrel pharmacological therapy

  18. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing

    Science.gov (United States)

    Johnson, JA; Gong, L; Whirl-Carrillo, M; Gage, BF; Scott, SA; Stein, CM; Anderson, JL; Kimmel, SE; Lee, MTM; Pirmohamed, M; Wadelius, M; Klein, TE; Altman, RB

    2011-01-01

    Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 geno-type data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.1 PMID:21900891

  19. Impact of a personal CYP2D6 testing workshop on physician assistant student attitudes toward pharmacogenetics.

    Science.gov (United States)

    O'Brien, Travis J; LeLacheur, Susan; Ward, Caitlin; Lee, Norman H; Callier, Shawneequa; Harralson, Arthur F

    2016-03-01

    We assessed the impact of personal CYP2D6 testing on physician assistant student competency in, and attitudes toward, pharmacogenetics (PGx). Buccal samples were genotyped for CYP2D6 polymorphisms. Results were discussed during a 3-h PGx workshop. PGx knowledge was assessed by pre- and post-tests. Focus groups assessed the impact of the workshop on attitudes toward the clinical utility of PGx. Both student knowledge of PGx, and its perceived clinical utility, increased immediately following the workshop. However, exposure to PGx on clinical rotations following the workshop seemed to influence student attitudes toward PGx utility. Personal CYP2D6 testing improves both knowledge and comfort with PGx. Continued exposure to PGx concepts is important for transfer of learning.

  20. Stevens-Johnson syndrome and toxic epidermal necrolysis: an update on pharmacogenetics studies in drug-induced severe skin reaction.

    Science.gov (United States)

    Rufini, Sara; Ciccacci, Cinzia; Politi, Cristina; Giardina, Emiliano; Novelli, Giuseppe; Borgiani, Paola

    2015-11-01

    Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, life-threatening drug reactions involving skin and membranes mucous, which are associated with significant morbidity and mortality and triggered, especially by drug exposure. Different studies have demonstrated that drug response is a multifactorial character and that the interindividual variability in this response depends on both environmental and genetic factors. The last ones have a relevant significance. In fact, the identification of new specific genetic markers involved in the response to drugs, will be of great utility to establish a more personalized therapeutic approach and to prevent the appearance of these adverse reactions. In this review, we summarize recent progresses in the Pharmacogenetics studies related to Stevens-Johnson syndrome/toxic epidermal necrolysis reporting the major genetic factors identified in the last years as associated with the disease and highlighting the use of some of these genomic variants in the clinical practice.

  1. Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Lazić Jelena

    2017-01-01

    Full Text Available Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR c.677C>T and MTHFR c.1298A>C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCRRFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C>T and MTHFR c.1298A>C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017, while MTHFR c.1298A>C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C>T and MTHFR c.1298A>C genotypes did not experience decreased overall survival (OAS or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C>T nor MTHFR c.1298A>C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III 41004

  2. Evidence used in model-based economic evaluations for evaluating pharmacogenetic and pharmacogenomic tests: a systematic review protocol.

    Science.gov (United States)

    Peters, Jaime L; Cooper, Chris; Buchanan, James

    2015-11-11

    Decision models can be used to conduct economic evaluations of new pharmacogenetic and pharmacogenomic tests to ensure they offer value for money to healthcare systems. These models require a great deal of evidence, yet research suggests the evidence used is diverse and of uncertain quality. By conducting a systematic review, we aim to investigate the test-related evidence used to inform decision models developed for the economic evaluation of genetic tests. We will search electronic databases including MEDLINE, EMBASE and NHS EEDs to identify model-based economic evaluations of pharmacogenetic and pharmacogenomic tests. The search will not be limited by language or date. Title and abstract screening will be conducted independently by 2 reviewers, with screening of full texts and data extraction conducted by 1 reviewer, and checked by another. Characteristics of the decision problem, the decision model and the test evidence used to inform the model will be extracted. Specifically, we will identify the reported evidence sources for the test-related evidence used, describe the study design and how the evidence was identified. A checklist developed specifically for decision analytic models will be used to critically appraise the models described in these studies. Variations in the test evidence used in the decision models will be explored across the included studies, and we will identify gaps in the evidence in terms of both quantity and quality. The findings of this work will be disseminated via a peer-reviewed journal publication and at national and international conferences. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  3. APPLIED ASPECTS OF SLCO1B1 PHARMACOGENETIC TESTING FOR PREDICTING OF STATIN-INDUCED MYOPATHY AND PERSONALIZATION OF STATINS THERAPY

    Directory of Open Access Journals (Sweden)

    D. A. Sychev

    2015-09-01

    Full Text Available The clinical significance of the SLCO1B1 gene polymorphism (encoding an organic anion transport polipeptide in the development of statin induced myopathy is considered. Possible tactics of statin dose determination on the basis of pharmacogenetic testing is discussed. Indications for the use of this approach in clinical practice that should increase the efficacy and safety of the statin therapy are also considered.

  4. Prevention of Fetal Congenital Malformations with Allowance for the Pharmacogenetic Features of the Metabolism of Antiepileptic Drugs and Hereditary Abnormalities in the Folate Cycle

    Directory of Open Access Journals (Sweden)

    D. V. Dmitrenko

    2014-01-01

    Full Text Available Fetal congenital malformations are among the most dangerous complications of pregnancy in women with epilepsy taking antiepileptic drugs. Valproic acid and phenobarbital have the greatest risk of teratogenic effects. Insights into the current mechanisms of teratogenic effect of antiepileptic drugs, pharmacogenetic features of the metabolism of valproates and hereditary abnormalities in the folate cycle enables prevention of fetal congenital malformations. 

  5. Bernard Lerer: recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine (Pacific Rim Association for Clinical Pharmacogenetics).

    Science.gov (United States)

    Ozdemir, Vural; Endrenyi, Laszlo; Aynacıoğlu, Sükrü; Bragazzi, Nicola Luigi; Dandara, Collet; Dove, Edward S; Ferguson, Lynnette R; Geraci, Christy Jo; Hafen, Ernst; Kesim, Belgin Eroğlu; Kolker, Eugene; Lee, Edmund J D; Llerena, Adrian; Nacak, Muradiye; Shimoda, Kazutaka; Someya, Toshiyuki; Srivastava, Sanjeeva; Tomlinson, Brian; Vayena, Effy; Warnich, Louise; Yaşar, Umit

    2014-04-01

    This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21(st) century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry--pharmacoepigenetics--that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a long way

  6. A Controlled Pharmacogenetic Trial of Sibutramine on Weight Loss and Body Composition in Obese or Overweight Adults

    Science.gov (United States)

    Grudell, April B.M.; Sweetser, Seth; Camilleri, Michael; Eckert, Deborah J.; Vazquez-Roque, Maria I.; Carlson, Paula J.; Burton, Duane D.; Braddock, Autumn E.; Clark, Matthew M.; Graszer, Karen M.; Kalsy, Sarah A.; Zinsmeister, Alan R.

    2008-01-01

    Background/ Aim Weight loss in response to sibutramine is highly variable. We assessed the association of specific markers of polymorphisms of candidate a2A adrenoreceptor, 5-HT transporter and GNβ3 genes and weight loss with sibutramine. Methods We conducted a randomized, double-blind, pharmacogenetic study of behavioral therapy and sibutramine (10 or 15 mg daily) or placebo for 12 weeks in 181 overweight or obese participants. We measured body weight, BMI, body composition, gastric emptying and genetic variation (α2A C1291G, 5-HTTLPR, and GNβ3 C825T genotypes). ANCOVA was used to assess treatment effects on, and associations of the specific markers of candidate genes with weight loss and body composition. Results Sibutramine, 10 and 15 mg, caused significant weight loss (p = 0.009); there was a statistically significant gene by dose interaction for GNβ3 genotype. For each candidate gene, significant treatment effects at 12 weeks were observed (psibutramine doses versus placebo): α2A CC genotype ( Δ ~5kg), GNβ3 TC/TT genotype (Δ ~6kg), and 5-HTTLPR LS/SS (Δ ~4.5kg). Gene pairs resulted in significantly greater sibutramine treatment effects on weight (both psibutramine also resulted in significantly greater reduction of body fat for specific α2A CC and GNβ3 TC/TT genotype variants individually (both psibutramine and behavioral therapy. PMID:18725220

  7. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype.

    Science.gov (United States)

    Relling, M V; McDonagh, E M; Chang, T; Caudle, K E; McLeod, H L; Haidar, C E; Klein, T; Luzzatto, L

    2014-08-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia (AHA) induced by a number of drugs. We provide guidance as to which G6PD genotypes are associated with G6PD deficiency in males and females. Rasburicase is contraindicated in G6PD-deficient patients due to the risk of AHA and possibly methemoglobinemia. Unless preemptive genotyping has established a positive diagnosis of G6PD deficiency, quantitative enzyme assay remains the mainstay of screening prior to rasburicase use. The purpose of this article is to help interpret the results of clinical G6PD genotype tests so that they can guide the use of rasburicase. Detailed guidelines on other aspects of the use of rasburicase, including analyses of cost-effectiveness, are beyond the scope of this document. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are published and updated periodically on https://www.pharmgkb.org/page/cpic to reflect new developments in the field.

  8. Pharmacogenetics and induction/consolidation therapy toxicities in acute lymphoblastic leukemia patients treated with AIEOP-BFM ALL 2000 protocol.

    Science.gov (United States)

    Franca, R; Rebora, P; Bertorello, N; Fagioli, F; Conter, V; Biondi, A; Colombini, A; Micalizzi, C; Zecca, M; Parasole, R; Petruzziello, F; Basso, G; Putti, M C; Locatelli, F; d'Adamo, P; Valsecchi, M G; Decorti, G; Rabusin, M

    2017-01-01

    Drug-related toxicities represent an important clinical concern in chemotherapy, genetic variants could help tailoring treatment to patient. A pharmacogenetic multicentric study was performed on 508 pediatric acute lymphoblastic leukemia patients treated with AIEOP-BFM 2000 protocol: 28 variants were genotyped by VeraCode and Taqman technologies, deletions of GST-M1 and GST-T1 by multiplex PCR. Toxicities were derived from a central database: 251 patients (49.4%) experienced at least one gastrointestinal (GI) or hepatic (HEP) or neurological (NEU) grade III/IV episode during the remission induction phase: GI occurred in 63 patients (12.4%); HEP in 204 (40.2%) and NEU in 44 (8.7%). Logistic regression model adjusted for sex, risk and treatment phase revealed that ITPA rs1127354 homozygous mutated patients showed an increased risk of severe GI and NEU. ABCC1 rs246240 and ADORA2A rs2236624 homozygous mutated genotypes were associated to NEU and HEP, respectively. These three variants could be putative predictive markers for chemotherapy-related toxicities in AIEOP-BFM protocols.

  9. Clinical impact of pharmacogenetic profiling with a clinical decision support tool in polypharmacy home health patients: A prospective pilot randomized controlled trial.

    Directory of Open Access Journals (Sweden)

    Lindsay S Elliott

    Full Text Available In polypharmacy patients under home health management, pharmacogenetic testing coupled with guidance from a clinical decision support tool (CDST on reducing drug, gene, and cumulative interaction risk may provide valuable insights in prescription drug treatment, reducing re-hospitalization and emergency department (ED visits. We assessed the clinical impact of pharmacogenetic profiling integrating binary and cumulative drug and gene interaction warnings on home health polypharmacy patients.This prospective, open-label, randomized controlled trial was conducted at one hospital-based home health agency between February 2015 and February 2016. Recruitment came from patient referrals to home health at hospital discharge. Eligible patients were aged 50 years and older and taking or initiating treatment with medications with potential or significant drug-gene-based interactions. Subjects (n = 110 were randomized to pharmacogenetic profiling (n = 57. The study pharmacist reviewed drug-drug, drug-gene, and cumulative drug and/or gene interactions using the YouScript® CDST to provide drug therapy recommendations to clinicians. The control group (n = 53 received treatment as usual including pharmacist guided medication management using a standard drug information resource. The primary outcome measure was the number of re-hospitalizations and ED visits at 30 and 60 days after discharge from the hospital. The mean number of re-hospitalizations per patient in the tested vs. untested group was 0.25 vs. 0.38 at 30 days (relative risk (RR, 0.65; 95% confidence interval (CI, 0.32-1.28; P = 0.21 and 0.33 vs. 0.70 at 60 days following enrollment (RR, 0.48; 95% CI, 0.27-0.82; P = 0.007. The mean number of ED visits per patient in the tested vs. untested group was 0.25 vs. 0.40 at 30 days (RR, 0.62; 95% CI, 0.31-1.21; P = 0.16 and 0.39 vs. 0.66 at 60 days (RR, 0.58; 95% CI, 0.34-0.99; P = 0.045. Differences in composite outcomes at 60 days (exploratory endpoints

  10. Phase 1 Pharmacogenetic and Pharmacodynamic Study of Sorafenib With Concurrent Radiation Therapy and Gemcitabine in Locally Advanced Unresectable Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chiorean, E. Gabriela, E-mail: gchiorea@uw.edu [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Department of Medicine, University of Washington, Seattle, Washington (United States); Schneider, Bryan P. [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Akisik, Fatih M. [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Perkins, Susan M. [Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana (United States); Anderson, Stephen [Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (United States); Johnson, Cynthia S. [Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana (United States); DeWitt, John [Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (United States); Helft, Paul; Clark, Romnee; Johnston, Erica L.; Spittler, A. John [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Deluca, Jill [Department of Radiation Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Bu, Guixue [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Shahda, Safi; Loehrer, Patrick J. [Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana (United States); Sandrasegaran, Kumar [Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Cardenes, Higinia R. [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana (United States)

    2014-06-01

    Purpose: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. Methods and Materials: Patients received gemcitabine 1000 mg/m{sup 2} intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m{sup 2} intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). Results: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K{sup trans} in responding patients. Conclusions: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival.

  11. Phase 1 Pharmacogenetic and Pharmacodynamic Study of Sorafenib With Concurrent Radiation Therapy and Gemcitabine in Locally Advanced Unresectable Pancreatic Cancer

    International Nuclear Information System (INIS)

    Chiorean, E. Gabriela; Schneider, Bryan P.; Akisik, Fatih M.; Perkins, Susan M.; Anderson, Stephen; Johnson, Cynthia S.; DeWitt, John; Helft, Paul; Clark, Romnee; Johnston, Erica L.; Spittler, A. John; Deluca, Jill; Bu, Guixue; Shahda, Safi; Loehrer, Patrick J.; Sandrasegaran, Kumar; Cardenes, Higinia R.

    2014-01-01

    Purpose: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. Methods and Materials: Patients received gemcitabine 1000 mg/m 2 intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m 2 intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). Results: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K trans in responding patients. Conclusions: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival

  12. Pharmacogenetics-based area-under-curve model can predict efficacy and adverse events from axitinib in individual patients with advanced renal cell carcinoma.

    Science.gov (United States)

    Yamamoto, Yoshiaki; Tsunedomi, Ryouichi; Fujita, Yusuke; Otori, Toru; Ohba, Mitsuyoshi; Kawai, Yoshihisa; Hirata, Hiroshi; Matsumoto, Hiroaki; Haginaka, Jun; Suzuki, Shigeo; Dahiya, Rajvir; Hamamoto, Yoshihiko; Matsuyama, Kenji; Hazama, Shoichi; Nagano, Hiroaki; Matsuyama, Hideyasu

    2018-03-30

    We investigated the relationship between axitinib pharmacogenetics and clinical efficacy/adverse events in advanced renal cell carcinoma (RCC) and established a model to predict clinical efficacy and adverse events using pharmacokinetic and gene polymorphisms related to drug metabolism and efflux in a phase II trial. We prospectively evaluated the area under the plasma concentration-time curve (AUC) of axitinib, objective response rate, and adverse events in 44 consecutive advanced RCC patients treated with axitinib. To establish a model for predicting clinical efficacy and adverse events, polymorphisms in genes including ABC transporters ( ABCB1 and ABCG2 ), UGT1A , and OR2B11 were analyzed by whole-exome sequencing, Sanger sequencing, and DNA microarray. To validate this prediction model, calculated AUC by 6 gene polymorphisms was compared with actual AUC in 16 additional consecutive patients prospectively. Actual AUC significantly correlated with the objective response rate ( P = 0.0002) and adverse events (hand-foot syndrome, P = 0.0055; and hypothyroidism, P = 0.0381). Calculated AUC significantly correlated with actual AUC ( P treatment precisely predicted actual AUC after axitinib treatment ( P = 0.0066). Our pharmacogenetics-based AUC prediction model may determine the optimal initial dose of axitinib, and thus facilitate better treatment of patients with advanced RCC.

  13. Bernard Lerer: Recipient of the 2014 Inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine (Pacific Rim Association for Clinical Pharmacogenetics)

    Science.gov (United States)

    Aynacıoğlu, Şükrü; Bragazzi, Nicola Luigi; Dandara, Collet; Dove, Edward S.; Ferguson, Lynnette R.; Geraci, Christy Jo; Hafen, Ernst; Kesim, Belgin Eroğlu; Kolker, Eugene; Lee, Edmund J.D.; LLerena, Adrian; Nacak, Muradiye; Shimoda, Kazutaka; Someya, Toshiyuki; Srivastava, Sanjeeva; Tomlinson, Brian; Vayena, Effy; Warnich, Louise; Yaşar, Ümit

    2014-01-01

    Abstract This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21st century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry—pharmacoepigenetics—that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a

  14. Pharmacogenetics and aromatase inhibitor induced side effects in breast cancer patients.

    Science.gov (United States)

    Sini, Valentina; Botticelli, Andrea; Lunardi, Gianluigi; Gori, Stefania; Marchetti, Paolo

    2017-06-01

    This paper reviews genetic variations mainly related to the onset of adverse events during aromatase inhibitors in early breast cancer. Genetic variability could occur at different steps. The analysis included studies that involved breast cancer patients, treated with an aromatase inhibitor, genotyped for CYP19A1 and/or CYP17A1 and/or CYP27B1 and/or TCLA1, and/or RANK/RANKL/OPG and/or ESR1/ESR2, and assessed for toxicity profile. Twenty-two articles were included for the analysis. Three studies evaluated outcomes and adverse events; 19 studies assessed only side effects. Functional variations may be useful in predicting the onset of toxicities. The identification of polymorphisms at increased risk of toxicity may enable patient management. However, more data are needed to be applied in the individualization of treatment in daily practice.

  15. Pharmacogenetics of steroid-responsive acute graft-versus-host disease.

    Science.gov (United States)

    Arora, Mukta; Weisdorf, Daniel J; Shanley, Ryan M; Thyagarajan, Bharat

    2017-05-01

    Glucocorticoids are central to effective therapy of acute graft-versus-host disease (GVHD). However, only about half of the patients respond to steroids in initial therapy. Based on postulated mechanisms for anti-inflammatory effectiveness, we explored genetic variations in glucocorticoid receptor, co-chaperone proteins, membrane transporters, inflammatory mediators, and variants in the T-cell receptor complex in hematopoietic cell transplant recipients with acute GVHD requiring treatment with steroids and their donors toward response at day 28 after initiation of therapy. A total of 300 recipient and donor samples were analyzed. Twenty-three SNPs in 17 genes affecting glucocorticoid pathways were included in the analysis. In multiple regression analysis, donor SNP rs3192177 in the ZAP70 gene (O.R. 2.8, 95% CI: 1.3-6.0, P=.008) and donor SNP rs34471628 in the DUSPI gene (O.R. 0.3, 95% CI: 0.1-1.0, P=.048) were significantly associated with complete or partial response. However, after adjustment for multiple testing, these SNPs did not remain statistically significant. Our results, on this small, exploratory, hypothesis generating analysis suggest that common genetic variation in glucocorticoid pathways may help identify subjects with differential response to glucocorticoids. This needs further assessment in larger datasets and if validated could help identify subjects for alternative treatments and design targeted treatments to overcome steroid resistance. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Review of the Reported Measures of Clinical Validity and Clinical Utility as Arguments for the Implementation of Pharmacogenetic Testing: A Case Study of Statin-Induced Muscle Toxicity

    Directory of Open Access Journals (Sweden)

    Marleen E. Jansen

    2017-08-01

    Full Text Available Advances from pharmacogenetics (PGx have not been implemented into health care to the expected extent. One gap that will be addressed in this study is a lack of reporting on clinical validity and clinical utility of PGx-tests. A systematic review of current reporting in scientific literature was conducted on publications addressing PGx in the context of statins and muscle toxicity. Eighty-nine publications were included and information was selected on reported measures of effect, arguments, and accompanying conclusions. Most authors report associations to quantify the relationship between a genetic variation an outcome, such as adverse drug responses. Conclusions on the implementation of a PGx-test are generally based on these associations, without explicit mention of other measures relevant to evaluate the test's clinical validity and clinical utility. To gain insight in the clinical impact and select useful tests, additional outcomes are needed to estimate the clinical validity and utility, such as cost-effectiveness.

  17. Pharmacogenetic Analysis of Captopril Effects on Blood Pressure: Possible Role of the Ednrb (Endothelin Receptor Type B) Candidate Gene

    Czech Academy of Sciences Publication Activity Database

    Zicha, Josef; Dobešová, Zdenka; Zídek, Václav; Šilhavý, Jan; Šimáková, Miroslava; Mlejnek, Petr; Vaněčková, Ivana; Kuneš, Jaroslav; Pravenec, Michal

    2014-01-01

    Roč. 63, č. 2 (2014), s. 263-265 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LH11049 Institutional support: RVO:67985823 Keywords : captopril * blood pressure * QTL * Ednrb gene * spontaneously hypertensive rat Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.293, year: 2014

  18. Comparative pharmacogenetic analysis of risk polymorphisms in Caucasian and Vietnamese children with acute lymphoblastic leukemia: prediction of therapeutic outcome?

    Science.gov (United States)

    Hoang, Phuong Thu Vu; Ambroise, Jérôme; Dekairelle, Anne-France; Durant, Jean-François; Butoescu, Valentina; Chi, Vu Luan Dang; Huynh, Nghia; Nguyen, Tan Binh; Robert, Annie; Vermylen, Christiane; Gala, Jean-Luc

    2015-03-01

    Acute lymphoblastic leukemia (ALL) is the most common of all paediatric cancers. Aside from predisposing to ALL, polymorphisms could also be associated with poor outcome. Indeed, genetic variations involved in drug metabolism could, at least partially, be responsible for heterogeneous responses to standardized leukemia treatments, hence requiring more personalized therapy. The aims of this study were to (a) to determine the prevalence of seven common genetic polymorphisms including those that affect the folate and/or thiopurine metabolic pathways, i.e. cyclin D1 (CCND1-G870A), γ-glutamyl hydrolase (GGH-C452T), methylenetetrahydrofolate reductase (MTHFR-C677T and MTHFR-A1298C), thymidylate synthase promoter (TYMS-TSER), thiopurine methyltransferase (TPMT*3A and TPMT*3C) and inosine triphosphate pyrophosphatase (ITPA-C94A), in Caucasian (n = 94, age Vietnamese (n = 141, age Vietnamese (P < 0.001 and P = 0.02, respectively). Compared with children with a low MGRS (≤ 3), those with a high MGRS (≥ 4) were 2.06 (95% CI = 1.01, 4.22; P = 0.04) times more likely to relapse. Adding MGRS into a multivariate Cox regression model with race/ethnicity and four clinical variables improved the predictive accuracy of the model (AUC from 0.682 to 0.709 at 24 months). Including MGRS into a clinical model improved the predictive accuracy of short and medium term prognosis, hence confirming the association between well determined pharmacogenotypes and outcome of paediatric ALL. Whether variants on other genes associated with folate metabolism can substantially improve the predictive value of current MGRS is not known but deserves further evaluation. © 2014 The British Pharmacological Society.

  19. The economics of biobanking and pharmacogenetics databasing: the case of an adaptive platform on breast cancer.

    Science.gov (United States)

    Huttin, Christine C; Liebman, Michael N

    2013-01-01

    This paper aims to discuss the economics of biobanking. Among the critical issues in evaluating potential ROI for creation of a bio-bank are: scale (e.g. local, national, international), centralized versus virtual/distributed, degree of sample annotation/QC procedures, targeted end-users and uses, types of samples, potential characterization, both of samples and annotations. The paper presents a review on cost models for an economic analysis of biobanking for different steps: data collection (e.g. biospecimens in different types of sites, storage, transport and distribution, information management for the different types of information (e.g. biological information such as cell, gene, and protein)). It also provides additional concepts to process biospecimens from laboratory to clinical practice and will help to identify how changing paradigms in translational medicine affect the economic modeling.

  20. Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).

    Science.gov (United States)

    Lévi, Francis; Karaboué, Abdoulaye; Saffroy, Raphaël; Desterke, Christophe; Boige, Valerie; Smith, Denis; Hebbar, Mohamed; Innominato, Pasquale; Taieb, Julien; Carvalho, Carlos; Guimbaud, Rosine; Focan, Christian; Bouchahda, Mohamed; Adam, René; Ducreux, Michel; Milano, Gérard; Lemoine, Antoinette

    2017-09-26

    The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1). VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.

  1. The effect of pharmacogenetic profiling with a clinical decision support tool on healthcare resource utilization and estimated costs in the elderly exposed to polypharmacy.

    Science.gov (United States)

    Brixner, D; Biltaji, E; Bress, A; Unni, S; Ye, X; Mamiya, T; Ashcraft, K; Biskupiak, J

    2016-01-01

    To compare healthcare resource utilization (HRU) and clinical decision-making for elderly patients based on cytochrome P450 (CYP) pharmacogenetic testing and the use of a comprehensive medication management clinical decision support tool (CDST), to a cohort of similar non-tested patients. An observational study compared a prospective cohort of patients ≥65 years subjected to pharmacogenetic testing to a propensity score (PS) matched historical cohort of untested patients in a claims database. Patients had a prescribed medication or dose change of at least one of 61 oral drugs or combinations of ≥3 drugs at enrollment. Four-month HRU outcomes examined included hospitalizations, emergency department (ED) and outpatient visits and provider acceptance of test recommendations. Costs were estimated using national data sources. There were 205 tested patients PS matched to 820 untested patients. Hospitalization rate was 9.8% in the tested group vs. 16.1% in the untested group (RR = 0.61, 95% CI = 0.39-0.95, p = 0.027), ED visit rate was 4.4% in the tested group vs. 15.4% in the untested group (RR = 0.29, 95% CI = 0.15-0.55, p = 0.0002) and outpatient visit rate was 71.7% in the tested group vs. 36.5% in the untested group (RR = 1.97, 95% CI = 1.74-2.23, p provider majority (95%) considered the test helpful and 46% followed CDST provided recommendations. Patients CYP DNA tested and treated according to the personalized prescribing system had a significant decrease in hospitalizations and emergency department visits, resulting in potential cost savings. Providers had a high satisfaction rate with the clinical utility of the system and followed recommendations when appropriate.

  2. [Pharmacogenetic approaches to predicting the efficiency and safety of amlodipine in patients with arterial hypertension].

    Science.gov (United States)

    Sychev, D A; Shih, N V; Kalle, E G; Ryzhikova, K A; Morozova, T E

    2017-10-01

    An open, non-comparative, prospective clinical study was conducted to evaluate the antihypertensive efficacy and tolerability of amlodipine, a calcium antagonist, in patients with arterial hypertension (AH) I-II stages, depending on the genotype for the polymorphic marker C3435T of the ABCB1 gene. The study included 100 patients with AH I-II stages, aged from 45 to 58 years. The initial dose of amlodipine was 5 mg, duration of treatment was 12 weeks. General clinical examination methods, office measurement and daily blood pressure monitoring, tolerance evaluation, and genotyping using the ABCB1 polymorphic marker C3435T by the PCR-RFLP method (polymerase chain reaction and restriction fragment length polymorphism) were used. The statistical analysis of results was carried out using the Mann-Whitney U test for quantitative variables, Kruskal-Wallis one-way analysis of variance (ANOVA) for three independent groups of quantitative data. Excellent antihypertensive efficacy with the CC genotype was found in 11.8% patients, with CT - 33.9%, with TT - 43.3%; good - 35.3%, 32.1%, and 33.3% respectively, satisfactory - 52.9%, 34,0% and 23.4% respectively. Six patients with the CT genotype and nine patients with the CC genotype required the increase in the dose to 10 mg. The number of patients with Adverse drug reactions (ADR) were found in 35.3% of patients with the CC genotype, 6.7% with the TT genotype and 11.3% with the CT genotype. The Kruskal-Wallis test revealed significant differences between CC and TT genotypes in the degree of decrease in SBP (p=0.02), antihypertensive efficacy parameter (p=0.02), an increase in dose requirements (p = 0.04) and the incidence of ADR(p=0.05). In AH patients (I-II stage) with the TT genotype of the C3435T gene polymorphism one can expect higher rates of antihypertensive efficacy of amlodipine in combination with a good safety profile and the lowest ADR percentage, while patients with the CC genotype more likely to develop ADR and

  3. Pharmacogenetics of statin therapy and the endothelial function parameters in patients with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Nadezhda O. Lebedeva

    2016-04-01

    Full Text Available Aim. To investigate the association of variation in lipid-lowering response and endothelial function (EF parameters after atorvastatin therapy in patients with type 2 diabetes mellitus (T2DM with genetic markers of atherosclerosis. Methods. We included 97 patients with T2DM who were prescribed atorvastatin. Fasting lipid profiles and EF parameters were assessed before and after 12 months of statin therapy. For EF evaluation, we performed pulse-wave analysis during reactive hyperaemia. The genotypes for polymorphic markers were identified by real-time polymerase chain reaction with TaqMan probes. The statistical analysis included Wilcoxon, Mann–Whitney and Kruskal–Wallis tests. P-values <0.05 were considered statistically significant. Results. With statin therapy, PPARG2Pro/Pro patients had significantly lower TC and LDL-C levels than PPARG2 Pro/Ala and PPARG2 Ala/Ala patients (TC: 20.74% vs. 4.6% and 5.61%; p = 0.04 and LDL-C: 26.00% vs. 6.11% and 7.32%; p = 0.029. Patients with АРОЕЕ4/Е4 had significantly lower TC and TG levels than other АРОЕ patients (TC: -46.25% for Е4/Е4 vs. +33.33% for Е4/Е2, +5.73% for Е3/Е2, +11.80% for Е3/Е4, -10.92% for Е3/Е3, р = 0,01; TG: -56.52% for Е4/Е4 vs. +24.43% for Е4/Е2, +19.63% for Е3/Е2, +8.05% for Е3/Е4, -20.00% for Е3/Е3, р = 0.04. The patients with GG for TNFα G(238A and GA for TNFα G(308A had significantly greater amplitude of post-occlusive wave increase (Apw than patients with GA for TNFα G(238A and GG for TNFα G(308A (+8.16 % vs. -0.93%, р = 0,04; +44% vs. -4.4%, p = 0.004, respectively. Conclusion. PPARG2Pro12Ala and АРОЕE2/Е3/Е4 polymorphism contributed to the between-patient variability in the response to statin therapy in patients with T2DM. Significant associations of the TNFαgene polymorphism with EF in patients with T2DM suggest an important role of inflammation in the pathogenesis of MVD.

  4. Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer

    Directory of Open Access Journals (Sweden)

    Dahan Laetitia

    2011-11-01

    Full Text Available Abstract Background We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (EGFR, EGF, CCND1 or antibody-directed cell cytotoxicity (FCGR2A and FCGR3A on outcome of colorectal cancer (CRC patients receiving cetuximab-based therapy. Methods Fifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1. The following polymorphisms were analyzed on blood DNA: EGFR (CA repeats in intron 1, -216 G > T, -191C > A, R497K, EGF (A61G, CCND1 (A870G, FCGR2A (R131H, FCGR3A (F158V. Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt vs wt/mut vs mut/mut, with the exception of -191C > A EGFR polymorphism (AA patient merged with CA patients. Results Analysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058. CCND1 A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP was significantly related to EGFR -191C > A polymorphism with a longer TTP in CC patients as compared to others, and to CCND1 A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained CCND1 polymorphism. Overall survival was significantly related to CCND1 polymorphism with a shorter survival in patients bearing the G allele, and to FCGR3A F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients. FCGR3A F158V and CCND1 A870G polymorphisms were significant independent predictors of overall survival. Conclusions Present original data obtained in wt KRas

  5. Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer

    International Nuclear Information System (INIS)

    Dahan, Laetitia; Seitz, Jean-François; Milano, Gérard; Norguet, Emmanuelle; Etienne-Grimaldi, Marie-Christine; Formento, Jean-Louis; Gasmi, Mohamed; Nanni, Isabelle; Gaudart, Jean; Garcia, Stéphane; Ouafik, L'Houcine

    2011-01-01

    We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (EGFR, EGF, CCND1) or antibody-directed cell cytotoxicity (FCGR2A and FCGR3A) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy. Fifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1). The following polymorphisms were analyzed on blood DNA: EGFR (CA repeats in intron 1, -216 G > T, -191C > A, R497K), EGF (A61G), CCND1 (A870G), FCGR2A (R131H), FCGR3A (F158V). Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt vs wt/mut vs mut/mut), with the exception of -191C > A EGFR polymorphism (AA patient merged with CA patients). Analysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058). CCND1 A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP) was significantly related to EGFR -191C > A polymorphism with a longer TTP in CC patients as compared to others, and to CCND1 A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained CCND1 polymorphism. Overall survival was significantly related to CCND1 polymorphism with a shorter survival in patients bearing the G allele, and to FCGR3A F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). FCGR3A F158V and CCND1 A870G polymorphisms were significant independent predictors of overall survival. Present original data obtained in wt KRas patients corresponding to the current cetuximab

  6. Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science.

    Science.gov (United States)

    Leeder, J Steven; Kearns, Gregory L; Spielberg, Stephen P; van den Anker, John

    2010-12-01

    Understanding the dose-exposure-response relationship across the pediatric age spectrum from preterm and term newborns to infants, children, adolescents, and adults is a major challenge for clinicians, pharmaceutical companies, and regulatory agencies. Over the past 3 decades, clinical investigations of many drugs commonly used in pediatric therapeutics have provided valuable insights into age-associated differences in drug disposition and action. However, our understanding of the contribution of genetic variation to variability in drug disposition and response in children generally has lagged behind that of adults. This article proposes a systematic approach that can be used to assess the relative contributions of ontogeny and genetic variation for a given compound. Application of the strategy is illustrated using the current regulatory dilemma posed by the safety and effectiveness of over-the-counter cough and cold remedies as an example. The results of the analysis can be used to aid in the design of studies to yield maximally informative data in pediatric populations of different ages and developmental stages and thereby improve the efficiency of study design.

  7. Race/Ethnicity and the Pharmacogenetics of Reported Suicidality With Efavirenz Among Clinical Trials Participants.

    Science.gov (United States)

    Mollan, Katie R; Tierney, Camlin; Hellwege, Jacklyn N; Eron, Joseph J; Hudgens, Michael G; Gulick, Roy M; Haubrich, Richard; Sax, Paul E; Campbell, Thomas B; Daar, Eric S; Robertson, Kevin R; Ventura, Diana; Ma, Qing; Edwards, Digna R Velez; Haas, David W

    2017-09-01

    We examined associations between suicidality and genotypes that predict plasma efavirenz exposure among AIDS Clinical Trials Group study participants in the United States. Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens; suicidality was defined as reported suicidal ideation or attempted or completed suicide. Genotypes that predict plasma efavirenz exposure were defined by CYP2B6 and CYP2A6 polymorphisms. Associations were evaluated with weighted Cox proportional hazards models stratified by race/ethnicity. Additional analyses adjusted for genetic ancestry and selected covariates. Among 1833 participants, suicidality was documented in 41 in exposed analyses, and 34 in on-treatment analyses. In unadjusted analyses based on 12 genotype levels, suicidality increased per level in exposed (hazard ratio, 1.11; 95% confidence interval, .96-1.27) and on-treatment 1.16; 1.01-1.34) analyses. In the on-treatment analysis, the association was strongest among white but nearly null among black participants. Considering 3 metabolizer levels (extensive, intermediate and slow), slow metabolizers were at increased risk. Results were similar after baseline covariate-adjustment for genetic ancestry, sex, age, weight, injection drug use history, and psychiatric history or recent psychoactive medication. Genotypes that predict higher plasma efavirenz exposure were associated with increased risk of suicidality. Strength of association varied by race/ethnicity. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

  8. Pharmacogenetic landscape of Metabolic Syndrome components drug response in Tunisia and comparison with worldwide populations.

    Science.gov (United States)

    Jmel, Haifa; Romdhane, Lilia; Ben Halima, Yosra; Hechmi, Meriem; Naouali, Chokri; Dallali, Hamza; Hamdi, Yosr; Shan, Jingxuan; Abid, Abdelmajid; Jamoussi, Henda; Trabelsi, Sameh; Chouchane, Lotfi; Luiselli, Donata; Abdelhak, Sonia; Kefi, Rym

    2018-01-01

    Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6.0 genotyping array. Variants located in 24 Very Important Pharmacogenes (VIP) involved in MetS drug response were extracted from the genotyping data. Analysis of variant distribution in Tunisian population compared to 20 worldwide populations publicly available was performed using R software packages. Common variants between Tunisians and the 20 investigated populations were extracted from genotyping data. Multidimensional screening showed that Tunisian population is clustered with North African and European populations. The greatest divergence was observed with the African and Asian population. In addition, we performed Inter-ethnic comparison based on the genotype frequencies of five VIP biomarkers. The genotype frequencies of the biomarkers rs3846662, rs1045642, rs7294 and rs12255372 located respectively in HMGCR, ABCB1, VKORC1 and TCF7L2 are similar between Tunisian, Tuscan (TSI) and European (CEU). The genotype frequency of the variant rs776746 located in CYP3A5 gene is similar between Tunisian and African populations and different from CEU and TSI. The present study shows that the genetic make up of the Tunisian population is relatively complex in regard to pharmacogenes and reflects previous historical events. It is important to consider this ethnic difference in drug prescription in order to optimize drug response to avoid serious adverse drug reactions. Taking into account similarities with

  9. Pharmacogenetic landscape of Metabolic Syndrome components drug response in Tunisia and comparison with worldwide populations

    Science.gov (United States)

    Jmel, Haifa; Romdhane, Lilia; Ben Halima, Yosra; Hechmi, Meriem; Naouali, Chokri; Dallali, Hamza; Hamdi, Yosr; Shan, Jingxuan; Abid, Abdelmajid; Jamoussi, Henda; Trabelsi, Sameh; Chouchane, Lotfi; Luiselli, Donata; Abdelhak, Sonia

    2018-01-01

    Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6.0 genotyping array. Variants located in 24 Very Important Pharmacogenes (VIP) involved in MetS drug response were extracted from the genotyping data. Analysis of variant distribution in Tunisian population compared to 20 worldwide populations publicly available was performed using R software packages. Common variants between Tunisians and the 20 investigated populations were extracted from genotyping data. Multidimensional screening showed that Tunisian population is clustered with North African and European populations. The greatest divergence was observed with the African and Asian population. In addition, we performed Inter-ethnic comparison based on the genotype frequencies of five VIP biomarkers. The genotype frequencies of the biomarkers rs3846662, rs1045642, rs7294 and rs12255372 located respectively in HMGCR, ABCB1, VKORC1 and TCF7L2 are similar between Tunisian, Tuscan (TSI) and European (CEU). The genotype frequency of the variant rs776746 located in CYP3A5 gene is similar between Tunisian and African populations and different from CEU and TSI. The present study shows that the genetic make up of the Tunisian population is relatively complex in regard to pharmacogenes and reflects previous historical events. It is important to consider this ethnic difference in drug prescription in order to optimize drug response to avoid serious adverse drug reactions. Taking into account similarities with

  10. Pharmacogenetic screening for polymorphisms in drug-metabolizing enzymes and drug transporters in a Dutch population.

    Science.gov (United States)

    Bosch, T M; Doodeman, V D; Smits, P H M; Meijerman, I; Schellens, J H M; Beijnen, J H

    2006-01-01

    A possible explanation for the wide interindividual variability in toxicity and efficacy of drug therapy is variation in genes encoding drug-metabolizing enzymes and drug transporters. The allelic frequency of these genetic variants, linkage disequilibrium (LD), and haplotype of these polymorphisms are important parameters in determining the genetic differences between patients. The aim of this study was to explore the frequencies of polymorphisms in drug-metabolizing enzymes (CYP1A1, CYP2C9, CYP2C19, CYP3A4, CYP2D6, CYP3A5, DPYD, UGT1A1, GSTM1, GSTP1, GSTT1) and drug transporters (ABCB1[MDR1] and ABCC2[MRP2]), and to investigate the LD and perform haplotype analysis of these polymorphisms in a Dutch population. Blood samples were obtained from 100 healthy volunteers and genomic DNA was isolated and amplified by PCR. The amplification products were sequenced and analyzed for the presence of polymorphisms by sequence alignment. In the study population, we identified 13 new single nucleotide polymorphisms (SNPs) in Caucasians and three new SNPs in non-Caucasians, in addition to previously recognized SNPs. Three of the new SNPs were found within exons, of which two resulted in amino acid changes (A428T in CYP2C9 resulting in the amino acid substitution D143V; and C4461T in ABCC2 in a non-Caucasian producing the amino acid change T1476M). Several LDs and haplotypes were found in the Caucasian individuals. In this Dutch population, the frequencies of 16 new SNPs and those of previously recognized SNPs were determined in genes coding for drug-metabolizing enzymes and drug transporters. Several LDs and haplotypes were also inferred. These data are important for further research to help explain the interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.

  11. Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6.

    Science.gov (United States)

    Bahar, Muh Akbar; Setiawan, Didik; Hak, Eelko; Wilffert, Bob

    2017-05-01

    Currently, most guidelines on drug-drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug-gene interaction (DGI) where there are multiple biotransformation pathways, which is referred to as drug-drug-gene interaction (DDGI). In this systematic review, we report the impact of pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes - CYP2C9, CYP2C19 and CYP2D6 - are central. We observed that several DDI and DDGI are highly gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take pharmacogenetics into account when drug interactions in clinical practice are expected.

  12. Haplotype association analysis of human disease traits using genotype data of unrelated individuals

    DEFF Research Database (Denmark)

    Tan, Qihua; Christiansen, Lene; Christensen, Kaare

    2005-01-01

    unphased multi-locus genotype data, ranging from the early approach by the simple gene-counting method to the recent work using the generalized linear model. However, these methods are either confined to case – control design or unable to yield unbiased point and interval estimates of haplotype effects....... Based on the popular logistic regression model, we present a new approach for haplotype association analysis of human disease traits. Using haplotype-based parameterization, our model infers the effects of specific haplotypes (point estimation) and constructs confidence interval for the risks...... on the well-known logistic regression model is a useful tool for haplotype association analysis of human disease traits....

  13. Pharmacogenetics of Risperidone-Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder.

    Science.gov (United States)

    Sukasem, Chonlaphat; Vanwong, Natchaya; Srisawasdi, Pornpen; Ngamsamut, Nattawat; Nuntamool, Nopphadol; Hongkaew, Yaowaluck; Puangpetch, Apichaya; Chamkrachangpada, Bhunnada; Limsila, Penkhae

    2018-07-01

    The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body-weight and height. Genotyping was performed by TaqMan real-time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP-binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag-SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) -2548G>A (rs7799039), ghrelin gene (GHRL) -604G>A (rs27647) and brain-derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results. © 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  14. Pharmacogenetic predictors of toxicity to platinum based chemotherapy in non-small cell lung cancer patients.

    Science.gov (United States)

    Pérez-Ramírez, Cristina; Cañadas-Garre, Marisa; Alnatsha, Ahmed; Villar, Eduardo; Delgado, Juan Ramón; Faus-Dáder, María José; Calleja-Hernández, Miguel Ÿngel

    2016-09-01

    Platinum-based chemotherapy is the standard treatment for NSCLC patients with EGFR wild-type, and as alternative to failure to EGFR inhibitors. However, this treatment is aggressive and most patients experience grade 3-4 toxicities. ERCC1, ERCC2, ERCC5, XRCC1, MDM2, ABCB1, MTHFR, MTR, SLC19A1, IL6 and IL16 gene polymorphisms may contribute to individual variation in toxicity to chemotherapy. The aim of this study was to evaluate the effect of these polymorphisms on platinum-based chemotherapy in NSCLC patients. A prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR Real-Time with Taqman(®) probes and sequencing. Patients with ERCC1 C118T-T allele (p=0.00345; RR=26.05; CI95%=4.33, 515.77) and ERCC2 rs50872-CC genotype (p=0.00291; RR=4.06; CI95%=1.66, 10.65) had higher risk of general toxicity for platinum-based chemotherapy. ERCC2 Asp312Asn G-alelle, ABCB1 C1236T-TT and the IL1B rs12621220-CT/TT genotypes conferred a higher risk to present multiple adverse events. The subtype toxicity analysis also revealed that ERCC2 rs50872-CC genotype (p=0.01562; OR=3.23; CI95%=1.29, 8.82) and IL16 rs7170924-T allele (p=0.01007; OR=3.19; CI95%=1.35, 7.97) were associated with grade 3-4 hematological toxicity. We did not found the influence of ERCC1 C8092A, ERCC2 Lys751Gln, ERCC2 Asp312Asn, ERCC5 Asp1104His, XRCC1 Arg194Trp, MDM2 rs1690924, ABCB1 C3435T, ABCB1 Ala893Ser/Thr, MTHFR A1298C, MTHFR C677T, IL1B rs1143623, IL1B rs16944, and IL1B rs1143627 on platinum-based chemotherapy toxicity. In conclusion, ERCC1 C118T, ERCC2 rs50872, ERCC2 Asp312Asn, ABCB1 C1236T, IL1B rs12621220 and IL16 rs7170924 polymorphisms may substantially act as prognostic factors in NSCLC patients treated with platinum-based chemotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Pharmacogenetic association study on clopidogrel response in Puerto Rican Hispanics with cardiovascular disease: a novel characterization of a Caribbean population

    Directory of Open Access Journals (Sweden)

    Hernandez-Suarez DF

    2018-06-01

    Full Text Available Dagmar F Hernandez-Suarez,1 Mariana R Botton,2 Stuart A Scott,2 Matthew I Tomey,3 Mario J Garcia,4 Jose Wiley,4 Pedro A Villablanca,5 Kyle Melin,6 Angel Lopez-Candales,7 Jessicca Y Renta,8 Jorge Duconge9 1Cardiovascular Medicine Division, Department of Medicine, University of Puerto Rico School of Medicine, San Juan, PR, USA; 2Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3Cardiovascular Medicine Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4Division of Cardiovascular Diseases, Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine New York, NY, USA; 5Division of Cardiology, Department of Medicine, New York University Langone Medical Center, New York, NY, USA; 6Department of Pharmacy Practice, University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA; 7Cardiovascular Medicine Division, Department of Medicine, University of Puerto Rico School of Medicine, San Juan, PR, USA; 8Department of Biochemistry, University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA; 9Pharmaceutical Sciences Department, University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA Introduction: High on-treatment platelet reactivity (HTPR to clopidogrel imparts an increased risk for ischemic events in adults with coronary artery disease. Platelet reactivity varies with ethnicity and is influenced by both clinical and genetic variables; however, no clopidogrel pharmacogenetic studies with Puerto Rican patients have been reported. Therefore, we sought to identify clinical and genetic determinants of on-treatment platelet reactivity in a cohort of Puerto Rican patients with cardiovascular disease. Methods: We performed a retrospective study of 111 patients on 75 mg/day maintenance dose of clopidogrel. Patients were allocated into 2 groups: Group I, without HTPR; and Group II, with HTPR. Platelet function was

  16. PHARMACOGENETICS OF METFORMIN

    DEFF Research Database (Denmark)

    Hougaard Christensen, Mette Marie; Andersen, Charlotte Brasch; Damkier, Per

    Introduction: Genetic polymorphisms in metformin transporters and their impact at the steady state metformin plasma concentrations is evaluated in a large well characterized type 2 diabetes cohort given by South Danish Diabetes Study. SNPs in PMAT, OCT1-2 and MATE 1-2 have been linked to reduced ...

  17. Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Carcas Antonio J

    2012-12-01

    Full Text Available Abstract Background Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE in patients with venous thromboembolism (VTE. Methods and design This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1 will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1 Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2 Time from the start of oral anticoagulant treatment

  18. Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial.

    Science.gov (United States)

    Carcas, Antonio J; Borobia, Alberto M; Velasco, Marta; Abad-Santos, Francisco; Díaz, Manuel Quintana; Fernández-Capitán, Carmen; Ruiz-Giménez, Nuria; Madridano, Olga; Sillero, Pilar Llamas

    2012-12-13

    Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE). This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic

  19. Farmacogenética de inibidores seletivos de recaptação de serotonina: uma revisão Pharmacogenetics of selective serotonine reuptake inhibitors: a review

    Directory of Open Access Journals (Sweden)

    Diana Klanovicz Silva

    2008-01-01

    candidate genes with response to SSRI, providing an overview on the current knowledge of this subject. The effect of SSRI treatment depends on the variability in genes coding proteins involved with the role of serotonin in the brain. The new data from the Human Genome Project allowed detection of these variations, and several of them proved to have pharmacogenetic importance. Therefore, some of the genes related to SSRI pharmacogenetics are already known. This reinforces the need of larger prospective investigations to determine the real use of this knowledge in clinical practice as to the possibility of determining the right dosage, and the right drug to each patient, a practice that has been called "personalized medicine".

  20. The study to understand the genetics of the acute response to metformin and glipizide in humans (SUGAR-MGH: design of a pharmacogenetic resource for type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Geoffrey A Walford

    Full Text Available Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH, NCT01762046 is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future.All individuals are challenged with 5 mg glipizide × 1; twice daily 500 mg metformin × 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured.Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels.SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes.ClinicalTrials.gov NCT01762046.

  1. Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1 in five populations: implications for pharmacogenetic research

    Directory of Open Access Journals (Sweden)

    Sughondhabirom Atapol

    2007-10-01

    Full Text Available Abstract Background GABA transporter-1 (GAT-1; genetic locus SLC6A1 is emerging as a novel target for treatment of neuropsychiatric disorders. To understand how population differences might influence strategies for pharmacogenetic studies, we identified patterns of genetic variation and linkage disequilibrium (LD in SLC6A1 in five populations representing three continental groups. Results We resequenced 12.4 kb of SLC6A1, including the promoters, exons and flanking intronic regions in African-American, Thai, Hmong, Finnish, and European-American subjects (total n = 40. LD in SLC6A1 was examined by genotyping 16 SNPs in larger samples. Sixty-three variants were identified through resequencing. Common population-specific variants were found in African-Americans, including a novel 21-bp promoter region variable number tandem repeat (VNTR, but no such variants were found in any of the other populations studied. Low levels of LD and the absence of major LD blocks were characteristic of all five populations. African-Americans had the highest genetic diversity. European-Americans and Finns did not differ in genetic diversity or LD patterns. Although the Hmong had the highest level of LD, our results suggest that a strategy based on the use of tag SNPs would not translate to a major improvement in genotyping efficiency. Conclusion Owing to the low level of LD and presence of recombination hotspots, SLC6A1 may be an example of a problematic gene for association and haplotype tagging-based genetic studies. The 21-bp promoter region VNTR polymorphism is a putatively functional candidate allele for studies focusing on variation in GAT-1 function in the African-American population.

  2. Novel drug metabolism indices for pharmacogenetic functional status based on combinatory genotyping of CYP2C9, CYP2C19 and CYP2D6 genes

    Science.gov (United States)

    Villagra, David; Goethe, John; Schwartz, Harold I; Szarek, Bonnie; Kocherla, Mohan; Gorowski, Krystyna; Windemuth, Andreas; Ruaño, Gualberto

    2011-01-01

    Aims We aim to demonstrate clinical relevance and utility of four novel drug-metabolism indices derived from a combinatory (multigene) approach to CYP2C9, CYP2C19 and CYP2D6 allele scoring. Each index considers all three genes as complementary components of a liver enzyme drug metabolism system and uniquely benchmarks innate hepatic drug metabolism reserve or alteration through CYP450 combinatory genotype scores. Methods A total of 1199 psychiatric referrals were genotyped for polymorphisms in the CYP2C9, CYP2C19 and CYP2D6 gene loci and were scored on each of the four indices. The data were used to create distributions and rankings of innate drug metabolism capacity to which individuals can be compared. Drug-specific indices are a combination of the drug metabolism indices with substrate-specific coefficients. Results The combinatory drug metabolism indices proved useful in positioning individuals relative to a population with regard to innate drug metabolism capacity prior to pharmacotherapy. Drug-specific indices generate pharmacogenetic guidance of immediate clinical relevance, and can be further modified to incorporate covariates in particular clinical cases. Conclusions We believe that this combinatory approach represents an improvement over the current gene-by-gene reporting by providing greater scope while still allowing for the resolution of a single-gene index when needed. This method will result in novel clinical and research applications, facilitating the translation from pharmacogenomics to personalized medicine, particularly in psychiatry where many drugs are metabolized or activated by multiple CYP450 isoenzymes. PMID:21861665

  3. Decreased fracture rate, pharmacogenetics and BMD response in 79 Swedish children with osteogenesis imperfecta types I, III and IV treated with Pamidronate.

    Science.gov (United States)

    Lindahl, K; Kindmark, A; Rubin, C-J; Malmgren, B; Grigelioniene, G; Söderhäll, S; Ljunggren, Ö; Åström, E

    2016-06-01

    Osteogenesis imperfecta (OI) is an inherited heterogeneous bone fragility disorder, usually caused by collagen I mutations. It is well established that bisphosphonate treatment increases lumbar spine (LS) bone mineral density (BMD), as well as improves vertebral geometry in severe OI; however, fracture reduction has been difficult to prove, pharmacogenetic studies are scarce, and it is not known at which age, or severity of disease, treatment should be initiated. COL1A1 and COL1A2 were analyzed in 79 children with OI (type I n=33, type III n=25 and type IV n=21) treated with Pamidronate. Data on LS BMD, height, and radiologically confirmed non-vertebral and vertebral fractures were collected prior to, and at several time points during treatment. An increase in LS BMD Z-score was observed for all types of OI, and a negative correlation to Δ LS BMD was observed for both age and LS BMD Z-score at treatment initiation. Supine height Z-scores were not affected by Pamidronate treatment, The fracture rate was reduced for all OI types at all time points during treatment (overall p4yrs Pamidronate. Twice as many boys as girls with OI type I were treated with Pamidronate, and the fracture rate the year prior treatment was 2.2 times higher for boys (p=0.0236). Greater Δ LS BMD, but smaller Δ fracture numbers were observed on Pamidronate for helical glycine mutations in COL1A1 vs. COL1A2. Vertebral compression fractures did not progress in any individual during treatment; however, they did not improve in 9%, and these individuals were all >11years of age at treatment initiation (p<0.0001). Pamidronate treatment in children with all types of OI increased LS BMD, decreased fracture rate, and improved vertebral compression fractures. Fracture reduction was prompt and maintained during treatment, irrespective of age at treatment initiation and collagen I mutation type. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Pharmacogenetic Study in Rectal Cancer Patients Treated With Preoperative Chemoradiotherapy: Polymorphisms in Thymidylate Synthase, Epidermal Growth Factor Receptor, GSTP1, and DNA Repair Genes

    International Nuclear Information System (INIS)

    Páez, David; Salazar, Juliana; Paré, Laia; Pertriz, Lourdes; Targarona, Eduardo; Rio, Elisabeth del; Barnadas, Agusti; Marcuello, Eugenio; Baiget, Montserrat

    2011-01-01

    Purpose: Several studies have been performed to evaluate the usefulness of neoadjuvant treatment using oxaliplatin and fluoropyrimidines for locally advanced rectal cancer. However, preoperative biomarkers of outcome are lacking. We studied the polymorphisms in thymidylate synthase, epidermal growth factor receptor, glutathione S-transferase pi 1 (GSTP1), and several DNA repair genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 128 rectal cancer patients treated with preoperative chemoradiotherapy. Methods and Materials: Blood samples were obtained from 128 patients with Stage II-III rectal cancer. DNA was extracted from the peripheral blood nucleated cells, and the genotypes were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were thymidylate synthase, (VNTR/5′UTR, 2R G>C single nucleotide polymorphism [SNP], 3R G>C SNP), epidermal growth factor receptor (Arg497Lys), GSTP1 (Ile105val), excision repair cross-complementing 1 (Asn118Asn, 8092C>A, 19716G>C), X-ray repair cross-complementing group 1 (XRCC1) (Arg194Trp, Arg280His, Arg399Gln), and xeroderma pigmentosum group D (Lys751Gln). The pathologic response, pathologic regression, progression-free survival, and overall survival were evaluated according to each genotype. Results: The ∗3/∗3 thymidylate synthase genotype was associated with a greater response rate (pathologic complete remission and microfoci residual tumor, 59% in ∗3/∗3 vs. 35% in ∗2/∗2 and ∗2/∗3; p = .013). For the thymidylate synthase genotype, the median progression-free survival was 103 months for the ∗3/∗3 patients and 84 months for the ∗2/∗2 and ∗2/∗3 patients (p = .039). For XRCC1 Arg399Gln SNP, the median progression-free survival was 101 months for the G/G, 78 months for the G/A, and 31 months for the A/A patients (p = .048). Conclusions: The thymidylate

  5. Pharmacogenetic Study in Rectal Cancer Patients Treated With Preoperative Chemoradiotherapy: Polymorphisms in Thymidylate Synthase, Epidermal Growth Factor Receptor, GSTP1, and DNA Repair Genes

    Energy Technology Data Exchange (ETDEWEB)

    Paez, David, E-mail: dpaez@santpau.cat [Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Salazar, Juliana; Pare, Laia [Centre for Biomedical Network Research on Rare Diseases, Barcelona (Spain); Department of Genetics, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Pertriz, Lourdes [Department of Radiotherapy, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Targarona, Eduardo [Department of Surgery, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Rio, Elisabeth del [Centre for Biomedical Network Research on Rare Diseases, Barcelona (Spain); Department of Genetics, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Barnadas, Agusti; Marcuello, Eugenio [Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Baiget, Montserrat [Centre for Biomedical Network Research on Rare Diseases, Barcelona (Spain); Department of Genetics, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain)

    2011-12-01

    Purpose: Several studies have been performed to evaluate the usefulness of neoadjuvant treatment using oxaliplatin and fluoropyrimidines for locally advanced rectal cancer. However, preoperative biomarkers of outcome are lacking. We studied the polymorphisms in thymidylate synthase, epidermal growth factor receptor, glutathione S-transferase pi 1 (GSTP1), and several DNA repair genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 128 rectal cancer patients treated with preoperative chemoradiotherapy. Methods and Materials: Blood samples were obtained from 128 patients with Stage II-III rectal cancer. DNA was extracted from the peripheral blood nucleated cells, and the genotypes were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were thymidylate synthase, (VNTR/5 Prime UTR, 2R G>C single nucleotide polymorphism [SNP], 3R G>C SNP), epidermal growth factor receptor (Arg497Lys), GSTP1 (Ile105val), excision repair cross-complementing 1 (Asn118Asn, 8092C>A, 19716G>C), X-ray repair cross-complementing group 1 (XRCC1) (Arg194Trp, Arg280His, Arg399Gln), and xeroderma pigmentosum group D (Lys751Gln). The pathologic response, pathologic regression, progression-free survival, and overall survival were evaluated according to each genotype. Results: The Asterisk-Operator 3/ Asterisk-Operator 3 thymidylate synthase genotype was associated with a greater response rate (pathologic complete remission and microfoci residual tumor, 59% in Asterisk-Operator 3/ Asterisk-Operator 3 vs. 35% in Asterisk-Operator 2/ Asterisk-Operator 2 and Asterisk-Operator 2/ Asterisk-Operator 3; p = .013). For the thymidylate synthase genotype, the median progression-free survival was 103 months for the Asterisk-Operator 3/ Asterisk-Operator 3 patients and 84 months for the Asterisk-Operator 2/ Asterisk-Operator 2 and Asterisk-Operator 2/ Asterisk

  6. EL RETO DE LA MUESTRA BIOLÓGICA EN LOS ESTUDIOS FARMACOGENÉTICOS O OBJETIVO DA MOSTRA BIOLÓGICA NOS ESTUDOS FARMACOGENÉTICOS BIOLOGICAL SAMPLE’S CHALLENGE ON PHARMACOGENETIC STUDIES

    Directory of Open Access Journals (Sweden)

    Alexandre Bota i Arqué

    2004-01-01

    Full Text Available Este trabajo parte de la constatación del importante incremento de estudios farmacológicos que lleva asociado un estudio farmacogenético sin que exista un conocimiento muy claro de sus consecuencias. Su primer reto es dilucidar si estos estudios tienen mayores implicaciones que las determinaciones de parámetros de rutina. No se puede obviar que la genética genera cierta preocupación debido, entre otros factores, al lenguaje técnico, la desinformación, las simplificaciones que generan los medios de comunicación, y su complejidad. El segundo objetivo es definir qué figura de propiedad tienen los investigadores o las empresas patrocinantes de las muestras biológicas y los datos genéticos en los estudios de farmacogenéticaEste trabalho parte da constatação do importante incremento dos estudos farmacológicos que leva associado um estudo farmacogenético sem que exista um conhecimento muito claro de suas conseqüências. Seu primeiro objetivo é esclarecer se estes estudos tem maiores implicações que as determinações de parâmetros de rotina. Não se pode considerar obvio que a genética gera certa preocupação devido, entre outros fatores, à linguagem técnica, à desinformação, às simplificações geradas pelos meios de comunicação, e sua complexidade. O segundo objetivo é definir que figura de propriedade tem os pesquisadores ou as empresas patrocinadoras das amostras biológicas e os dados genéticos nos estudos de farmacogenéticaThis work starts stating the great increase of pharmacological studies associated with pharmacogenetic studies without clear knowledge of their consequences. The first challenge is to find out whether pharmacogenetic studies have greater implications than the determination of routine parameters. We cannot obviate that genetics engenders special worries due to several factors, such as: technical language, lack of information, media simplifications and complexity. The second goal is to define

  7. Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems

    Czech Academy of Sciences Publication Activity Database

    Ueno, T.; Tremblay, J.; Kuneš, Jaroslav; Zicha, Josef; Dobešová, Zdenka; Pausova, Z.; Deng, A. Y.; Sun, Y. L.; Jacob, H. J.; Hamet, P.

    2003-01-01

    Roč. 81, č. 1 (2003), s. 51-60 ISSN 0946-2716 R&D Projects: GA AV ČR IAA7011711 Grant - others:CIHR(CA) MOP-11463; CIHR(CA) MT-12574; CIHR(CA) MOP-36378; AHA(US) AD-12-FMCQ 0140149N Institutional research plan: CEZ:AV0Z5011922 Keywords : genetic analysis * blood pressure * vasoactive system balance Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.101, year: 2003

  8. A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration

    Science.gov (United States)

    Kitchens, John W; Kassem, Nawal; Wood, William; Stone, Thomas W; Isernhagen, Rick; Wood, Edward; Hancock, Brad A; Radovich, Milan; Waymire, Josh; Li, Lang; Schneider, Bryan P

    2013-01-01

    Purpose To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD). Methods Patients with “wet” AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes. Results 101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT. Conclusion Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy. PMID:24143065

  9. Farmacogenética aplicada al tratamiento de la leucemia linfoide aguda Pharmacogenetics applied to the treatment of acute lymphoid leukemia

    Directory of Open Access Journals (Sweden)

    Yalena Prado Vizcaíno

    2011-09-01

    -methyltransferase, methylen-tetrahydropholate-reductase and glutathione-transferase are detoxifying systems of some of the chemotherapeutic drugs that are used for the treatment of acute lymphoid leukemia. This paper reviewed the genetic characteristics of the enzymes, the frequency of polymorphisms and the clinical implications of their expression. Similarly, the importance and the benefits of genotyping before the treatment were discussed in order to change the drug doses to maximize the therapeutic effect and reduce toxicity. Pharmacogenetics has experienced great development in the last few years and draws growing interest; the knowledge about and the implementation of this discipline will take us to the customized medicine.

  10. Translating pharmacogenetics to primary care

    NARCIS (Netherlands)

    Swen, Joachim Jesse

    2011-01-01

    In many patients drugs do not show the expected efficacy, whereas in other patients they cause toxic effects, sometimes even at low dose. Response rates to major classes of drugs range from 25 to 60 percent. For some patients, the reason for this variability may be explained by genetic variation.

  11. Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population.

    Science.gov (United States)

    Krishna Kumar, Dhakchinamoorthi; Shewade, Deepak Gopal; Loriot, Marie-Anne; Beaune, Philippe; Balachander, Jayaraman; Sai Chandran, B V; Adithan, Chandrasekaran

    2014-01-01

    To determine the influence of genetic polymorphisms on warfarin maintenance dose and to explicate an algorithm using the pharmacogenetic and clinical factors to determine the maintenance and/or starting dose of warfarin in South Indian patients receiving warfarin therapy. Patients receiving stabilized warfarin therapy (n=257) were included in the study. Single nucleotide polymorphisms (SNPs) of CYP2C9 (rs1799853 and rs1057910), VKORC1 (rs9923231, rs7196161, rs2884737, rs9934438, rs8050894, rs2359612 and rs7294), CYP4F2 (rs2108622) and GGCX (rs11676382) were genotyped by the quantitative real time-PCR method. The mean daily maintenance dose of warfarin was found to be 4.7 ± 2.1 mg/day. Patients with the CYP2C9*1/*2, *1/*3 and *2/*3 variant genotypes required a 51.0 (2.8 mg), 60.9 (2.3 mg) and 62.2 % (2.2 mg) lower daily maintenance dose of warfarin, respectively, than those patients with the CYP2C9*1/*1 wild-type genotype (5.2 mg) (pmaintenance dose. Genetic polymorphisms of CYP2C9, VKORC1, CYP4F2 and GGCX are important predictive factors of warfarin maintenance dose, and the developed algorithm will be useful to predict the required maintenance and/or starting warfarin dose in South Indian populations.

  12. Pharmacogenetic evaluation of ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase polymorphisms in teratogenicity of anti-epileptic drugs in women with epilepsy

    Directory of Open Access Journals (Sweden)

    Manna Jose

    2014-01-01

    Full Text Available Aim: Pregnancy in women with epilepsy (WWE who are on anti-epileptic drugs (AEDs has two- to three-fold increased risk of fetal malformations. AEDs are mostly metabolized by Cyp2C9, Cyp2C19 and Cyp3A4 and transported by ABCB1. Patients on AED therapy can have folate deficiency. We hypothesize that the polymorphisms in ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase (MTHFR might result in differential expression resulting in differential drug transport, drug metabolism and folate metabolism, which in turn may contribute to the teratogenic impact of AEDs. Materials and Methods: The ABCB1, Cyp2C9, Cyp2C19 and MTHFR polymorphisms were genotyped for their role in teratogenic potential and the nature of teratogenecity in response to AED treatment in WWE. The allelic, genotypic associations were tested in 266 WWE comprising of 143 WWE who had given birth to babies with WWE-malformation (WWE-M and 123 WWE who had normal offsprings (WWE-N. Results: In WWE-M, CC genotype of Ex07 + 139C/T was overrepresented (P = 0.0032 whereas the poor metabolizer allele FNx012 and FNx012 FNx012 genotype of CYP2C219 was significantly higher in comparison to WWE-N group (P = 0.007 and P = 0.005, respectively. All these observations were independent of the nature of malformation (cardiac vs. non cardiac malformations. Conclusion: Our study indicates the possibility that ABCB1 and Cyp2C19 may play a pivotal role in the AED induced teratogenesis, which is independent of nature of malformation. This is one of the first reports indicating the pharmacogenetic role of Cyp2C19 and ABCB1 in teratogenesis of AED in pregnant WWE.

  13. Microdose pharmacogenetic study of ¹⁴C-tolbutamide in healthy subjects with accelerator mass spectrometry to examine the effects of CYP2C9∗3 on its pharmacokinetics and metabolism.

    Science.gov (United States)

    Ikeda, Toshihiko; Aoyama, Shinsuke; Tozuka, Zenzaburo; Nozawa, Kohei; Hamabe, Yoshimi; Matsui, Takao; Kainuma, Michiko; Hasegawa, Setsuo; Maeda, Kazuya; Sugiyama, Yuichi

    2013-07-16

    Microdose study enables us to understand the pharmacokinetic profiles of drugs in humans prior to the conventional clinical trials. The advantage of microdose study is that the unexpected pharmacological/toxicological effects of drugs caused by drug interactions or genetic polymorphisms of metabolic enzymes/transporters can be avoided due to the limited dose. With a combination use of accelerator mass spectrometry (AMS) and (14)C-labaled compounds, the pharmacokinetics of both parent drug and its metabolites can be sensitively monitored. Thus, to demonstrate the usability of microdose study with AMS for the prediction of the impact of genetic polymorphisms of CYP enzyme on the pharmacokinetics of unchanged drugs and metabolites, we performed microdose pharmacogenetic study using tolbutamide as a CYP2C9 probe drug. A microdose of (14)C-tolbutamide (100 μg) was administered orally to healthy volunteers with the CYP2C9(∗)1/(∗)1 or CYP2C9(∗)1/(∗)3 diplotype. Area under the plasma concentration-time curve for the (14)C-radioactivity, determined by AMS, or that for the parent drug, determined by liquid chromatography/mass spectrometry, was about 1.6 times or 1.7 times greater in the CYP2C9(∗)1/(∗)3 than in the CYP2C9(∗)1/(∗)1 group, which was comparable to the previous reports at therapeutic dose. In the plasma and urine, tolbutamide, carboxytolbutamide, and 4-hydroxytolbutamide were detected and practically no other metabolites could be found in both diplotype groups. The fraction of metabolites in plasma radioactivity was slightly lower in the CYP2C9(∗)1/(∗)3 group. Microdose study can be used for the prediction of the effects of genetic polymorphisms of enzymes on the pharmacokinetics and metabolic profiles of drugs with minimal care of their pharmacological/toxicological effects. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. A haplotype-based study of lithium responding patients with bipolar affective disorder on the Faroe Islands

    DEFF Research Database (Denmark)

    Ewald, H; Wang, A G; Vang, M

    1999-01-01

    markers. In order to obtain as homogeneous a sample as possible, strict inclusion criteria based on severity of phenotype, geography and treatment response, were applied. Evidence suggestive of increased haplotype sharing on the distal part of chromosome 18q23 in the region implicated by Freimer and co-workers...

  15. A haplotype-based study of lithium responding patients with bipolar affective disorder on the Faroe Islands

    DEFF Research Database (Denmark)

    Ewald, Henrik; Wang, August G; Vang, Maria

    1999-01-01

    , the Faroese population is perhaps the most valuable European population for genetic mapping of complex disease genes. The present study searched for haplotype sharing on chromosome 18 among eight lithium responding patients with bipolar affective disorder related, on average, 6.2 generations ago, using 30 DNA...

  16. SimHap GUI: an intuitive graphical user interface for genetic association analysis.

    Science.gov (United States)

    Carter, Kim W; McCaskie, Pamela A; Palmer, Lyle J

    2008-12-25

    Researchers wishing to conduct genetic association analysis involving single nucleotide polymorphisms (SNPs) or haplotypes are often confronted with the lack of user-friendly graphical analysis tools, requiring sophisticated statistical and informatics expertise to perform relatively straightforward tasks. Tools, such as the SimHap package for the R statistics language, provide the necessary statistical operations to conduct sophisticated genetic analysis, but lacks a graphical user interface that allows anyone but a professional statistician to effectively utilise the tool. We have developed SimHap GUI, a cross-platform integrated graphical analysis tool for conducting epidemiological, single SNP and haplotype-based association analysis. SimHap GUI features a novel workflow interface that guides the user through each logical step of the analysis process, making it accessible to both novice and advanced users. This tool provides a seamless interface to the SimHap R package, while providing enhanced functionality such as sophisticated data checking, automated data conversion, and real-time estimations of haplotype simulation progress. SimHap GUI provides a novel, easy-to-use, cross-platform solution for conducting a range of genetic and non-genetic association analyses. This provides a free alternative to commercial statistics packages that is specifically designed for genetic association analysis.

  17. Pharmacogenetics of OATP Transporters Reveals That SLCO1B1 c.388A>G Variant Is Determinant of Increased Atorvastatin Response

    Directory of Open Access Journals (Sweden)

    Rosario D. C. Hirata

    2011-09-01

    Full Text Available Aims: The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated. Material and Methods: One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks. They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA estimation by SNaPshot® and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C and SLCO2B1 (−71T>C gene polymorphisms were identified by TaqMan® Real-time PCR. Results: Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034. Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%:1.3–8.0, p < 0.05. Conclusion: SLCO1B1 c.388A>G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy.

  18. SLCO1B1 and SLC19A1 gene variants and irinotecan-induced rapid response and survival: a prospective multicenter pharmacogenetics study of metastatic colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Liu Huang

    Full Text Available Rapid response to chemotherapy in metastatic colorectal cancer (mCRC patients (response within 12 weeks of chemotherapy may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens.Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658. The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing.Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively. The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher's exact test p=0.002. Their significances were all maintained even after multiple testing (all p c < 0.05. The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037. None of the SNPs predicted overall survival.Polymorphisms of solute carriers' may be useful to predict rapid response to irinotecan plus fluoropyrimidine and PFS in m

  19. Drug Transporter Genetic Variants Are Not Associated with TDF-Related Renal Dysfunction in Patients with HIV-1 Infection: A Pharmacogenetic Study.

    Directory of Open Access Journals (Sweden)

    Takeshi Nishijima

    Full Text Available To investigate whether single nucleotide polymorphisms (SNP of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement.This study investigated the association between 3 SNPs (ABCC2-24, 1249, and ABCB1 2677, which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes (>10ml/min/1.73m2 decrement in eGFR relative to baseline, >25% decrement in eGFR, and eGFR 10ml/min/1.73m2 and those without such decrement (ABCC2: -24, p = 0.53, 1249, p = 0.68; ABCB1: 2677, p = 0.74, nor between those without and with the other two renal outcomes (>25% decrement: ABCC2: -24, p = 0.83, 1249, p = 0.97, ABCB1: 2677, p = 0.40; eGFR <60ml/min/1.73m2: ABCC2: -24, p = 0.51, 1249, p = 0.81, ABCB1: 2677, p = 0.94. Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results.SNPs of the drug transporters for TDF are not associated with clinically important renal outcomes in patients who initiated TDF-containing ART.

  20. Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range - study protocol for a randomized controlled trial.

    Science.gov (United States)

    Marcatto, Leiliane Rodrigues; Sacilotto, Luciana; Bueno, Carolina Tosin; Facin, Mirella; Strunz, Celia Maria Cassaro; Darrieux, Francisco Carlos Costa; Scanavacca, Maurício Ibrahim; Krieger, Jose Eduardo; Pereira, Alexandre Costa; Santos, Paulo Caleb Junior Lima

    2016-11-17

    Time in therapeutic range (TTR) is a measurement of quality of warfarin therapy and lower TTR values (algorithm specifically calibrated for a Brazilian patient sample. The aims of this study are: to evaluate the impact of a genetic-based algorithm, compared to traditional anticoagulation, in the time to achieve the therapeutic target and in TTR percentage; and to assess the cost-effectiveness of genotype-guided warfarin dosing in a specific cohort of patients with low TTR (algorithm will be used. At the second, third, fourth and fifth consultations (with an interval of 7 days each) INR will be measured and, if necessary, the dose will be adjusted based on guidelines. Afterwards, patients who are INR stable will begin measuring their INR in 30 day intervals; if the patient's INR is not stable, the patient will return in 7 days for a new measurement of the INR. Outcomes measures will include the time to achieve the therapeutic target and the percentage of TTR at 4 and 12 weeks. In addition, as a secondary end-point, pharmacoeconomic analysis will be carried out. Ethical approval was granted by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital of the University of São Paulo Medical School. This randomized study will include patients with low TTR and it will evaluate whether a population-specific genetic algorithm might be more effective than traditional anticoagulation for a selected group of poorly anticoagulated patients. ClinicalTrials.gov, NCT02592980 . Registered on 29 October 2015.

  1. Pharmacogenetics-Based Warfarin Dosing in Patients With Cardiac Valve Replacement: The Effects of CYP2C9 and VKORC1 Gene Polymorphisms.

    Science.gov (United States)

    Farzamikia, Negin; Sakhinia, Ebrahim; Afrasiabirad, Abbas

    2017-12-22

    Many lines of evidence suggest that warfarin dosing variability is significantly associated with cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles. Therefore, we investigated the influence of CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms on warfarin dose requirements in patients who underwent cardiac valve surgery during the postoperative period.A total of 100 patients with heart valve replacement who had a prescribed target international normalized ratio (INR) range of 2-3 were enrolled in the study. Genotyping of CYP2C9 and VKORC1 was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The demographic and clinical data were collected using a precodified questionnaire and clinical examination and then were analyzed.Our findings revealed that the prevalence of CYP2C9 *2, *3 and VKORC1 -1639A alleles in patients were 10.5%, 39%, and 48%, respectively. We also found that patients with CYP2C9 *1 and VKORC1 -1639G alleles required the highest dosages of warfarin, while the carriers of CYP2C9 variant *2 and *3 alleles and VKORC1 -1639A required less warfarin. Univariate regression analysis showed that age and presence of CYP2C9 *2 allele significantly influenced the daily warfarin dose requirement. Our findings provide additional evidence to support the hypothesis that CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms explain a considerable proportion of interindividual variability in warfarin dose. Therefore, testing for these variants might be helpful for adjusting patient warfarin dosage to an effective and safe level. © American Society for Clinical Pathology 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Applications of Pharmacogenetics in Revealing Variations in ...

    African Journals Online (AJOL)

    This review article presents the latest findings of genetic variations in pharmacological targets related to disorders of major systems such as central nervous system, cardiovascular system, and the respiratory system especially in relation to asthma and the HLA antigen genotype in hypersensitivity reactions. East and Central ...

  3. Applications of Pharmacogenetics in Revealing Variations in ...

    African Journals Online (AJOL)

    acer

    taking place in molecular biology techniques. Drug action is now more ... the latest findings of genetic variations in pharmacological targets related to disorders of major .... Similarly, Gly 9 allele. (Ser9Gly) of the dopamine D3 receptor gene.

  4. Acute pharmacogenetic activation of medial prefrontal cortex ...

    Indian Academy of Sciences (India)

    Sthitapranjya Pati

    2018-01-24

    Jan 24, 2018 ... Exclusively Activated by Designer Drugs (DREADDs) have provided novel ... ad libitum access to food and water. ... testing. 2.3 Drug treatment and behavioural tests .... IL cortex (figure 3E, two-way ANOVA: interaction effect,.

  5. Irinotecan: from clinical pharmacokinetics to pharmacogenetics

    NARCIS (Netherlands)

    A.H.J. Mathijssen (Ron)

    2002-01-01

    textabstractFour decades ago, a plant alkaloid was isolated from the Chinese tree Camptotheca acuminata (Nyssaceae family), which showed promising antitumor activity in vitro (1 ). At that moment, a relatively new class of anticancer agents was born. Unfortunately, during clinical trials, this

  6. One size fits one: pharmacogenetics in gastroenterology.

    Science.gov (United States)

    Porayette, Prashanth; Flockhart, David; Gupta, Sandeep K

    2014-04-01

    Individual variability in response and development of adverse effects to drugs is a major challenge in clinical practice. Pharmacogenomics refers to the aspect of personalized medicine where the patient's genetic information instructs the selection and dosage of therapy while also predicting its adverse effects profile. Sequencing of the entire human genome has given us the opportunity to study commonly used drugs as well as newer therapeutic agents in a new light, opening up opportunities for better drug efficacy and decreased adverse effects. This article highlights developments in pharmacogenomics, relates these to practice of gastroenterology, and outlines roadblocks in translation of this knowledge into clinical practice. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  7. The Genetics, Neurogenetics and Pharmacogenetics of Addiction.

    Science.gov (United States)

    Demers, Catherine H; Bogdan, Ryan; Agrawal, Arpana

    2014-03-01

    Addictions are prevalent psychiatric disorders that confer remarkable personal and social burden. Despite substantial evidence for their moderate, yet robust, heritability (approx. 50%), specific genetic mechanisms underlying their development and maintenance remain unclear. The goal of this selective review is to highlight progress in unveiling the genetic underpinnings of addiction. First, we revisit the basis for heritable variation in addiction before reviewing the most replicable candidate gene findings and emerging signals from genomewide association studies for alcohol, nicotine and cannabis addictions. Second, we survey the modest but growing field of neurogenetics examining how genetic variation influences corticostriatal structure, function, and connectivity to identify neural mechanisms that may underlie associations between genetic variation and addiction. Third, we outline how extant genomic findings are being used to develop and refine pharmacotherapies. Finally, as sample sizes for genetically informed studies of addiction approach critical mass, we posit five exciting possibilities that may propel further discovery (improved phenotyping, rare variant discovery, gene-environment interplay, epigenetics, and novel neuroimaging designs).

  8. Pharmacogenetics in the oncological clinical practice

    International Nuclear Information System (INIS)

    Gruber, S.

    2004-01-01

    The genetic control of drug metabolism allows new insights into the bioavailability, toxicity, and efficacy of chemotherapy. In addition, molecular expression profiles of tumors offers the potential for targeted therapy to be directed more specifically to the biologic behavior of the cancer. Together these strategies are likely to change the practice of clinical oncology. However, appropriate clinical trials will be required to demonstrate the utility of these approaches before they are broadly implemented the biologic behavior of the cancer. Together these strategies are likely to change the practice of clinical oncology. However, appropriate clinical trials will be required to demonstrate the utility of these approaches before they are broadly implemented

  9. Genetics and pharmacogenetics of mood disorders.

    Science.gov (United States)

    Serretti, Alessandro

    2017-04-30

    Genetic research in Psychiatry is viewed by clinicians with both hope and curiosity sometimes mixed with disillusionment. Indeed, in the last 30 years many results have not been confirmed and clinical applications are still missing. However recent findings suggest that we are at the beginning of a new era. A set of variants within neuroplasticity and inflammation genes have been identified as a valid basis for both bipolar disorder and major depression. Similarly, a set of genes has been identified as a liability factor for response and tolerability to antidepressants and the first clinical applications are already in the market. However, some caution should be applied until definite findings are available.

  10. Analysis

    DEFF Research Database (Denmark)

    Mathiesen, Brian Vad; Liu, Wen; Zhang, Xiliang

    2014-01-01

    three major technological changes: energy savings on the demand side, efficiency improvements in energy production, and the replacement of fossil fuels by various sources of renewable energy. Consequently, the analysis of these systems must include strategies for integrating renewable sources...

  11. Association test with the principal component analysis in case ...

    Indian Academy of Sciences (India)

    type data provide an unprecedented opportunity for identify- ing genes underlying complex traits. When multiple markers are available, haplotype-based methods and genotype-based methods are commonly used for conducting association between complex traits and a series of possibly linked mark- ers. Owing to the ...

  12. Efficiency of haplotype-based methods to fine-map QTLs and embryonic lethals variants affecting fertility: illustration with a deletion segregating in Nordic Red cattle Corresponding

    DEFF Research Database (Denmark)

    Kadri, Naveen Kumar; Sahana, Goutam; Guldbrandtsen, Bernt

    2014-01-01

    Despite its importance, fertility has been declining in many cattle populations. In dairy cattle, this decline is often attributed to the negative correlation between fertility and productions traits. Recent studies showed that embryonic lethal variants might also account for a non-negligible fra...

  13. Development of COS-SNP and HRM markers for cost efficient and reliable haplotype-based detection of Lr14a in durum wheat (Triticum durum Desf.)

    Science.gov (United States)

    Leaf rust (Puccinia triticina Eriks. & Henn.) is a major disease affecting durum wheat production. The Lr14a leaf rust resistant gene present in the durum wheat cv. Creso and its derivative Colosseo is one of the best characterized leaf rust resistance sources presently deployed in durum wheat breed...

  14. Association between SLC19A1 gene polymorphism and high dose methotrexate toxicity in childhood acute lymphoblastic leukaemia and non Hodgkin malignant lymphoma: introducing a haplotype based approach

    Directory of Open Access Journals (Sweden)

    Kotnik Barbara Faganel

    2017-09-01

    Full Text Available We investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL and non Hodgkin malignant lymphoma (NHML.

  15. A comprehensive association analysis of homocysteine metabolic pathway genes in Singaporean Chinese with ischemic stroke.

    Directory of Open Access Journals (Sweden)

    Hui-Qi Low

    Full Text Available BACKGROUND: The effect of genetic factors, apart from 5,10-methylenetetrahydrofolate reductase (MTHFR polymorphisms, on elevated plasma homocysteine levels and increasing ischemic stroke risk have not been fully elucidated. We conducted a comprehensive analysis of 25 genes involved in homocysteine metabolism to investigate association of common variants within these genes with ischemic stroke risk. METHODOLOGY/PRINCIPAL FINDINGS: The study was done in two stages. In the initial study, SNP and haplotype-based association analyses were performed using 147 tagging Single Nucleotide Polymorphisms (SNPs in 360 stroke patients and 354 non-stroke controls of Singaporean Chinese ethnicity. Joint association analysis of significant SNPs was then performed to assess the cumulative effect of these variants on ischemic stroke risk. In the replication study, 8 SNPs were selected for validation in an independent set of 420 matched case-control pairs of Singaporean Chinese ethnicity. SNP analysis from the initial study suggested 3 risk variants in the MTRR, SHMT1 and TCN2 genes which were moderately associated with ischemic stroke risk, independent of known stroke risk factors. Although the replication study failed to support single-SNP associations observed in the initial study, joint association analysis of the 3 variants in combined initial and replication samples revealed a trend of elevated risk with an increased number of risk alleles (Joint P(trend = 1.2×10(-6. CONCLUSIONS: Our study did not find direct evidence of associations between any single polymorphisms of homocysteine metabolic pathway genes and ischemic stroke, but suggests that the cumulative effect of several small to moderate risk variants from genes involved in homocysteine metabolism may jointly confer a significant impact on ischemic stroke risk.

  16. Full-length sequencing and identification of novel polymorphisms in ...

    Indian Academy of Sciences (India)

    Rosalia Di Gerlando

    2017-08-16

    Aug 16, 2017 ... ANNA MARIA SUTERA, MARIA TERESA SARDINA. ∗ ... SNPs that might be important in future studies and laid the basis for further association analyses needed to ..... Haplotype-based analysis can provide higher power,.

  17. Utilization of genetic tests: analysis of gene-specific billing in Medicare claims data.

    Science.gov (United States)

    Lynch, Julie A; Berse, Brygida; Dotson, W David; Khoury, Muin J; Coomer, Nicole; Kautter, John

    2017-08-01

    We examined the utilization of precision medicine tests among Medicare beneficiaries through analysis of gene-specific tier 1 and 2 billing codes developed by the American Medical Association in 2012. We conducted a retrospective cross-sectional study. The primary source of data was 2013 Medicare 100% fee-for-service claims. We identified claims billed for each laboratory test, the number of patients tested, expenditures, and the diagnostic codes indicated for testing. We analyzed variations in testing by patient demographics and region of the country. Pharmacogenetic tests were billed most frequently, accounting for 48% of the expenditures for new codes. The most common indications for testing were breast cancer, long-term use of medications, and disorders of lipid metabolism. There was underutilization of guideline-recommended tumor mutation tests (e.g., epidermal growth factor receptor) and substantial overutilization of a test discouraged by guidelines (methylenetetrahydrofolate reductase). Methodology-based tier 2 codes represented 15% of all claims billed with the new codes. The highest rate of testing per beneficiary was in Mississippi and the lowest rate was in Alaska. Gene-specific billing codes significantly improved our ability to conduct population-level research of precision medicine. Analysis of these data in conjunction with clinical records should be conducted to validate findings.Genet Med advance online publication 26 January 2017.

  18. Human longevity and common variations in the LMNA gene: a meta-analysis

    Science.gov (United States)

    Conneely, Karen N.; Capell, Brian C.; Erdos, Michael R.; Sebastiani, Paola; Solovieff, Nadia; Swift, Amy J.; Baldwin, Clinton T.; Budagov, Temuri; Barzilai, Nir; Atzmon, Gil; Puca, Annibale A.; Perls, Thomas T.; Geesaman, Bard J.; Boehnke, Michael; Collins, Francis S.

    2012-01-01

    Summary A mutation in the LMNA gene is responsible for the most dramatic form of premature aging, Hutchinson-Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physiological cellular senescence. To explore further LMNA's possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (US Caucasians with age ≥95 years, N=873) and genetically matched younger controls (N=443). We tested all common non-redundant haplotypes (frequency ≥ 0.05) based on subgroups of these 16 SNPs for association with longevity. The most significant haplotype, based on 4 SNPs, remained significant after adjustment for multiple testing (OR = 1.56, P=2.5×10−5, multiple-testing-adjusted P=0.0045). To attempt to replicate these results, we genotyped 3448 subjects from four independent samples of long-lived individuals and control subjects from 1) the New England Centenarian Study (NECS) (N=738), 2) the Southern Italian Centenarian Study (SICS) (N=905), 3) France (N=1103), and 4) the Einstein Ashkenazi Longevity Study (N=702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR = 1.60, P=0.0023), but not in the other three samples (P>.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR = 1.18, P=7.5×10−4, multiple-testing-adjusted P=0.037). These results suggest that LMNA variants may play a role in human lifespan. PMID:22340368

  19. Genome-wide haplotype analysis of cis expression quantitative trait loci in monocytes.

    Directory of Open Access Journals (Sweden)

    Sophie Garnier

    Full Text Available In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either through additive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitative trait loci (eQTL was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for which genome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypic regulation through investigation of ~2,1 × 10(9 haplotypic combinations. 2,650 probes demonstrated haplotypic p-values >10(4-fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412 probes for which SNPs (or proxies that defined the detected haplotypes were available in the Gutenberg Health Study composed of 1,374 individuals. At the Bonferroni correction level of 1.2 × 10(-4 (~0.05/412, 193 haplotypic signals replicated. 1000 G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputed SNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additive effects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypic pattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the need for conducting haplotype-based and 1000 G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.

  20. Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence.

    Science.gov (United States)

    Ma, Jennie Z; Beuten, Joke; Payne, Thomas J; Dupont, Randolph T; Elston, Robert C; Li, Ming D

    2005-06-15

    DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within the 7p11 region that showed a 'suggestive linkage' to ND in our previous genome-wide scan in the Framingham Heart Study population. In the present study, we tested eight single nucleotide polymorphisms (SNPs) within DDC for association with ND, which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) score, in a total of 2037 smokers and non-smokers from 602 nuclear families of African- or European-American (AA or EA, respectively) ancestry. Association analysis for individual SNPs using the PBAT-GEE program indicated that SNP rs921451 was significantly associated with two of the three adjusted ND measures in the EA sample (P=0.01-0.04). Haplotype-based association analysis revealed a protective T-G-T-G haplotype for rs921451-rs3735273-rs1451371-rs2060762 in the AA sample, which was significantly associated with all three adjusted ND measures after correction for multiple testing (min Z=-2.78, P=0.006 for HSI). In contrast, we found a high-risk T-G-T-G haplotype for a different SNP combination in the EA sample, rs921451-rs3735273-rs1451371-rs3757472, which showed a significant association after Bonferroni correction with the SQ and FTND score (max Z=2.73, P=0.005 for FTND). In summary, our findings provide the first evidence for the involvement of DDC in the susceptibility to ND and, further, reveal the racial specificity of its impact.

  1. Influence of genetic variants on toxicity to anti-tubercular agents: a systematic review and meta-analysis (protocol).

    Science.gov (United States)

    Richardson, Marty; Kirkham, Jamie; Dwan, Kerry; Sloan, Derek; Davies, Geraint; Jorgensen, Andrea

    2017-07-13

    Tuberculosis patients receiving anti-tuberculosis treatment may experience serious adverse drug reactions, such as hepatotoxicity. Genetic risk factors, such as polymorphisms of the NAT2, CYP2E1 and GSTM1 genes, may increase the risk of experiencing such toxicity events. Many pharmacogenetic studies have investigated the association between genetic variants and anti-tuberculosis drug-related toxicity events, and several meta-analyses have synthesised data from these studies, although conclusions from these meta-analyses are conflicting. Many meta-analyses also have serious methodological limitations, such as applying restrictive inclusion criteria, or not assessing the quality of included studies. Most also only consider hepatotoxicity outcomes and specific genetic variants. The purpose of this systematic review and meta-analysis is to give a comprehensive evaluation of the evidence base for associations between any genetic variant and anti-tuberculosis drug-related toxicity. We will search for studies in MEDLINE, EMBASE, BIOSIS and Web of Science. We will also hand search reference lists from relevant studies and contact experts in the field. We will include cohort studies, case-control studies and randomised controlled trials that recruited patients with tuberculosis who were either already established on anti-tuberculosis treatment or were commencing treatment and who were genotyped to investigate the effect of genetic variants on any anti-tuberculosis drug-related toxicity outcome. One author will screen abstracts to identify potentially relevant studies and will then obtain the full text for each potentially relevant study in order to assess eligibility. At each of these stages, a second author will independently screen/assess 10% of studies. Two authors will independently extract data and assess the quality of studies using a pre-piloted data extraction form. If appropriate, we will pool estimates of effect for each genotype on each outcome using meta

  2. Genetic variants as ovarian cancer first-line treatment hallmarks: A systematic review and meta-analysis.

    Science.gov (United States)

    Assis, Joana; Pereira, Carina; Nogueira, Augusto; Pereira, Deolinda; Carreira, Rafael; Medeiros, Rui

    2017-12-01

    The potential predictive value of genetic polymorphisms in ovarian cancer first-line treatment is inconsistently reported. We aimed to review ovarian cancer pharmacogenetic studies to update and summarize the available data and to provide directions for further research. A systematic review followed by a meta-analysis was conducted on cohort studies assessing the involvement of genetic polymorphisms in ovarian cancer first-line treatment response retrieved through a MEDLINE database search by November 2016. Studies were pooled and summary estimates and 95% confidence intervals (CI) were calculated using random or fixed-effects models as appropriate. One hundred and forty-two studies gathering 106871 patients were included. Combined data suggested that GSTM1-null genotype patients have a lower risk of death compared to GSTM1-wt carriers, specifically in advanced stages (hazard ratio (HR), 0.68; 95% CI, 0.48-0.97) and when submitted to platinum-based chemotherapy (aHR, 0.61; 95% CI, 0.39-0.94). ERCC1 rs11615 and rs3212886 might have also a significant impact in treatment outcome (aHR, 0.67; 95% CI, 0.51-0.89; aHR, 1.28; 95% CI, 1.01-1.63, respectively). Moreover, ERCC2 rs13181 and rs1799793 showed a distinct ethnic behavior (Asians: aHR, 1.41; 95% CI, 0.80-2.49; aHR, 1.07; 95% CI, 0.62-1.86; Caucasians: aHR, 0.10; 95% CI, 0.01-0.96; aHR, 0.18; 95% CI, 0.05-0.68, respectively). The definition of integrative predictive models should encompass genetic information, especially regarding GSTM1 homozygous deletion. Justifying additional pharmacogenetic investigation are variants in ERCC1 and ERCC2, which highlight the DNA Repair ability to ovarian cancer prognosis. Further knowledge could aid to understand platinum-treatment failure and to tailor chemotherapy strategies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Searching for genes for cleft lip and/or palate based on breakpoint analysis of a balanced translocation t(9;17)(q32;q12).

    Science.gov (United States)

    Machida, Junichiro; Félix, Têmis M; Murray, Jeffrey C; Yoshiura, Koh-ichiro; Tanemura, Mitsuyo; Kamamoto, Munefumi; Shimozato, Kazuo; Sonta, Shin-ichi; Ono, Takao

    2009-09-01

    Identification of the breakpoints of disease-associated chromosome rearrangements can provide informative clues to a positional cloning approach for genes responsible for inherited diseases. Recently, we found a three-generation Japanese family segregating balanced chromosome translocation t(9;17)(q32;q12). One of the subjects had cleft lip and palate. We examined whether regions near the breakpoint could be associated with cleft lip and/or palate. We determined the breakpoints involved in the translocation by fluorescence in situ hybridization analysis and subsequent long-range polymerase chain reaction. In order to study the role of these disrupted regions in nonsyndromic cleft lip and/or palate, we performed mutation analysis and a haplotype-based transmission disequilibrium test using tagging single-nucleotide polymorphisms in the flanking regions of the breakpoints in white and Filipino nonsyndromic cleft lip and/or palate populations. Sequence analysis demonstrated that two genes, SLC31A1 (solute carrier family 31 member 1) on chromosome 9 and CCL2 (chemokine ligand 2) on chromosome 17, were rearranged with the breaks occurring within their introns. It is interesting that SLC31A1 lies closed to BSPRY (B-box and SPRY domain), which is a candidate for involvement with cleft lip and/or palate. Some of the variants in BSPRY and CCL2 showed significant p values in the cleft lip and/or palate population compared with the control population. There was also statistically significant evidence of transmission distortion for haplotypes on both chromosomes 9 and 17. The data support previous reports that genes on chromosomal regions of 9q and 17q play an important role in facial development.

  4. ACE (I/D polymorphism and response to treatment in coronary artery disease: a comprehensive database and meta-analysis involving study quality evaluation

    Directory of Open Access Journals (Sweden)

    Kitsios Georgios

    2009-06-01

    Full Text Available Abstract Background The role of angiotensin-converting enzyme (ACE gene insertion/deletion (I/D polymorphism in modifying the response to treatment modalities in coronary artery disease is controversial. Methods PubMed was searched and a database of 58 studies with detailed information regarding ACE I/D polymorphism and response to treatment in coronary artery disease was created. Eligible studies were synthesized using meta-analysis methods, including cumulative meta-analysis. Heterogeneity and study quality issues were explored. Results Forty studies involved invasive treatments (coronary angioplasty or coronary artery by-pass grafting and 18 used conservative treatment options (including anti-hypertensive drugs, lipid lowering therapy and cardiac rehabilitation procedures. Clinical outcomes were investigated by 11 studies, while 47 studies focused on surrogate endpoints. The most studied outcome was the restenosis following coronary angioplasty (34 studies. Heterogeneity among studies (p ACE I/D polymorphism on the response to treatment for the rest outcomes (coronary events, endothelial dysfunction, left ventricular remodeling, progression/regression of atherosclerosis, individual studies showed significance; however, results were discrepant and inconsistent. Conclusion In view of available evidence, genetic testing of ACE I/D polymorphism prior to clinical decision making is not currently justified. The relation between ACE genetic variation and response to treatment in CAD remains an unresolved issue. The results of long-term and properly designed prospective studies hold the promise for pharmacogenetically tailored therapy in CAD.

  5. [Drug-Drug Interactions with Consideration of Pharmacogenetics].

    Science.gov (United States)

    Ozawa, Shogo

    2018-01-01

     Elderly patients often suffer from a variety of diseases and therefore may be prescribed several kinds of drugs. Interactions between these drugs may cause problems in some patients. Guidelines for drug interactions were released on July 8, 2014 "Drug Interaction Guideline for Drug Development and Labeling Recommendations (Final Draft)". These guidelines include the theoretical basis for evaluating the mechanisms of drug interaction, the possible extent of drug interactions, and take into consideration special populations (e.g., infants, children, elderly patients, patients with hepatic or renal dysfunction, and subjects with minor deficient alleles for drug metabolizing enzymes and drug transporters). In this symposium article, I discuss this last special population: altered drug metabolism and drug interactions in subjects with minor alleles of genes encoding deficient drug metabolizing enzymes. I further discuss a drug label for eliglustat (Cerdelga) with instructions for patients with ultra-rapid, extensive, intermediate, and poor metabolizer phenotypes that arise from different CYP2D6 gene alleles.

  6. Pharmacogenetics Influence Treatment Efficacy in Childhood Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Devidsen, M.L.; Dalhoff, K.; Schmiegelow, K.

    2008-01-01

    in treatment resistance and toxic side effects. As most childhood acute lymphoblastic leukemia treatment protocols include up to 13 different chemotherapeutic agents, the impact of individual SNPs has been difficult to evaluate. So far Focus has mainly been on the widely used glucocorticosteroids, methotrexate...

  7. Breaking barriers in the genomics and pharmacogenetics of drug addiction

    Science.gov (United States)

    Ho, MK; Goldman, D; Heinz, A; Kaprio, J; Kreek, MJ; Li, MD; Munafò, MR; Tyndale, RF

    2013-01-01

    Drug addictions remain a substantial health issue, with limited treatment options currently available. Despite considerable advances in the understanding of our genetic architecture, the genetic underpinning of complex disorders remains elusive. Numerous candidate genes have been implicated in the etiology and response to treatment for different addictions based on our current understanding of the neurobiology. Genome-wide association studies have also provided novel targets. However, replication of these studies is often lacking which complicates interpretation; this will improve as issues such as phenotypic characterization, the apparent “missing heritability”, the identification of functional variants, and possible gene-environment interactions are addressed. In addition, there is growing evidence that genetic information can be useful for refining the choice of addiction treatment. As genetic testing becomes more common in the practice of medicine, a variety of ethical and practical challenges, some of which are unique to drug addiction, will also need to be considered. PMID:20981002

  8. Pharmacogenetics and Pharmacokinetics in high-dose alkylating chemotherapy

    NARCIS (Netherlands)

    Ekhart, G.C. (Corine)

    2008-01-01

    High-dose chemotherapy in combination with peripheral blood progenitor cell transplantation has been developed as a possible curative treatment modality in several solid tumours. A frequently used high-dose regimen in the Netherlands is the CTC regimen, which is a 4-day course of cyclophosphamide,

  9. The Pharmacogenetics of Metformin in Women with PCOS

    DEFF Research Database (Denmark)

    Pedersen, Andreas J T; Stage, Tore Bjerregaard; Glintborg, Dorte

    2018-01-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin transport......Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin...... transporters, their transcriptional regulators or in metformin target genes on metformin response in women with PCOS is unclear. Associations between pharmacodynamic responses to metformin (changes in weight, lipid profile, insulin sensitivity evaluated by oral glucose tolerance testing) and polymorphisms...... in OCT1 (rs12208357 and rs72552763), HNF1A (rs1169288 and rs2464196), MATE1 (rs2289669 and rs2252281), MATE2-K (rs12943590) and ATM (rs11212617) were studied in 40 women with PCOS randomized to 12 months of treatment with metformin 1000 mg twice daily ± oral contraceptive pills (150 mg desogestrel + 30...

  10. RELATIONSHIPS BETWEEN GENETIC POLYMORPHISM AND DRUG: FORENSIC PHARMACOGENETIC

    OpenAIRE

    Çevik, Filiz Ekim; Balcıoğlu, Yasin Hasan; Karadayı, Şükriye; Çakan, Hüseyin

    2015-01-01

    Filiz Ekim ÇEVİK1, Yasin Hasan BALCIOĞLU1, Şükriye KARADAYI2, Hüseyin ÇAKAN1 1İstanbul University, Forensic Medicine Institute, TÜRKİYE 2İstanbul University, Public Health Directorate, TÜRKİYE

  11. Genetics of Psoriasis and Pharmacogenetics of Biological Drugs

    Directory of Open Access Journals (Sweden)

    Rocío Prieto-Pérez

    2013-01-01

    Full Text Available Psoriasis is a chronic inflammatory disease of the skin. The causes of psoriasis are unknown, although family and twin studies have shown genetic factors to play a key role in its development. The many genes associated with psoriasis and the immune response include TNFα, IL23, and IL12. Advances in knowledge of the pathogenesis of psoriasis have enabled the development of new drugs that target cytokines (e.g., etanercept, adalimumab, and infliximab, which target TNFα, and ustekinumab, which targets the p40 subunit of IL23 and IL12. These drugs have improved the safety and efficacy of treatment in comparison with previous therapies. However, not all patients respond equally to treatment, possibly owing to interindividual genetic variability. In this review, we describe the genes associated with psoriasis and the immune response, the biological drugs used to treat chronic severe plaque psoriasis, new drugs in phase II and III trials, and current knowledge on the implications of pharmacogenomics in predicting response to these treatments.

  12. Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children

    Directory of Open Access Journals (Sweden)

    Ida Aka

    2017-11-01

    Full Text Available Cytochrome P450 (CYP enzymes are commonly involved in drug metabolism, and genetic variation in the genes encoding CYPs are associated with variable drug response. While genotype-guided therapy has been clinically implemented in adults, these associations are less well established for pediatric patients. In order to understand the frequency of pediatric exposures to drugs with known CYP interactions, we compiled all actionable drug–CYP interactions with a high level of evidence using Clinical Pharmacogenomic Implementation Consortium (CPIC data and surveyed 10 years of electronic health records (EHR data for the number of children exposed to CYP-associated drugs. Subsequently, we performed a focused literature review for drugs commonly used in pediatrics, defined as more than 5000 pediatric patients exposed in the decade-long EHR cohort. There were 48 drug–CYP interactions with a high level of evidence in the CPIC database. Of those, only 10 drugs were commonly used in children (ondansetron, oxycodone, codeine, omeprazole, lansoprazole, sertraline, amitriptyline, citalopram, escitalopram, and risperidone. For these drugs, reports of the drug–CYP interaction in cohorts including children were sparse. There are adequate data for implementation of genotype-guided therapy for children for three of the 10 commonly used drugs (codeine, omeprazole and lansoprazole. For the majority of commonly used drugs with known CYP interactions, more data are required to support pharmacogenomic implementation in children.

  13. Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response.

    Science.gov (United States)

    Shahin, Mohamed H; Johnson, Julie A

    2016-04-01

    Thiazide (TZD) diuretics are among the most commonly prescribed antihypertensives globally; however their chronic blood pressure (BP) lowering mechanism remains unclear. Herein we discuss the current evidence regarding specific mechanisms regulating the antihypertensive effects of TZDs, suggesting that TZDs act via multiple complex and interacting mechanisms, including natriuresis with short term use and direct vasodilatory effects chronically. Additionally, we review pharmacogenomics signals that have been associated with TZDs BP-response in several cohorts (i.e. NEDD4L, PRKCA, EDNRA-GNAS, and YEATS4) and discuss how these genes might be related to TZD BP-response mechanism. Understanding the association between these genes and TZD BP mechanism might facilitate the development of new drugs and therapeutic approaches based on a deeper understanding of the determinants of BP-response. Copyright © 2016. Published by Elsevier Ltd.

  14. [Pharmacogenetic aspects of the immunodepressive action of cyclophosphamide].

    Science.gov (United States)

    Telegin, L Iu

    1979-03-01

    The alkylating and immunodepressive activity of the serum of CBA, BALB/c and DBA/2 mice was studied after the cyclophosphamide administration. The interstrain differences between the indices under study were revealed; no direct correlation was shown between them. DBA/2 mice were found to be the most sensitive to the immunodepressive action of cyclophosphamide, and had the highest blood serum immunodepressive activity.

  15. Towards optimal dosing of coumarin derivatives: the role of pharmacogenetics

    NARCIS (Netherlands)

    van Schie, R.M.F.

    2013-01-01

    Coumarin derivatives are effective in the prevention and treatment of thromboembolic diseases. Examples of indications are atrial fibrillation and venous thromboembolism. Although coumarins are on the market for decades, it is still challenging to find the optimal dosage for each patient since

  16. Pharmacogenetics of thiopurines. Can posology be guided by laboratory data?

    International Nuclear Information System (INIS)

    Stocco, G.; Decorti, G.; Bartoli, F.; Giraldi, T.; Martelossi, S.; Ventura, A.; Malusa, N.

    2004-01-01

    Background. The purpose of this study was to investigate the relationships between the presence of mutations in the TPMT gene, the consequent reduced enzymatic activity, and the clinical toxicity of the treatment with thiopurine antimetabolite drugs. Materials and methods. The study was performed on 44 patients with inflammatory bowel disease treated with AZA. DNA was extracted from blood samples collected from each patient, and genotyping was performed using specific polymerase chain reaction assays in order to detect the three more frequent mutations of the gene. Enzymatic activity was measured on red blood cell lysates by HPLC. Results. Among the subjects, 4 (9.0%) were heterozygous for mutations in the TPMT gene; no subject was homozygous for mutations in the TPMT gene. A complete concordance between TPMT mutated genotype and reduced enzymatic activity could be determined. The incidence of toxicity in the subjects with a mutated genotype was not different from that observed in the patients with a normal TPMT gene. Conclusion. Genotyping methods provide a simple and reliable DNA-based strategy to identify TPMT homozygotes that should avoid thiopurines administration. However, it seems that the most common, less dangerous forms of thiopurine toxicity could be caused by factors different from TPMT gene mutations examined. (author)

  17. Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Levinsen, Mette; Rotevatn, Elisabeth Orskov; Rosthøj, Susanne

    2014-01-01

    BACKGROUND: Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMT(LA)) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMT(WT)) when treated with 6 MP maintenance ther...

  18. Pharmacogenetic investigations with special reference to forensic medicine

    DEFF Research Database (Denmark)

    Buchard, Anders

    Dansk Resumé Mennesker reagerer forskelligt på lægemidler. Den samme dosis af et givent lægemiddel vil hos nogle individer resultere i bivirkninger, mens andre vil opleve ringe eller ingen effekt. Der kan være mange årsager til dette, bl.a. genetiske forskelle mellem individer. Farmakogenetik kan...

  19. Warfarin dosage response related pharmacogenetics in Chinese population.

    Directory of Open Access Journals (Sweden)

    Siyue Li

    Full Text Available As the most frequently prescribed anticoagulant, warfarin has large inter-individual variability in dosage. Genetic polymorphisms could largely explain the differences in dosage requirement. rs9923231 (VKORC1, rs7294 (VKORC1, rs1057910 (CYP2C9, rs2108622 (CYP4F2, and rs699664 (GGCX involved in the warfarin action mechanism and the circulatory vitamin K were selected to investigate their polymorphism characteristics and their effects on the pharmacodynamics and pharmacokinetics of warfarin in Chinese population.220 patients with cardiac valve replacement were recruited. International normalized ratio and plasma warfarin concentrations were determined. The five genetic polymorphisms were genotyping by pyro-sequencing. The relationships of maintenance dose, plasma warfarin concentration and INR were assessed among groups categorized by genotypes.rs9923231 and rs7294 in VKORC1 had the analogous genotype frequencies (D': 0.969. 158 of 220 recruited individuals had the target INR (1.5-2.5. Patients with AA of rs9923231 and CC of rs7294 required a significantly lower maintenance dose and plasma concentration than those with AG and TC, respectively. The mean weekly maintenance dose was also significantly lower in CYP2C9 rs1057910 mutated heterozygote than in patients with the wild homozygote. Eliminating the influence from environment factors (age, body weight and gender, rs9923231 and rs1057910 could explain about 32.0% of the variability in warfarin maintenance dose; rs7294 could explain 26.7% of the variability in plasma concentration. For patients with allele G of rs9923231 and allele T of rs7294, higher plasma concentration was needed to achieve the similar goal INR.A better understanding of the genetic variants in individuals can be the foundation of warfarin dosing algorithm and facilitate the reasonable and effective use of warfarin in Chinese.

  20. Pharmacogenetics of Methylphenidate Response in Preschoolers with ADHD

    Science.gov (United States)

    McGough, James; McCracken, James; Swanson, James; Riddle, Mark; Kollins, Scott; Greenhill, Laurence; Abikoff, Howard; Davies, Mark; Chuang, Shirley; Wigal, Tim; Wigal, Sharon; Posner, Kelly; Skrobala, Anne; Kastelic, Elizabeth; Ghuman, Jaswinder; Cunningham, Charles; Shigawa, Sharon; Moyzis, Robert; Vitiello, Benedetto

    2006-01-01

    Objective: The authors explored genetic moderators of symptom reduction and side effects in methylphenidate-treated preschool-age children diagnosed with attention-deficit/hyperactivity disorder (ADHD). Method: DNA was isolated from 81 subjects in a double-blind, placebo-controlled, crossover methylphenidate titration. Parents and teachers…

  1. Advances in drug metabolism and pharmacogenetics research in Australia.

    Science.gov (United States)

    Mackenzie, Peter I; Somogyi, Andrew A; Miners, John O

    2017-02-01

    Metabolism facilitates the elimination, detoxification and excretion in urine or bile (as biotransformation products) of a myriad of structurally diverse drugs and other chemicals. The metabolism of drugs, non-drug xenobiotics and many endogenous compounds is catalyzed by families of drug metabolizing enzymes (DMEs). These include the hemoprotein-containing cytochromes P450, which function predominantly as monooxygenases, and conjugation enzymes that transfer a sugar, sulfate, acetate or glutathione moiety to substrates containing a suitable acceptor functional group. Drug and chemical metabolism, especially the enzymes that catalyse these reactions, has been the research focus of several groups in Australia for over four decades. In this review, we highlight the role of recent and current drug metabolism research in Australia, including elucidation of the structure and function of enzymes from the various DME families, factors that modulate enzyme activity in humans (e.g. drug-drug interactions, gene expression and genetic polymorphism) and the application of in vitro approaches for the prediction of drug metabolism parameters in humans, along with the broader pharmacological/clinical pharmacological and toxicological significance of drug metabolism and DMEs and their relevance to drug discovery and development, and to clinical practice. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Clinical pharmacology quality assurance program: models for longitudinal analysis of antiretroviral proficiency testing for international laboratories.

    Science.gov (United States)

    DiFrancesco, Robin; Rosenkranz, Susan L; Taylor, Charlene R; Pande, Poonam G; Siminski, Suzanne M; Jenny, Richard W; Morse, Gene D

    2013-10-01

    Among National Institutes of Health HIV Research Networks conducting multicenter trials, samples from protocols that span several years are analyzed at multiple clinical pharmacology laboratories (CPLs) for multiple antiretrovirals. Drug assay data are, in turn, entered into study-specific data sets that are used for pharmacokinetic analyses, merged to conduct cross-protocol pharmacokinetic analysis, and integrated with pharmacogenomics research to investigate pharmacokinetic-pharmacogenetic associations. The CPLs participate in a semiannual proficiency testing (PT) program implemented by the Clinical Pharmacology Quality Assurance program. Using results from multiple PT rounds, longitudinal analyses of recovery are reflective of accuracy and precision within/across laboratories. The objectives of this longitudinal analysis of PT across multiple CPLs were to develop and test statistical models that longitudinally: (1) assess the precision and accuracy of concentrations reported by individual CPLs and (2) determine factors associated with round-specific and long-term assay accuracy, precision, and bias using a new regression model. A measure of absolute recovery is explored as a simultaneous measure of accuracy and precision. Overall, the analysis outcomes assured 97% accuracy (±20% of the final target concentration of all (21) drug concentration results reported for clinical trial samples by multiple CPLs). Using the Clinical Laboratory Improvement Act acceptance of meeting criteria for ≥2/3 consecutive rounds, all 10 laboratories that participated in 3 or more rounds per analyte maintained Clinical Laboratory Improvement Act proficiency. Significant associations were present between magnitude of error and CPL (Kruskal-Wallis P Kruskal-Wallis P < 0.001).

  3. Risk factors for calcineurin inhibitor nephrotoxicity after renal transplantation: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Xia T

    2018-02-01

    Full Text Available Tianyi Xia, Sang Zhu, Yan Wen, Shouhong Gao, Mingming Li, Xia Tao, Feng Zhang, Wansheng Chen Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China Background: Nephrotoxicity of calcineurin inhibitors (CNIs is the major concern for long-term allograft survival despite its predominant role in current immunosuppressive regime after renal transplantation. CNI nephrotoxicity is multifactorial with demographic, environmental, and pharmacogenetic flexibility, whereas studies indicating risk factors for CNI nephrotoxicity obtained incomplete or conflicting results.Methods: A systematic review and meta-analysis of risk factors for CNI nephrotoxicity was performed on all retrieved studies through a comprehensive research of network database. Data were analyzed by Review Manager 5.2 with heterogeneity assessed using the Cochrane Q and I2 tests. CNI nephrotoxicity was primarily indicated with protocol biopsy or index-based clinical diagnosis, and the secondary outcome was defined as delayed graft function.Results: Twelve observational studies containing a total of 2,849 cases were identified. Donor age (odds ratio [OR], 1.01; 95% CI, 1.01–1.03; p=0.02, recipient zero-time arteriosclerosis (OR, 1.44; 95% CI, 1.04–1.99; p=0.03, and CYP3A5*3/*3 genotype (OR, 2.80; 95% CI, 2.63–2.98; p=0.00 were confirmed as risk factors for CNI nephrotoxicity. Subgroup and sensitivity analysis claimed donor age as a significant contributor in Asian and Caucasian areas.Conclusion: Older donor age, recipient zero-time arteriosclerosis, and CYP3A5*3/*3 genotype might add up the risk for CNI nephrotoxicity, which could be interpreted into a robust biomarker system. Keywords: calcineurin inhibitor, transplantation, nephrotoxicity, risk factor, systematic review, meta-analysis

  4. Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines.

    Directory of Open Access Journals (Sweden)

    Edwin Choy

    2008-11-01

    Full Text Available Lymphoblastoid cell lines (LCLs, originally collected as renewable sources of DNA, are now being used as a model system to study genotype-phenotype relationships in human cells, including searches for QTLs influencing levels of individual mRNAs and responses to drugs and radiation. In the course of attempting to map genes for drug response using 269 LCLs from the International HapMap Project, we evaluated the extent to which biological noise and non-genetic confounders contribute to trait variability in LCLs. While drug responses could be technically well measured on a given day, we observed significant day-to-day variability and substantial correlation to non-genetic confounders, such as baseline growth rates and metabolic state in culture. After correcting for these confounders, we were unable to detect any QTLs with genome-wide significance for drug response. A much higher proportion of variance in mRNA levels may be attributed to non-genetic factors (intra-individual variance--i.e., biological noise, levels of the EBV virus used to transform the cells, ATP levels than to detectable eQTLs. Finally, in an attempt to improve power, we focused analysis on those genes that had both detectable eQTLs and correlation to drug response; we were unable to detect evidence that eQTL SNPs are convincingly associated with drug response in the model. While LCLs are a promising model for pharmacogenetic experiments, biological noise and in vitro artifacts may reduce power and have the potential to create spurious association due to confounding.

  5. An analysis of growth, differentiation and apoptosis genes with risk of renal cancer.

    Directory of Open Access Journals (Sweden)

    Linda M Dong

    2009-03-01

    Full Text Available We conducted a case-control study of renal cancer (987 cases and 1298 controls in Central and Eastern Europe and analyzed genomic DNA for 319 tagging single-nucleotide polymorphisms (SNPs in 21 genes involved in cellular growth, differentiation and apoptosis using an Illumina Oligo Pool All (OPA. A haplotype-based method (sliding window analysis of consecutive SNPs was used to identify chromosome regions of interest that remained significant at a false discovery rate of 10%. Subsequently, risk estimates were generated for regions with a high level of signal and individual SNPs by unconditional logistic regression adjusting for age, gender and study center. Three regions containing genes associated with renal cancer were identified: caspase 1/5/4/12(CASP 1/5/4/12, epidermal growth factor receptor (EGFR, and insulin-like growth factor binding protein-3 (IGFBP3. We observed that individuals with CASP1/5/4/12 haplotype (spanning area upstream of CASP1 through exon 2 of CASP5 GGGCTCAGT were at higher risk of renal cancer compared to individuals with the most common haplotype (OR:1.40, 95% CI:1.10-1.78, p-value = 0.007. Analysis of EGFR revealed three strong signals within intron 1, particularly a region centered around rs759158 with a global p = 0.006 (GGG: OR:1.26, 95% CI:1.04-1.53 and ATG: OR:1.55, 95% CI:1.14-2.11. A region in IGFBP3 was also associated with increased risk (global p = 0.04. In addition, the number of statistically significant (p-value<0.05 SNP associations observed within these three genes was higher than would be expected by chance on a gene level. To our knowledge, this is the first study to evaluate these genes in relation to renal cancer and there is need to replicate and extend our findings. The specific regions associated with risk may have particular relevance for gene function and/or carcinogenesis. In conclusion, our evaluation has identified common genetic variants in CASP1, CASP5, EGFR, and IGFBP3 that could be

  6. Simple, Low-Cost Detection of Candida parapsilosis Complex Isolates and Molecular Fingerprinting of Candida orthopsilosis Strains in Kuwait by ITS Region Sequencing and Amplified Fragment Length Polymorphism Analysis.

    Science.gov (United States)

    Asadzadeh, Mohammad; Ahmad, Suhail; Hagen, Ferry; Meis, Jacques F; Al-Sweih, Noura; Khan, Ziauddin

    2015-01-01

    Candida parapsilosis has now emerged as the second or third most important cause of healthcare-associated Candida infections. Molecular studies have shown that phenotypically identified C. parapsilosis isolates represent a complex of three species, namely, C. parapsilosis, C. orthopsilosis and C. metapsilosis. Lodderomyces elongisporus is another species phenotypically closely related to the C. parapsilosis-complex. The aim of this study was to develop a simple, low cost multiplex (m) PCR assay for species-specific identification of C. parapsilosis complex isolates and to study genetic relatedness of C. orthopsilosis isolates in Kuwait. Species-specific amplicons from C. parapsilosis (171 bp), C. orthopsilosis (109 bp), C. metapsilosis (217 bp) and L. elongisporus (258 bp) were obtained in mPCR. Clinical isolates identified as C. parapsilosis (n = 380) by Vitek2 in Kuwait and an international collection of 27 C. parapsilosis complex and L. elongisporus isolates previously characterized by rDNA sequencing were analyzed to evaluate mPCR. Species-specific PCR and DNA sequencing of internal transcribed spacer (ITS) region of rDNA were performed to validate the results of mPCR. Fingerprinting of 19 clinical C. orthopsilosis isolates (including 4 isolates from a previous study) was performed by amplified fragment length polymorphism (AFLP) analysis. Phenotypically identified C. parapsilosis isolates (n = 380) were identified as C. parapsilosis sensu stricto (n = 361), C. orthopsilosis (n = 15), C. metapsilosis (n = 1) and L. elongisporus (n = 3) by mPCR. The mPCR also accurately detected all epidemiologically unrelated C. parapsilosis complex and L. elongisporus isolates. The 19 C. orthopsilosis isolates obtained from 16 patients were divided into 3 haplotypes based on ITS region sequence data. Seven distinct genotypes were identified among the 19 C. orthopsilosis isolates by AFLP including a dominant genotype (AFLP1) comprising 11 isolates recovered from 10 patients. A

  7. Y-chromosome phylogeographic analysis of the Greek-Cypriot population reveals elements consistent with Neolithic and Bronze Age settlements.

    Science.gov (United States)

    Voskarides, Konstantinos; Mazières, Stéphane; Hadjipanagi, Despina; Di Cristofaro, Julie; Ignatiou, Anastasia; Stefanou, Charalambos; King, Roy J; Underhill, Peter A; Chiaroni, Jacques; Deltas, Constantinos

    2016-01-01

    The archeological record indicates that the permanent settlement of Cyprus began with pioneering agriculturalists circa 11,000 years before present, (ca. 11,000 y BP). Subsequent colonization events followed, some recognized regionally. Here, we assess the Y-chromosome structure of Cyprus in context to regional populations and correlate it to phases of prehistoric colonization. Analysis of haplotypes from 574 samples showed that island-wide substructure was barely significant in a spatial analysis of molecular variance (SAMOVA). However, analyses of molecular variance (AMOVA) of haplogroups using 92 binary markers genotyped in 629 Cypriots revealed that the proportion of variance among the districts was irregularly distributed. Principal component analysis (PCA) revealed potential genetic associations of Greek-Cypriots with neighbor populations. Contrasting haplogroups in the PCA were used as surrogates of parental populations. Admixture analyses suggested that the majority of G2a-P15 and R1b-M269 components were contributed by Anatolia and Levant sources, respectively, while Greece Balkans supplied the majority of E-V13 and J2a-M67. Haplotype-based expansion times were at historical levels suggestive of recent demography. Analyses of Cypriot haplogroup data are consistent with two stages of prehistoric settlement. E-V13 and E-M34 are widespread, and PCA suggests sourcing them to the Balkans and Levant/Anatolia, respectively. The persistent pre-Greek component is represented by elements of G2-U5(xL30) haplogroups: U5*, PF3147, and L293. J2b-M205 may contribute also to the pre-Greek strata. The majority of R1b-Z2105 lineages occur in both the westernmost and easternmost districts. Distinctively, sub-haplogroup R1b- M589 occurs only in the east. The absence of R1b- M589 lineages in Crete and the Balkans and the presence in Asia Minor are compatible with Late Bronze Age influences from Anatolia rather than from Mycenaean Greeks.

  8. Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment.

    Science.gov (United States)

    Turner, Steve; Francis, Ben; Vijverberg, Susanne; Pino-Yanes, Maria; Maitland-van der Zee, Anke H; Basu, Kaninika; Bignell, Lauren; Mukhopadhyay, Somnath; Tavendale, Roger; Palmer, Colin; Hawcutt, Daniel; Pirmohamed, Munir; Burchard, Esteban G; Lipworth, Brian

    2016-07-01

    The Gly-to-Arg substitution at the 16 position (rs1042713) in the β2-adrenoceptor gene (ADRB2) is associated with enhanced downregulation and uncoupling of β2-receptors. We sought to undertake a meta-analysis to test the hypothesis that there is an interaction between the A allele of rs1042713 (Arg16 amino acid) and long-acting β-agonist (LABA) exposure for asthma exacerbations in children. Children with diagnosed asthma were recruited in 5 populations (BREATHE, Genes-Environments and Admixture in Latino Americans II, PACMAN, the Paediatric Asthma Gene Environment Study, and the Pharmacogenetics of Adrenal Suppression with Inhaled Steroid Study). A history of recent exacerbation and asthma treatment was determined from questionnaire data. DNA was extracted, and the Gly16Arg genotype was determined. Data from 4226 children of white Northern European and Latino origin were analyzed, and the odds ratio for exacerbation increased by 1.52 (95% CI, 1.17-1.99; P = .0021) for each copy of the A allele among the 637 children treated with inhaled corticosteroids (ICSs) plus LABAs but not for treatment with ICSs alone (n = 1758) or ICSs plus leukotriene receptor antagonist (LTRAs; n = 354) or ICSs plus LABAs plus LTRAs (n = 569). The use of a LABA but not an LTRA as an "add-on controller" is associated with increased risk of asthma exacerbation in children carrying 1 or 2 A alleles at rs1042713. Prospective genotype-stratified clinical trials are now required to explore the potential role of rs1042713 genotyping for personalized asthma therapy in children. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  9. Analysis of the association between CFH Y402H polymorphism and response to intravitreal ranibizumab in patients with neovascular age-related macular degeneration (nAMD

    Directory of Open Access Journals (Sweden)

    Nur Afiqah Mohamad

    2018-03-01

    Full Text Available Pharmacogenetic studies indicate that a variable response to anti-vascular endothelial growth factor (VEGF therapy in patients with neovascular form of AMD (nAMD may be due to polymorphisms in the complement factor H gene (CFH. This study is the first to investigate the association between CFH Y402H polymorphism and the response to ranibizumab therapy in Malaysian patients with nAMD. We included 134 patients with nAMD, examined between September 2014 and February 2016. The diagnosis of nAMD was confirmed by ophthalmologic examination, before ranibizumab therapy was started. Each patient received an intravitreal injection of 0.5 mg/0.05 ml ranibizumab following a treat-and-extend (TE regimen. Best-corrected visual acuity (BCVA and central retinal thickness (CRT were recorded after 3 and 6 months following the first injection and compared with the baseline values. Genotyping of Y402H (rs1061170 polymorphism was performed using PCR-RFLP and the amplified product was digested with MluCI restriction enzyme. Association between the Y402H genotypes and response to treatment was determined by a logistic regression analysis of responder (n = 49 and non-responder (n = 84 group. Significantly worse mean BCVA was observed for the CC genotype compared to the TT + CT genotype in the total sample after 6-month follow-up (p = 0.018. Comparing the baseline and 6-month point measurements, improved mean BCVA was observed in responder group, while worse mean BCVA was recorded for non-responder group. However, our regression analysis, adjusted for confounding factors, showed no significant association between the Y402H genotypes and response to treatment in nAMD patients under the recessive model (p > 0.05. Overall, our results suggest that factors other than Y402H polymorphism may be involved in the progression of nAMD after treatment with anti-VEGF agents, in Malaysian population.

  10. Decision analysis multicriteria analysis

    International Nuclear Information System (INIS)

    Lombard, J.

    1986-09-01

    The ALARA procedure covers a wide range of decisions from the simplest to the most complex one. For the simplest one the engineering judgement is generally enough and the use of a decision aiding technique is therefore not necessary. For some decisions the comparison of the available protection option may be performed from two or a few criteria (or attributes) (protection cost, collective dose,...) and the use of rather simple decision aiding techniques, like the Cost Effectiveness Analysis or the Cost Benefit Analysis, is quite enough. For the more complex decisions, involving numerous criteria or for decisions involving large uncertainties or qualitative judgement the use of these techniques, even the extended cost benefit analysis, is not recommended and appropriate techniques like multi-attribute decision aiding techniques are more relevant. There is a lot of such particular techniques and it is not possible to present all of them. Therefore only two broad categories of multi-attribute decision aiding techniques will be presented here: decision analysis and the outranking analysis

  11. Performance analysis

    International Nuclear Information System (INIS)

    2008-05-01

    This book introduces energy and resource technology development business with performance analysis, which has business division and definition, analysis of current situation of support, substance of basic plan of national energy, resource technique development, selection of analysis index, result of performance analysis by index, performance result of investigation, analysis and appraisal of energy and resource technology development business in 2007.

  12. Instrumental analysis

    International Nuclear Information System (INIS)

    Jae, Myeong Gi; Lee, Won Seong; Kim, Ha Hyeok

    1989-02-01

    This book give description of electronic engineering such as circuit element and device, circuit analysis and logic digital circuit, the method of electrochemistry like conductometry, potentiometry and current measuring, spectro chemical analysis with electromagnetic radiant rays, optical components, absorption spectroscopy, X-ray analysis, atomic absorption spectrometry and reference, chromatography like gas-chromatography and liquid-chromatography and automated analysis on control system evaluation of automated analysis and automated analysis system and reference.

  13. Instrumental analysis

    Energy Technology Data Exchange (ETDEWEB)

    Jae, Myeong Gi; Lee, Won Seong; Kim, Ha Hyeok

    1989-02-15

    This book give description of electronic engineering such as circuit element and device, circuit analysis and logic digital circuit, the method of electrochemistry like conductometry, potentiometry and current measuring, spectro chemical analysis with electromagnetic radiant rays, optical components, absorption spectroscopy, X-ray analysis, atomic absorption spectrometry and reference, chromatography like gas-chromatography and liquid-chromatography and automated analysis on control system evaluation of automated analysis and automated analysis system and reference.

  14. Instrumental analysis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Seung Jae; Seo, Seong Gyu

    1995-03-15

    This textbook deals with instrumental analysis, which consists of nine chapters. It has Introduction of analysis chemistry, the process of analysis and types and form of the analysis, Electrochemistry on basic theory, potentiometry and conductometry, electromagnetic radiant rays and optical components on introduction and application, Ultraviolet rays and Visible spectrophotometry, Atomic absorption spectrophotometry on introduction, flame emission spectrometry and plasma emission spectrometry. The others like infrared spectrophotometry, X-rays spectrophotometry and mass spectrometry, chromatography and the other instrumental analysis like radiochemistry.

  15. Instrumental analysis

    International Nuclear Information System (INIS)

    Kim, Seung Jae; Seo, Seong Gyu

    1995-03-01

    This textbook deals with instrumental analysis, which consists of nine chapters. It has Introduction of analysis chemistry, the process of analysis and types and form of the analysis, Electrochemistry on basic theory, potentiometry and conductometry, electromagnetic radiant rays and optical components on introduction and application, Ultraviolet rays and Visible spectrophotometry, Atomic absorption spectrophotometry on introduction, flame emission spectrometry and plasma emission spectrometry. The others like infrared spectrophotometry, X-rays spectrophotometry and mass spectrometry, chromatography and the other instrumental analysis like radiochemistry.

  16. Sensitivity analysis

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/003741.htm Sensitivity analysis To use the sharing features on this page, please enable JavaScript. Sensitivity analysis determines the effectiveness of antibiotics against microorganisms (germs) ...

  17. Real analysis

    CERN Document Server

    McShane, Edward James

    2013-01-01

    This text surveys practical elements of real function theory, general topology, and functional analysis. Discusses the maximality principle, the notion of convergence, the Lebesgue-Stieltjes integral, function spaces and harmonic analysis. Includes exercises. 1959 edition.

  18. Isoflavonoid compounds extracted from Pueraria lobata suppress alcohol preference in a pharmacogenetic rat model of alcoholism.

    Science.gov (United States)

    Lin, R C; Guthrie, S; Xie, C Y; Mai, K; Lee, D Y; Lumeng, L; Li, T K

    1996-06-01

    The extract from an edible vine, Pueraria lobata, has long been used in China to lessen alcohol intoxication. We have previously shown that daidzin, one of the major components from this plant extract, is efficacious in lowering blood alcohol levels and shortens sleep time induced by alcohol ingestion. This study was conducted to test the antidipsotropic effect of daidzin and two other major isoflavonoids, daidzein and puerarin, from Pueraria lobata administered by the oral route. An alcohol-preferring rat model, the selectively-bred P line of rats, was used for the study. All three isoflavonoid compounds were effective in suppressing voluntary alcohol consumption by the P rats. When given orally to P rats at a dose of 100 mg/kg/day, daidzein, daidzin, and puerarin decreased ethanol intake by 75%, 50%, and 40%, respectively. The decrease in alcohol consumption was accompanied by an increase in water intake, so that the total fluid volume consumed daily remained unchanged. The effects of these isoflavonoid compounds on alcohol and water intake were reversible. Suppression of alcohol consumption was evident after 1 day of administration and became maximal after 2 days. Similarly, alcohol preference returned to baseline levels 2 days after discontinuation of the isoflavonoids. Rats receiving the herbal extracts ate the same amounts of food as control animals, and they gained weight normally during the experiments. When administered orally, none of these compounds affected the activities of liver alcohol dehydrogenase and aldehyde dehydrogenase. Therefore, the reversal of alcohol preference produced by these compounds may be mediated via the CNS. Data demonstrate that isoflavonoid compounds extracted from Pueraria lobata is effective in suppressing the appetite for alcohol when taken orally, raising the possibility that other constituents of edible plants may exert similar and more potent actions.

  19. Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

    DEFF Research Database (Denmark)

    Serna, María José; Rivera-Caravaca, José Miguel; Gonzalez-Conejero, Rocío

    2018-01-01

    BACKGROUND: Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive...... performance for major bleeding using the HAS-BLED score. MATERIAL AND METHODS: We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0-3.0) during at least the previous 6 months. A baseline venous blood sample was obtained for DNA extraction. We gave an extra point to the HAS...

  20. Pharmacogenetic Aspects of Airways’ Obstruction Relief Therapy of Bronchial Asthma Attacks in Schoolchildren

    Directory of Open Access Journals (Sweden)

    L.V. Mikaluk

    2013-03-01

    Full Text Available On the base of a complex examination of 215 schoolchildren who suffer bronchial asthma, there have been established that clinical manifestations of severity of bronchial obstructive syndrome during disease exacerbation do not depend on acetylating status. However, a homozygosity on both alleles of the glutathione transferase gene (GSTT1+M1+ has been connected to greater severity of asthma attacks, while a lack of the T-allele in children with slow acetylating phenotype has been associated with more frequent use of systemic corticosteroids and somewhat better results of airways obstruction relief therapy. Occurrence of GSTT1+M1+ genotype in patients with accelerated processes of acetylation significantly increased the risk of the inefficiency of bronchial obstruction relief therapy (odds ratio 12.4, relative risk — 6.4, the absolute risk — 50 %.

  1. Pharmacogenetic characterization of naturally occurring germline NT5C1A variants to chemotherapeutic nucleoside analogs

    Science.gov (United States)

    Saliba, Jason; Zabriskie, Ryan; Ghosh, Rajarshi; Powell, Bradford C; Hicks, Stephanie; Kimmel, Marek; Meng, Qingchang; Ritter, Deborah I; Wheeler, David A; Gibbs, Richard A; Tsai, Francis T F; Plon, Sharon E

    2016-01-01

    Background Mutations or alteration in expression of the 5’ nucleotidase gene family can confer altered responses to treatment with nucleoside analogs. While investigating leukemia susceptibility genes, we discovered a very rare p.L254P NT5C1A missense variant in the substrate recognition motif. Given the paucity of cellular drug response data from NT5C1A germline variation, we characterized p.L254P and eight rare variants of NT5C1A from genomic databases. Methods Through lentiviral infection, we created HEK293 cell lines that stably overexpress wildtype NT5C1A, p.L254P, or eight NT5C1A variants reported in the NHLBI Exome Variant server (one truncating and seven missense). IC50 values were determined by cytotoxicity assays after exposure to chemotherapeutic nucleoside analogs (Cladribine, Gemcitabine, 5-Fluorouracil). In addition, we used structure-based homology modeling to generate a 3D model for the C-terminal region of NT5C1A. Results The p.R180X (truncating), p.A214T, and p.L254P missense changes were the only variants that significantly impaired protein function across all nucleotide analogs tested (>5-fold difference versus WT; p<.05). Several of the remaining variants individually displayed differential effects (both more and less resistant) across the analogs tested. The homology model provided a structural framework to understand the impact of NT5C1A mutants on catalysis and drug processing. The model predicted active site residues within NT5C1A motif III and we experimentally confirmed that p.K314 (not p.K320) is required for NT5C1A activity. Conclusion We characterized germline variation and predicted protein structures of NT5C1A. Individual missense changes showed substantial variation in response to the different nucleoside analogs tested, which may impact patients’ responses to treatment. PMID:26906009

  2. Pharmacogenetics and individual responses to treatment of hyperglycemia in type 2 diabetes

    DEFF Research Database (Denmark)

    Engelbrechtsen, Line; Galijatovic, Ehm Astrid Andersson; Roepstorff, Søren

    2015-01-01

    The aim of this study was to summarize current knowledge and provide perspectives on the relationships between human genetic variants, type 2 diabetes, antidiabetic treatment, and disease progression. Type 2 diabetes is a complex disease with clear-cut diagnostic criteria and treatment guidelines...

  3. MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?

    Directory of Open Access Journals (Sweden)

    Rafael eDe La Torre

    2012-11-01

    Full Text Available In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, were selected as archetypes to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their high abuse prevalence in society. Methamphetamine behaves as both a weak substrate and competitive inhibitor of CYP2D6, while MDMA acts as a high affinity substrate and potent mechanism-based inhibitor (MBI of the enzyme. The MBI behavior of MDMA on CYP2D6 implies that subjects, irrespective of their genotype/phenotype, are phenocopied to the poor metabolizer phenotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than expected from in vitro studies. Other isoenzymes of cytochrome P450 and a relevant contribution of renal excretion play a part in their clearance. These facts tune down the potential contribution of CYP2D6 polymorphism in the clinical outcomes of both substances. Globally, the clinical relevance of CYP2D6 polymorphism is lower than that predicted by in vitro studies.

  4. Reappraisal of the genetic diversity and pharmacogenetic assessment of CES1

    DEFF Research Database (Denmark)

    Ferrero-Miliani, Laura; Bjerre, Ditte; Stage, Claus

    2017-01-01

    The CES1 gene encodes a hydrolase that metabolizes important drugs. Variants generated by exchange of segments with CES1P1 complicate genotyping of CES1. Using a highly specific procedure we examined DNA samples from 200 Caucasians and identified 46 single nucleotide variants (SNVs) in CES1 and 2...

  5. Pharmacogenetic testing for clopidogrel using the rapid INFINITI analyzer: a dose-escalation study.

    Science.gov (United States)

    Gladding, Patrick; White, Harvey; Voss, Jamie; Ormiston, John; Stewart, Jim; Ruygrok, Peter; Bvaldivia, Badi; Baak, Ruth; White, Catherine; Webster, Mark

    2009-11-01

    Our aim was to assess whether a higher clopidogrel maintenance dose has a greater antiplatelet effect in CYP2C19*2 allele carriers compared with noncarriers. Clopidogrel is a prodrug that is biotransformed by the cytochrome P450 enzymes CYP2C19, 2C9, and 3A4, 2B6, 1A2. The CYPC219*2 loss of function variant has been associated with a reduced antiplatelet response to clopidogrel and a 3-fold risk of stent thrombosis. Forty patients on standard maintenance dosage clopidogrel (75 mg), for 9.4 +/- 9.2 weeks, were enrolled into a dose escalation study. Platelet function was assessed at baseline and after 1 week of 150 mg once daily using the VerifyNow platelet function analyzer (Accumetrics Ltd., San Diego, California). Genomic DNA was hybridized to a BioFilmChip microarray on the INFINITI analyzer (AutoGenomics Inc., Carlsbad, California) and analyzed for the CYP19*2, *4, *17, and CYP2C9*2, *3 polymorphisms. Platelet inhibition increased over 1 week, mean +8.6 +/- 13.5% (p = 0.0003). Carriers of the CYP2C19*2 allele had significantly reduced platelet inhibition at baseline (median 18%, range 0% to 72%) compared with wildtype (wt) (median 59%, range 11% to 95%, p = 0.01) and at 1 week (p = 0.03). CYP2C19*2 allele carriers had an increase in platelet inhibition of (mean +9 +/- 11%, p = 0.03) and reduction in platelet reactivity (mean -26 +/- 38 platelet response unit, p = 0.04) with a higher dose. Together CYP2C19*2 and CYP2C9*3 loss of function carriers had a greater change in platelet inhibition with 150 mg daily than wt/wt (+10.9% vs. +0.7%, p = 0.04). Increasing the dose of clopidogrel in patients with nonresponder polymorphisms can increase antiplatelet response. Personalizing clopidogrel dosing using pharmacogenomics may be an effective method of optimizing treatment.

  6. Genomic variation in CYP3A4: type, frequencies and potential implications for pharmacogenetic understanding.

    OpenAIRE

    Creemer, O.

    2012-01-01

    The human cytochrome P450 3A subfamily metabolises endogenous substances and approximately half of all currently available drugs. There is marked inter-individual variation in hepatic expression of the major adult isoform, CYP3A4; the genetic component of this variability is estimated at 60-90% and, as yet, remains largely uncharacterised. Elucidation of genetic factors determining CYP3A4 activity would permit personalised dose-adjustment in therapies with CYP3A4 drug substrates. CYP3A4 genom...

  7. Current use of pharmacogenetic testing: a national survey of thiopurine methyltransferase testing prior to azathioprine prescription.

    Science.gov (United States)

    Fargher, E A; Tricker, K; Newman, W; Elliott, R; Roberts, S A; Shaffer, J L; Bruce, I; Payne, K

    2007-04-01

    Azathioprine is an immunosuppressant prescribed for the treatment of inflammatory conditions and after organ transplantation. Risk of neutropaenia has limited the effective use of azathioprine (AZA) and driven requirements for careful monitoring and blood tests. Thiopurine methyltransferase (TPMT) is a genetically moderated key enzyme involved in the metabolism of AZA that can be used to stratify individuals into different levels of risk of developing neutropaenia. Two techniques can be used to measure TPMT status: enzyme-level testing (phenotype testing) and DNA based testing (genotype testing). To identify the current uptake of TPMT enzyme-level testing, TPMT genotype testing, and, the role of guidelines; to inform the prescribing and monitoring of AZA. A survey was mailed to a consultant dermatologist, gastroenterologist, and rheumatologist at every NHS Hospital Trust in England. The survey comprised mainly closed questions exploring: use of AZA and monitoring; use of TPMT enzyme-level testing and genotype testing; and, the role of guidelines to guide prescribing practice. A 70% (n=287) response rate was obtained. The majority of respondents reported prescribing AZA (99%, n=283). Prescribing and monitoring patterns differed between individual respondents and between the three disciplines. TPMT enzyme-level testing was reportedly used by 67% (n=189) of respondents, but this differed by discipline (dermatologists 94%, gastroenterologists 60%, rheumatologists 47%). In 91% of cases enzyme-level testing was carried out prior to prescribing AZA. Genotype testing is not typically available to NHS clinicians but 15 clinicians (six dermatologists, six gastroenterologists, three rheumatologists) reported using it. Most consultants (82%) reported using guidelines to inform their AZA prescribing and monitoring (dermatologists 81%, gastroenterologists 75%, rheumatologists 94%). Two-thirds of the consultants surveyed in England are using TPMT enzyme-level testing, prior to AZA treatment. Uptake differs between specialities. High uptake of TPMT enzyme-level testing by dermatologists, compared with gastroenterologists and rheumatologists, may reflect national guidelines advocating its use prior to AZA. Uptake of enzyme-level testing may alter in other specialties as other guidelines are developed.

  8. The sensitivity of murine spermiogenesis to miglustat is a quantitative trait: a pharmacogenetic study

    Directory of Open Access Journals (Sweden)

    Boomkamp Stephanie

    2007-01-01

    Full Text Available Abstract Background A major event in the post-meiotic development of male germ cells is the formation of the acrosome. This process can be perturbed in C57BL/6 mice by administration of the small molecule miglustat (N-butyldeoxynojirimycin, NB-DNJ. The miglustat-treated mice produce morphologically abnormal spermatozoa that lack acrosomes and are poorly motile. In C57BL/6 mice, miglustat can be used to maintain long-term reversible infertility. In contrast, when miglustat was evaluated in normal men, it did not affect spermatogenesis. To gain more insight into this species difference we have now evaluated the reproductive effects of miglustat in rabbits, in multiple mouse strains and in interstrain hybrid mice. Methods Male mice of 18 inbred strains were administered miglustat orally or via miniosmotic pumps. Rabbits were given the compound in their food. Fourth-generation interstrain hybrid mice, bred from C57BL/6 and FVB/N mice (which differ in their response to miglustat, also received the drug. Data on fertility (natural mating, sperm motility and morphology, acrosome status, and serum drug levels were collected. Results In rabbits the drug did not induce aberrations of sperm shape or motility, although the serum level of miglustat in rabbits far exceeded the level in C57BL/6 mice (8.4 μM and 0.5 μM, respectively. In some strains of the Swiss and Castle lineages of inbred mice miglustat did not cause infertility, severe morphological sperm aberrations or reduced sperm motility. In these strains miglustat only had milder effects. However, miglustat strongly disturbed acrosome and sperm nucleus development in AKR/J and BALB/c mice and in a number of C57BL/6-related strains. The consequences of drug administration in the interstrain hybrid mice were highly variable. Judging by the number of grossly abnormal spermatozoa, these genetically heterogeneous mice displayed a continuous range of intermediate responses, distinct from either of their parental strains. Conclusion The effects of miglustat on spermatogenesis in mice are strain-dependent, while in rabbits the drug is ineffective. Evaluation of interstrain hybrid mice indicated that the sensitivity of spermatogenesis to miglustat is a quantitative trait. These studies pave the way for identifying the genetic factors underlying the strain/species differences in the effect of miglustat.

  9. Role of the UGT2B17 deletion in exemestane pharmacogenetics.

    Science.gov (United States)

    Luo, S; Chen, G; Truica, C; Baird, C C; Leitzel, K; Lazarus, P

    2018-04-01

    Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of breast cancer. The major metabolic pathway for EXE is reduction to form the active 17β-dihydro-EXE (17β-DHE) and subsequent glucuronidation to 17β-hydroxy-EXE-17-O-β-D-glucuronide (17β-DHE-Gluc) by UGT2B17. The aim of the present study was to determine the effects of UGT2B17 copy number variation on the levels of urinary and plasma 17β-DHE-Gluc and 17β-DHE in patients taking EXE. Ninety-six post-menopausal Caucasian breast cancer patients with ER+ breast tumors taking 25 mg EXE daily were recruited into this study. UGT2B17 copy number was determined by a real-time PCR copy number variant assay and the levels of EXE, 17β-DHE and 17β-DHE-Gluc were quantified by UPLC/MS in patients' urine and plasma. A 39-fold decrease (P<0.0001) in the levels of creatinine-adjusted urinary 17β-DHE-Gluc was observed among UGT2B17 (*2/*2) subjects vs subjects with the UGT2B17 (*1/*1) genotype. The plasma levels of 17β-DHE-Gluc was decreased 29-fold (P<0.0001) in subjects with the UGT2B17 (*2/*2) genotype vs subjects with UGT2B17 (*1/*1) genotype. The levels of plasma EXE-adjusted 17β-DHE was 28% higher (P=0.04) in subjects with the UGT2B17 (*2/*2) genotype vs subjects with the UGT2B17 (*1/*1) genotype. These data indicate that UGT2B17 is the major enzyme responsible for 17β-DHE-Gluc formation in vivo and that the UGT2B17 copy number variant may play a role in inter-individual variability in 17β-DHE levels in vivo.

  10. Effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy: a pharmacogenetic study.

    Directory of Open Access Journals (Sweden)

    Daniela Caronia

    Full Text Available Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response.In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs and 2 Copy Number Variants (CNVs in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1×10⁻⁵, and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9×10⁻⁵, rs1128503 and rs10276036 (r² = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value = 7.9×10⁻⁵. Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values [permutation test] ≤ 0.03.Our findings suggest that these polymorphisms may affect osteosarcoma treatment efficacy. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of osteosarcoma, helping in the design of individualized therapy.

  11. Pharmacogenetic markers to predict the clinical response to methotrexate in south Indian Tamil patients with psoriasis.

    Science.gov (United States)

    Indhumathi, S; Rajappa, Medha; Chandrashekar, Laxmisha; Ananthanarayanan, P H; Thappa, D M; Negi, V S

    2017-08-01

    Despite the advent of several new systemic therapies, methotrexate remains the gold standard for the treatment of moderate to severe psoriasis. However, there exists a significant heterogeneity in individual response to methotrexate. There are no consistently reliable markers to predict methotrexate treatment response till date. We aimed to demonstrate the association of certain genetic variants in the HLA (HLA-A2, HLA-B17, and HLA-Cw6) and the non-HLA genes including T-helper (Th)-1, Th-2, Th-17 cytokine genes (IFN-γ, IL-2, IL-4, IL-10, IL-12B, and IL-23R), and T-regulatory gene (FOXP3) with the methotrexate treatment response in South Indian Tamil patients with psoriasis. Of the 360 patients recruited, 189 patients with moderate to severe psoriasis were treated with methotrexate. Of the 189 patients, 132 patients responded to methotrexate and the remaining 57 patients were non-responders. We analyzed the association of aforesaid polymorphisms with the methotrexate treatment outcome using binary logistic regression. We observed that there were significant differences between genotype frequencies of HLA-Cw6 and FOXP3 (rs3761548) among the responders compared to non-responders, with conservative estimation. We observed that pro-inflammatory cytokines such as IFN-γ, IL-2, IL-12, and IL-23 were markedly reduced with the use of methotrexate, in comparison to the baseline levels, while the plasma IL-4 levels were increased posttreatment. Our results serve as preliminary evidence for the clinical use of genetic markers as predictors of response to methotrexate in psoriasis. This might aid in the future in the development of a point-of-care testing (POCT) gene chip, to predict optimal treatment response in patients with psoriasis, based on their individual genotypic profile.

  12. Kynurenine pathway and cognitive impairments in schizophrenia: Pharmacogenetics of galantamine and memantine

    Directory of Open Access Journals (Sweden)

    Maju Mathew Koola

    2016-06-01

    Full Text Available The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS project designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia, identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the α7 nicotinic receptors. Memantine is an N-methyl-D-aspartate (NMDA receptor antagonist. There is evidence to suggest that the combination of galantamine and memantine may be effective in the treatment of cognitive impairments in schizophrenia. There is a growing body of evidence that excess kynurenic acid (KYNA is associated with cognitive impairments in schizophrenia. The α-7 nicotinic and the NMDA receptors may counteract the effects of kynurenic acid (KYNA resulting in cognitive enhancement. Galantamine and memantine through its α-7 nicotinic and NMDA receptors respectively may counteract the effects of KYNA thereby improving cognitive impairments. The Single Nucleotide Polymorphisms in the Cholinergic Receptor, Nicotinic, Alpha 7 gene (CHRNA7, Glutamate (NMDA Receptor, Metabotropic 1 (GRM1 gene, Dystrobrevin Binding Protein 1 (DTNBP1 and kynurenine 3-monooxygenase (KMO gene may predict treatment response to galantamine and memantine combination for cognitive impairments in schizophrenia in the kynurenine pathway.

  13. Pharmacogenetics of clopidogrel: comparison between a standard and a rapid genetic testing.

    Science.gov (United States)

    Saracini, Claudia; Vestrini, Anna; Galora, Silvia; Armillis, Alessandra; Abbate, Rosanna; Giusti, Betti

    2012-06-01

    CYP2C19 variant alleles are independent predictors of clopidogrel response variability and occurrence of major adverse cardiovascular events in high-risk vascular patients on clopidogrel therapy. Increasing evidence suggests a combination of platelet function testing with CYP2C19 genetic testing may be more effective in identifying high-risk individuals for alternative antiplatelet therapeutic strategies. A crucial point in evaluating the use of these polymorphisms in clinical practice, besides test accuracy, is the cost of the genetic test and rapid availability of the results. One hundred acute coronary syndrome patients were genotyped for CYP2C19*2,*3,*4,*5, and *17 polymorphisms with two platforms: Verigene(®) and the TaqMan(®) system. Genotyping results obtained by the classical TaqMan approach and the rapid Verigene approach showed a 100% concordance for all the five polymorphisms investigated. The Verigene system had shorter turnaround time with respect to TaqMan. The cost of reagents for TaqMan genotyping was lower than that for the Verigene system, but the effective manual staff involvement and the relative cost resulted in higher cost for TaqMan than for Verigene. The Verigene system demonstrated good performance in terms of turnaround time and cost for the evaluation of the clopidogrel poor metabolizer status, giving genetic information in suitable time (206 min) for a therapeutic strategy decision.

  14. Pharmacogenetic diversification by alternative translation initiation: background channels to the fore.

    Science.gov (United States)

    Abbott, G W

    2014-02-15

    Unanticipated complexity of drug-target interactions creates a headache for those attempting to rationalize and create simple models of antiarrhythmic action, but can also introduce opportunities for increased drug specificity, or for potentially advantageous spatial and temporal variation in drug effects. The newest findings reported by Kisselbach et al. in this issue are a case in point. Building upon previous pioneering work demonstrating that neuronal K 2P 2.1 potassium-selective "background" channels can become permeable to sodium ions depending upon alternative translation initiation (ATI) (Thomas et al., 2008), the Thomas lab now shows that ATI of K 2P 2.1 and K 2P 10.1, which are also expressed in the heart, can cause a fivefold shift in sensitivity to block by the β-receptor (and potassium channel) antagonist, carvedilol (Kisselbach et al., 2014). This article is protected by copyright. All rights reserved.

  15. Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Froehlich, Tanya E.; Epstein, Jeffery N.; Nick, Todd G.; Melguizo Castro, Maria S.; Stein, Mark A.; Brinkman, William B.; Graham, Amanda J.; Langberg, Joshua M.; Kahn, Robert S.

    2011-01-01

    Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method:…

  16. New developments on the neurobiological and pharmaco-genetic mechanisms underlying internet and videogame addiction.

    Science.gov (United States)

    Weinstein, Aviv; Lejoyeux, Michel

    2015-03-01

    There is emerging evidence that the psychobiological mechanisms underlying behavioral addictions such as internet and videogame addiction resemble those of addiction for substances of abuse. Review of brain imaging, treatment and genetic studies on videogame and internet addiction. Literature search of published articles between 2009 and 2013 in Pubmed using "internet addiction" and "videogame addiction" as the search word. Twenty-nine studies have been selected and evaluated under the criteria of brain imaging, treatment, and genetics. Brain imaging studies of the resting state have shown that long-term internet game playing affected brain regions responsible for reward, impulse control and sensory-motor coordination. Brain activation studies have shown that videogame playing involved changes in reward and loss of control and that gaming pictures have activated regions similarly to those activated by cue-exposure to drugs. Structural studies have shown alterations in the volume of the ventral striatum possible as result of changes in reward. Furthermore, videogame playing was associated with dopamine release similar in magnitude to those of drugs of abuse and that there were faulty inhibitory control and reward mechanisms videogame addicted individuals. Finally, treatment studies using fMRI have shown reduction in craving for videogames and reduced associated brain activity. Videogame playing may be supported by similar neural mechanisms underlying drug abuse. Similar to drug and alcohol abuse, internet addiction results in sub-sensitivity of dopamine reward mechanisms. Given the fact that this research is in its early stage it is premature to conclude that internet addiction is equivalent to substance addictions. © American Academy of Addiction Psychiatry.

  17. Pharmacogenetics and Pharmacotherapy of Military Personnel Suffering from Post-traumatic Stress Disorder.

    Science.gov (United States)

    Naß, Janine; Efferth, Thomas

    2017-01-01

    Posttraumatic stress disorder (PTSD) is a severe problem among soldiers with combating experience difficult to treat. The pathogenesis is still not fully understood at the psychological level. Therefore, genetic research became a focus of interest. The identification of single nucleotide polymorphisms (SNPs) may help to predict, which persons are at high risk to develop PTSD as a starting point to develop novel targeted drugs for treatment. We conducted a systematic review on SNPs in genes related to PTSD pathology and development of targeted pharmacological treatment options based on PubMed database searches. We focused on clinical trials with military personnel. SNPs in 22 human genes have been linked to PTSD. These genes encode proteins acting as neurotransmitters and receptors, downstream signal transducers and metabolizing enzymes. Pharmacological inhibitors may serve as drug candidates for PTSD treatment, e.g. β2 adrenoreceptor antagonists, dopamine antagonists, partial dopamine D2 receptor agonists, dopamine β hydroxylase inhibitors, fatty acid amid hydrolase antagonists, glucocorticoid receptor agonists, tropomyosin receptor kinase B agonists, selective serotonin reuptake inhibitors, catechol-O-methyltransferase inhibitors, gamma-amino butyric acid receptor agonists, glutamate receptor inhibitors, monoaminoxidase B inhibitors, N-methyl-d-aspartate receptor antagonists. The combination of genetic and pharmacological research may lead to novel targetbased drug developments with improved specificity and efficacy to treat PTSD. Specific SNPs may be identified as reliable biomarkers to assess individual disease risk. Focusing on soldiers suffering from PTSD will not only help to improve treatment options for this specific group, but for all PTSD patients and the general population. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Pharmacogenetics and Pharmacotherapy of Military Personnel Suffering from Post-traumatic Stress Disorder

    OpenAIRE

    Naß, Janine; Efferth, Thomas

    2017-01-01

    Background: Posttraumatic stress disorder (PTSD) is a severe problem among soldiers with combating experience difficult to treat. The pathogenesis is still not fully understood at the psychological level. Therefore, genetic research became a focus of interest. The identification of single nucleotide polymorphisms (SNPs) may help to predict, which persons are at high risk to develop PTSD as a starting point to develop novel targeted drugs for treatment. Methods: We conducted a systematic revie...

  19. Strain-specific response to anaesthetics and analgesics in rat and rabbit : A pharmacogenetic approach

    NARCIS (Netherlands)

    Avsaroglu, H.

    2008-01-01

    The response of (laboratory) animals to anaesthetics and analgesics is known to show intraspecies variability. Apart from environmental influences, this may also be caused by genetic factors. In this thesis, rabbit and rat inbred strains were used to identify differences in response to anaesthetics

  20. [Bartter syndrome, severe rare orphan kidney disease: a step towards therapy through pharmacogenetic and epidemiological studies].

    Science.gov (United States)

    Conte, Elena; Imbrici, Paola; Sahbani, Dalila; Liantonio, Antonella; Conte, Diana

    2018-05-01

    Bartter syndromes (BS) types 1-5 are rare salt-losing tubulopathies presenting with overlapping clinical phenotypes including marked salt wasting and hypokalemia leading to polyuria, polydipsia, volume contraction, muscle weakness and growth retardation. These diseases are due to an impairment of sodium, potassium, chloride reabsorption caused by mutations in genes encoding for ion channel or transporters expressed in specific nephron tubule segments. Particularly, BS type 3 is a clinically heterogeneous form caused by mutations in CLCNKB gene which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. Specific therapy for BS is lacking and the only pharmacotherapy up today available is purely symptomatic and characterized by limiting side effects. The improvement of our understanding of the phenotype/genotype correlation and of the precise pathogenic mechanisms associated with BS type 3 as well as the pharmacological characterization of ClC-K chloride channels are fundamental to design therapies tailored upon patients' mutation. This mini review focused on recent studies representing relevant forward steps in the field as well as noteworthy examples of how basic and clinical research can cooperate to gain insight into the pathophysiology of this renal channelopathy, paving the way for a personalized therapy. Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.

  1. The Pharmacogenetics of Tacrolimus in Corticosteroid-Sparse Pediatric and Adult Kidney Transplant Recipients

    DEFF Research Database (Denmark)

    Juul Madsen, Mads; Bergmann, Troels K; Brøsen, Kim

    2017-01-01

    INTRODUCTION: Tacrolimus is a calcineurin inhibitor used as an immunosuppressant drug in solid organ transplantation, and is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. Studies have shown an association between the CYP3A5 genotype and tacrolimus dose-adjusted trough concentrations...

  2. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing

    DEFF Research Database (Denmark)

    Relling, M V; Gardner, E E; Sandborn, W J

    2011-01-01

    Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TP...

  3. Human thiopurine methyltransferase pharmacogenetics: effect of phenotype on sensitivity of cultured lymphocytes to 6-mercaptopurine

    International Nuclear Information System (INIS)

    Van Loon, J.; Weinshilboum, R.

    1986-01-01

    Thiopurine methyltransferase (EC 2.1.1.67, TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP). TPMT activity in human lymphocytes and other tissues is controlled by a common genetic polymorphism. These experiments were designed to study the relationship between TPMT phenotype and the effect of 6-MP on 3 H-thymidine ( 3 H-TdR) incorporation into phytohemaglutinin (PHA) stimulated human peripheral blood lymphocytes. Lymphocytes were obtained from the blood of nine subjects, three subjects with each TPMT phenotype. 6-MP dose response curves were performed at optimal (10 μg/ml) and suboptimal (1 μg/ml) concentrations of PHA. ED50 values for 6-MP with lymphocytes from subjects who genetically lacked TPMT activity were higher than ED50 values for lymphocytes from subjects with genetically intermediate or high TPMT activity. However, ED50 values decreased as level of stimulation increased. Therefore, the effects of 6-MP were studied at a series of PHA concentrations that ranged from 0.1 μg/ml to 10 μg/ml. Lymphocytes from subjects who lacked TPMT activity had significantly higher K/sub ii/ values (1.37 +/- 0.340 μM; mean +/- SEM) for inhibition of 3 H-TdR incorporation by 6-MP than did lymphocytes from subjects with intermediate or high TPMT activity (0.529 +/- 0.068 μM and 0.327 +/- 0.064 μM, respectively, P < .05 for both comparisons)

  4. Human thiopurine methyltransferase pharmacogenetics: effect of phenotype on sensitivity of cultured lymphocytes to 6-mercaptopurine

    Energy Technology Data Exchange (ETDEWEB)

    Van Loon, J.; Weinshilboum, R.

    1986-03-05

    Thiopurine methyltransferase (EC 2.1.1.67, TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP). TPMT activity in human lymphocytes and other tissues is controlled by a common genetic polymorphism. These experiments were designed to study the relationship between TPMT phenotype and the effect of 6-MP on /sup 3/H-thymidine (/sup 3/H-TdR) incorporation into phytohemaglutinin (PHA) stimulated human peripheral blood lymphocytes. Lymphocytes were obtained from the blood of nine subjects, three subjects with each TPMT phenotype. 6-MP dose response curves were performed at optimal (10 ..mu..g/ml) and suboptimal (1 ..mu..g/ml) concentrations of PHA. ED50 values for 6-MP with lymphocytes from subjects who genetically lacked TPMT activity were higher than ED50 values for lymphocytes from subjects with genetically intermediate or high TPMT activity. However, ED50 values decreased as level of stimulation increased. Therefore, the effects of 6-MP were studied at a series of PHA concentrations that ranged from 0.1 ..mu..g/ml to 10 ..mu..g/ml. Lymphocytes from subjects who lacked TPMT activity had significantly higher K/sub ii/ values (1.37 +/- 0.340 ..mu..M; mean +/- SEM) for inhibition of /sup 3/H-TdR incorporation by 6-MP than did lymphocytes from subjects with intermediate or high TPMT activity (0.529 +/- 0.068 ..mu..M and 0.327 +/- 0.064 ..mu..M, respectively, P < .05 for both comparisons).

  5. A pharmacogenetics-based warfarin maintenance dosing algorithm from Northern Chinese patients.

    Directory of Open Access Journals (Sweden)

    Jinxing Chen

    Full Text Available Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551, warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%, CYP2C9*3(7.0%, body surface area(4.2%, age(2.7%, target INR(1.4%, CYP4F2 rs2108622 (0.7%, amiodarone use(0.6%, diabetes mellitus(0.6%, and digoxin use(0.5%, which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236, the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, P<0.001. Our algorithm could improve the personalized management of warfarin use in Northern Chinese patients.

  6. Pharmacogenetics-Oriented Therapeutic drug monitoring of Digoxin in critically ill patients

    International Nuclear Information System (INIS)

    Ebid, Abdel-Hameed I.; Mokhtar, Mohammed Sherif; Abdel-Shafi, Sana'a; El-Feky, Gina Samy

    2006-01-01

    This study was performed to outline the different MDR-1 (Multi-Drug Resistance-1) genotypes in a sample of 37 Egyptian patients, suffering from atrial fibrillation (AF) and/or congestive heart failure (CHF) and is using digoxin, to assess the role of MDR-1 genotypes polymorphism in affecting steady state serum digoxin therapeutic levels, and studying the consequences on patient's clinical outcome. Two venous blood samples were drawn from each patient; the 1st sample was taken, on admission, for DNA extraction and genotyping and the 2nd was taken, 6 hours post dose after reaching steady state concentration, for serum digoxin assay. Serum digoxin levels were assayed using EMIT 2000 analyzer, and MDR-1 genotyping was done using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Twenty patients (54.1%) showed serum digoxin levels within the therapeutic range, 12 patients (32.4%) showed serum digoxin levels under the minimum effective concentration ( 2 ng/ml), with P value of 0.0001 among three groups. MDR-1 genotyping revealed ten patients (27%) carrying the homozygous mutant TT genotype, 27 patients (73%) carrying the heterozygous mutant CT genotype, with no patient showing the wild CC genotype Allelic distribution showed 42% for the wild type C allele while 58% for the homozygous mutant C allele. Patients carrying the homozygous mutant TT genotype showed significantly lower serum digoxin levels compared with those carrying the heterozygous mutant CT genotype (P value: 0.009). Patients with significant improvement carried the CT genotype and had serum digoxin levels within the therapeutic range. In conclusion, patients with different MDR-1 genotypes had variations in their serum digoxin levels and identification of MDR-1 variations was found useful in predicting therapy outcome. We recommend further extensive work on large samples to study the important role of MDR-1 gene in affecting the disposition of different substrates, to be able for individualizing them according to the patient's genetic profile in order to improve drug therapy and reduce inter-patient variability. (author)

  7. The future of warfarin pharmacogenetics in under-represented minority groups

    Science.gov (United States)

    Cavallari, Larisa H; Perera, Minoli A

    2012-01-01

    Genotype-based dosing recommendations are provided in the US FDA-approved warfarin labeling. However, data that informed these recommendations were from predominately Caucasian populations. Studies show that variants contributing to warfarin dose requirements in Caucasians provide similar contributions to dose requirements in US Hispanics, but significantly lesser contributions in African–Americans. Further data demonstrate that variants occurring commonly in individuals of African ancestry, but rarely in other racial groups, significantly influence dose requirements in African–Americans. These data suggest that it is important to consider variants specific for African–Americans when implementing genotype-guided warfarin dosing in this population. PMID:22871196

  8. A Pharmacogenetics-Based Warfarin Maintenance Dosing Algorithm from Northern Chinese Patients

    Science.gov (United States)

    Luo, Fang; Wang, Jin'e; Shi, Yi; Tan, Yu; Chen, Qianlong; Zhang, Yu; Hui, Rutai; Wang, Yibo

    2014-01-01

    Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551), warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2 rs2108622 (0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236), the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, Pwarfarin use in Northern Chinese patients. PMID:25126975

  9. CSF analysis

    Science.gov (United States)

    Cerebrospinal fluid analysis ... Analysis of CSF can help detect certain conditions and diseases. All of the following can be, but ... An abnormal CSF analysis result may be due to many different causes, ... Encephalitis (such as West Nile and Eastern Equine) Hepatic ...

  10. Semen analysis

    Science.gov (United States)

    ... analysis URL of this page: //medlineplus.gov/ency/article/003627.htm Semen analysis To use the sharing features on this page, please enable JavaScript. Semen analysis measures the amount and quality of a man's semen and sperm. Semen is ...

  11. Functional analysis

    CERN Document Server

    Kantorovich, L V

    1982-01-01

    Functional Analysis examines trends in functional analysis as a mathematical discipline and the ever-increasing role played by its techniques in applications. The theory of topological vector spaces is emphasized, along with the applications of functional analysis to applied analysis. Some topics of functional analysis connected with applications to mathematical economics and control theory are also discussed. Comprised of 18 chapters, this book begins with an introduction to the elements of the theory of topological spaces, the theory of metric spaces, and the theory of abstract measure space

  12. Pioglitazone could induce remission in major depression: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Colle R

    2016-12-01

    Full Text Available Romain Colle,1,* Delphine de Larminat,1,* Samuel Rotenberg,1 Franz Hozer,1 Patrick Hardy,1 Céline Verstuyft,2 Bruno Fève,3,* Emmanuelle Corruble1,* 1Psychiatry Department, Hôpital Bicêtre, INSERM, UMR S1178, University Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France; 2Molecular Genetic, Pharmacogenetics and Hormonology Department, Hôpital Bicêtre, INSERM UMR_S1184, Centre IMVA, University Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France; 3Endocrinology Department, INSERM UMR_S938, Hôpital Saint-Antoine, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire ICAN, Sorbonne Universités, Université Pierre et Marie Curie, Assistance Publique des Hôpitaux de Paris, Paris, France *These authors contributed equally to this work Background: Pioglitazone, a selective agonist of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ, prescribed for the treatment of type 2 diabetes, could have antidepressant properties. However, its potential to induce remission of major depressive episodes, the optimal clinical target for an antidepressant drug, is a matter of concern. Indeed, only one out of four double-blind randomized controlled trials show higher remission rates with pioglitazone than with control treatments. Hence, the main aim of this study was to perform a meta-analysis of the efficacy of pioglitazone for the treatment of MDE, focusing on remission rates.Methods: Four double-blind randomized controlled trials, comprising 161 patients with an MDE, were included in this meta-analysis. Pioglitazone was studied either alone (one study or as add-on therapy to conventional treatments (antidepressant drugs or lithium salts. It was compared either to placebo (three studies or to metformin (one study. Remission was defined by a Hamilton Depression Rating Scale score <8 after treatment.Results: Pioglitazone could induce higher remission

  13. Post-mortem analysis of suicide victims shows ABCB1 haplotype 1236T-2677T-3435T as a candidate predisposing factor behind adverse drug reactions in females.

    Science.gov (United States)

    Rahikainen, Anna-Liina; Palo, Jukka U; Haukka, Jari; Sajantila, Antti

    2018-04-01

    Genetic variation in efflux transporter, permeability glycoprotein (P-gp), has recently been associated with completed violent suicides and also violent suicide attempts. As depression is known to be a risk factor for suicide and many antidepressants are P-gp substrates, it has been speculated that inadequate antidepressant treatment response or adverse side effects could be involved. The aim of this study was to investigate whether there is an association between the P-gp coding ABCB1 gene and completed suicides in citalopram users. Also, the effect of sex and suicide method used (violent vs. non-violent) was evaluated. All cases included in the study population, 349 completed suicide victims and 284 controls, were shown to be positive for antidepressant citalopram in a post-mortem toxicological drug screen. ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms were determined by TaqMan genotyping assays. Haplotypes were constructed from genotype data using the PHASE software. The association between the manner of death and the ABCB1 haplotype was tested with logistic regression analysis. No statistically significant differences were observed in the ABCB1 allele or genotype frequencies between the suicide and control groups. However, the ABCB1 1236T-2677T-3435T haplotype was associated with completed suicides of female citalopram users (odds ratio: 2.23; 95% confidence interval: 1.22-4.07; P=0.009). After stratification by the method used for suicide, the association emerged in fatal intoxications (odds ratio: 2.51; 95% confidence interval: 1.29-4.87; P=0.007). In other groups, no statistically significant associations were observed. Our results suggest that female citalopram users with ABCB1 1236T-2677T-3435T are more vulnerable to adverse effects of the drugs as this haplotype was enriched in non-violent suicides of female citalopram users. Even though the biological mechanism behind this observation is unknown, the results provide another example of the importance

  14. Image analysis

    International Nuclear Information System (INIS)

    Berman, M.; Bischof, L.M.; Breen, E.J.; Peden, G.M.

    1994-01-01

    This paper provides an overview of modern image analysis techniques pertinent to materials science. The usual approach in image analysis contains two basic steps: first, the image is segmented into its constituent components (e.g. individual grains), and second, measurement and quantitative analysis are performed. Usually, the segmentation part of the process is the harder of the two. Consequently, much of the paper concentrates on this aspect, reviewing both fundamental segmentation tools (commonly found in commercial image analysis packages) and more advanced segmentation tools. There is also a review of the most widely used quantitative analysis methods for measuring the size, shape and spatial arrangements of objects. Many of the segmentation and analysis methods are demonstrated using complex real-world examples. Finally, there is a discussion of hardware and software issues. 42 refs., 17 figs

  15. Semiotic Analysis.

    Science.gov (United States)

    Thiemann, Francis C.

    Semiotic analysis is a method of analyzing signs (e.g., words) to reduce non-numeric data to their component parts without losing essential meanings. Semiotics dates back to Aristotle's analysis of language; it was much advanced by nineteenth-century analyses of style and logic and by Whitehead and Russell's description in this century of the role…

  16. Dimensional Analysis

    Indian Academy of Sciences (India)

    Dimensional analysis is a useful tool which finds important applications in physics and engineering. It is most effective when there exist a maximal number of dimensionless quantities constructed out of the relevant physical variables. Though a complete theory of dimen- sional analysis was developed way back in 1914 in a.

  17. Job Analysis

    OpenAIRE

    Bravená, Helena

    2009-01-01

    This bacherlor thesis deals with the importance of job analysis for personnel activities in the company. The aim of this work is to find the most suitable method of job analysis in a particular enterprise, and continues creating descriptions and specifications of each job.

  18. Incidents analysis

    International Nuclear Information System (INIS)

    Francois, P.

    1996-01-01

    We undertook a study programme at the end of 1991. To start with, we performed some exploratory studies aimed at learning some preliminary lessons on this type of analysis: Assessment of the interest of probabilistic incident analysis; possibility of using PSA scenarios; skills and resources required. At the same time, EPN created a working group whose assignment was to define a new approach for analysis of incidents on NPPs. This working group gave thought to both aspects of Operating Feedback that EPN wished to improve: Analysis of significant incidents; analysis of potential consequences. We took part in the work of this group, and for the second aspects, we proposed a method based on an adaptation of the event-tree method in order to establish a link between existing PSA models and actual incidents. Since PSA provides an exhaustive database of accident scenarios applicable to the two most common types of units in France, they are obviously of interest for this sort of analysis. With this method we performed some incident analyses, and at the same time explores some methods employed abroad, particularly ASP (Accident Sequence Precursor, a method used by the NRC). Early in 1994 EDF began a systematic analysis programme. The first, transient phase will set up methods and an organizational structure. 7 figs

  19. Incidents analysis

    Energy Technology Data Exchange (ETDEWEB)

    Francois, P

    1997-12-31

    We undertook a study programme at the end of 1991. To start with, we performed some exploratory studies aimed at learning some preliminary lessons on this type of analysis: Assessment of the interest of probabilistic incident analysis; possibility of using PSA scenarios; skills and resources required. At the same time, EPN created a working group whose assignment was to define a new approach for analysis of incidents on NPPs. This working group gave thought to both aspects of Operating Feedback that EPN wished to improve: Analysis of significant incidents; analysis of potential consequences. We took part in the work of this group, and for the second aspects, we proposed a method based on an adaptation of the event-tree method in order to establish a link between existing PSA models and actual incidents. Since PSA provides an exhaustive database of accident scenarios applicable to the two most common types of units in France, they are obviously of interest for this sort of analysis. With this method we performed some incident analyses, and at the same time explores some methods employed abroad, particularly ASP (Accident Sequence Precursor, a method used by the NRC). Early in 1994 EDF began a systematic analysis programme. The first, transient phase will set up methods and an organizational structure. 7 figs.

  20. Numerical analysis

    CERN Document Server

    Khabaza, I M

    1960-01-01

    Numerical Analysis is an elementary introduction to numerical analysis, its applications, limitations, and pitfalls. Methods suitable for digital computers are emphasized, but some desk computations are also described. Topics covered range from the use of digital computers in numerical work to errors in computations using desk machines, finite difference methods, and numerical solution of ordinary differential equations. This book is comprised of eight chapters and begins with an overview of the importance of digital computers in numerical analysis, followed by a discussion on errors in comput

  1. Trace analysis

    International Nuclear Information System (INIS)

    Warner, M.

    1987-01-01

    What is the current state of quantitative trace analytical chemistry? What are today's research efforts? And what challenges does the future hold? These are some of the questions addressed at a recent four-day symposium sponsored by the National Bureau of Standards (NBS) entitled Accuracy in Trace Analysis - Accomplishments, Goals, Challenges. The two plenary sessions held on the first day of the symposium reviewed the history of quantitative trace analysis, discussed the present situation from academic and industrial perspectives, and summarized future needs. The remaining three days of the symposium consisted of parallel sessions dealing with the measurement process; quantitation in materials; environmental, clinical, and nutrient analysis; and advances in analytical techniques

  2. Recursive analysis

    CERN Document Server

    Goodstein, R L

    2010-01-01

    Recursive analysis develops natural number computations into a framework appropriate for real numbers. This text is based upon primary recursive arithmetic and presents a unique combination of classical analysis and intuitional analysis. Written by a master in the field, it is suitable for graduate students of mathematics and computer science and can be read without a detailed knowledge of recursive arithmetic.Introductory chapters on recursive convergence and recursive and relative continuity are succeeded by explorations of recursive and relative differentiability, the relative integral, and

  3. Analysis I

    CERN Document Server

    Tao, Terence

    2016-01-01

    This is part one of a two-volume book on real analysis and is intended for senior undergraduate students of mathematics who have already been exposed to calculus. The emphasis is on rigour and foundations of analysis. Beginning with the construction of the number systems and set theory, the book discusses the basics of analysis (limits, series, continuity, differentiation, Riemann integration), through to power series, several variable calculus and Fourier analysis, and then finally the Lebesgue integral. These are almost entirely set in the concrete setting of the real line and Euclidean spaces, although there is some material on abstract metric and topological spaces. The book also has appendices on mathematical logic and the decimal system. The entire text (omitting some less central topics) can be taught in two quarters of 25–30 lectures each. The course material is deeply intertwined with the exercises, as it is intended that the student actively learn the material (and practice thinking and writing ri...

  4. Analysis II

    CERN Document Server

    Tao, Terence

    2016-01-01

    This is part two of a two-volume book on real analysis and is intended for senior undergraduate students of mathematics who have already been exposed to calculus. The emphasis is on rigour and foundations of analysis. Beginning with the construction of the number systems and set theory, the book discusses the basics of analysis (limits, series, continuity, differentiation, Riemann integration), through to power series, several variable calculus and Fourier analysis, and then finally the Lebesgue integral. These are almost entirely set in the concrete setting of the real line and Euclidean spaces, although there is some material on abstract metric and topological spaces. The book also has appendices on mathematical logic and the decimal system. The entire text (omitting some less central topics) can be taught in two quarters of 25–30 lectures each. The course material is deeply intertwined with the exercises, as it is intended that the student actively learn the material (and practice thinking and writing ri...

  5. Nuclear analysis

    International Nuclear Information System (INIS)

    1988-01-01

    Basic studies in nuclear analytical techniques include the examination of underlying assumptions and the development and extention of techniques involving the use of ion beams for elemental and mass analysis. 1 ref., 1 tab

  6. Biorefinery Analysis

    Energy Technology Data Exchange (ETDEWEB)

    2016-06-01

    Fact sheet summarizing NREL's techno-economic analysis and life-cycle assessment capabilities to connect research with future commercial process integration, a critical step in the scale-up of biomass conversion technologies.

  7. Nonlinear analysis

    CERN Document Server

    Gasinski, Leszek

    2005-01-01

    Hausdorff Measures and Capacity. Lebesgue-Bochner and Sobolev Spaces. Nonlinear Operators and Young Measures. Smooth and Nonsmooth Analysis and Variational Principles. Critical Point Theory. Eigenvalue Problems and Maximum Principles. Fixed Point Theory.

  8. Hydroeconomic analysis

    DEFF Research Database (Denmark)

    Bauer-Gottwein, Peter; Riegels, Niels; Pulido-Velazquez, Manuel

    2017-01-01

    Hydroeconomic analysis and modeling provides a consistent and quantitative framework to assess the links between water resources systems and economic activities related to water use, simultaneously modeling water supply and water demand. It supports water managers and decision makers in assessing...... trade-offs between different water uses, different geographic regions, and various economic sectors and between the present and the future. Hydroeconomic analysis provides consistent economic performance criteria for infrastructure development and institutional reform in water policies and management...... organizations. This chapter presents an introduction to hydroeconomic analysis and modeling, and reviews the state of the art in the field. We review available economic water-valuation techniques and summarize the main types of decision problems encountered in hydroeconomic analysis. Popular solution strategies...

  9. Conversation Analysis.

    Science.gov (United States)

    Schiffrin, Deborah

    1990-01-01

    Summarizes the current state of research in conversation analysis, referring primarily to six different perspectives that have developed from the philosophy, sociology, anthropology, and linguistics disciplines. These include pragmatics; speech act theory; interactional sociolinguistics; ethnomethodology; ethnography of communication; and…

  10. Factor analysis

    CERN Document Server

    Gorsuch, Richard L

    2013-01-01

    Comprehensive and comprehensible, this classic covers the basic and advanced topics essential for using factor analysis as a scientific tool in psychology, education, sociology, and related areas. Emphasizing the usefulness of the techniques, it presents sufficient mathematical background for understanding and sufficient discussion of applications for effective use. This includes not only theory but also the empirical evaluations of the importance of mathematical distinctions for applied scientific analysis.

  11. Radioactivation analysis

    International Nuclear Information System (INIS)

    1959-01-01

    Radioactivation analysis is the technique of radioactivation analysis of the constituents of a very small sample of matter by making the sample artificially radioactive. The first stage is to make the sample radioactive by artificial means, e.g. subject it to neutron bombardment. Once the sample has been activated, or made radioactive, the next task is to analyze the radiations given off by the sample. This analysis would indicate the nature and quantities of the various elements present in the sample. The reason is that the radiation from a particular radioisotope. In 1959 a symposium on 'Radioactivation Analysis' was organized in Vienna by the IAEA and the Joint Commission on Applied Radioactivity (ICSU). It was pointed out that there are certain factors creating uncertainties and elaborated how to overcome them. Attention was drawn to the fact that radioactivation analysis had proven a powerful tool tackling fundamental problems in geo- and cosmochemistry, and a review was given of the recent work in this field. Because of its extreme sensitivity radioactivation analysis had been principally employed for trace detection and its most extensive use has been in control of semiconductors and very pure metals. An account of the experience gained in the USA was given, where radioactivation analysis was being used by many investigators in various scientific fields as a practical and useful tool for elemental analyses. Much of this work had been concerned with determining sub microgramme and microgramme concentration of many different elements in samples of biological materials, drugs, fertilizers, fine chemicals, foods, fuels, glass, ceramic materials, metals, minerals, paints, petroleum products, resinous materials, soils, toxicants, water and other materials. In addition to these studies, radioactivation analysis had been used by other investigators to determine isotopic ratios of the stable isotopes of some of the elements. Another paper dealt with radioactivation

  12. Radioactivation analysis

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1959-07-15

    Radioactivation analysis is the technique of radioactivation analysis of the constituents of a very small sample of matter by making the sample artificially radioactive. The first stage is to make the sample radioactive by artificial means, e.g. subject it to neutron bombardment. Once the sample has been activated, or made radioactive, the next task is to analyze the radiations given off by the sample. This analysis would indicate the nature and quantities of the various elements present in the sample. The reason is that the radiation from a particular radioisotope. In 1959 a symposium on 'Radioactivation Analysis' was organized in Vienna by the IAEA and the Joint Commission on Applied Radioactivity (ICSU). It was pointed out that there are certain factors creating uncertainties and elaborated how to overcome them. Attention was drawn to the fact that radioactivation analysis had proven a powerful tool tackling fundamental problems in geo- and cosmochemistry, and a review was given of the recent work in this field. Because of its extreme sensitivity radioactivation analysis had been principally employed for trace detection and its most extensive use has been in control of semiconductors and very pure metals. An account of the experience gained in the USA was given, where radioactivation analysis was being used by many investigators in various scientific fields as a practical and useful tool for elemental analyses. Much of this work had been concerned with determining sub microgramme and microgramme concentration of many different elements in samples of biological materials, drugs, fertilizers, fine chemicals, foods, fuels, glass, ceramic materials, metals, minerals, paints, petroleum products, resinous materials, soils, toxicants, water and other materials. In addition to these studies, radioactivation analysis had been used by other investigators to determine isotopic ratios of the stable isotopes of some of the elements. Another paper dealt with radioactivation

  13. Panel Analysis

    DEFF Research Database (Denmark)

    Brænder, Morten; Andersen, Lotte Bøgh

    2014-01-01

    Based on our 2013-article, ”Does Deployment to War Affect Soldiers' Public Service Motivation – A Panel Study of Soldiers Before and After their Service in Afghanistan”, we present Panel Analysis as a methodological discipline. Panels consist of multiple units of analysis, observed at two or more...... in research settings where it is not possible to distribute units of analysis randomly or where the independent variables cannot be manipulated. The greatest disadvantage in regard to using panel studies is that data may be difficult to obtain. This is most clearly vivid in regard to the use of panel surveys...... points in time. In comparison with traditional cross-sectional studies, the advantage of using panel studies is that the time dimension enables us to study effects. Whereas experimental designs may have a clear advantage in regard to causal inference, the strength of panel studies is difficult to match...

  14. Real analysis

    CERN Document Server

    Loeb, Peter A

    2016-01-01

    This textbook is designed for a year-long course in real analysis taken by beginning graduate and advanced undergraduate students in mathematics and other areas such as statistics, engineering, and economics. Written by one of the leading scholars in the field, it elegantly explores the core concepts in real analysis and introduces new, accessible methods for both students and instructors. The first half of the book develops both Lebesgue measure and, with essentially no additional work for the student, general Borel measures for the real line. Notation indicates when a result holds only for Lebesgue measure. Differentiation and absolute continuity are presented using a local maximal function, resulting in an exposition that is both simpler and more general than the traditional approach. The second half deals with general measures and functional analysis, including Hilbert spaces, Fourier series, and the Riesz representation theorem for positive linear functionals on continuous functions with compact support....

  15. Numerical analysis

    CERN Document Server

    Scott, L Ridgway

    2011-01-01

    Computational science is fundamentally changing how technological questions are addressed. The design of aircraft, automobiles, and even racing sailboats is now done by computational simulation. The mathematical foundation of this new approach is numerical analysis, which studies algorithms for computing expressions defined with real numbers. Emphasizing the theory behind the computation, this book provides a rigorous and self-contained introduction to numerical analysis and presents the advanced mathematics that underpin industrial software, including complete details that are missing from most textbooks. Using an inquiry-based learning approach, Numerical Analysis is written in a narrative style, provides historical background, and includes many of the proofs and technical details in exercises. Students will be able to go beyond an elementary understanding of numerical simulation and develop deep insights into the foundations of the subject. They will no longer have to accept the mathematical gaps that ex...

  16. Numerical analysis

    CERN Document Server

    Rao, G Shanker

    2006-01-01

    About the Book: This book provides an introduction to Numerical Analysis for the students of Mathematics and Engineering. The book is designed in accordance with the common core syllabus of Numerical Analysis of Universities of Andhra Pradesh and also the syllabus prescribed in most of the Indian Universities. Salient features: Approximate and Numerical Solutions of Algebraic and Transcendental Equation Interpolation of Functions Numerical Differentiation and Integration and Numerical Solution of Ordinary Differential Equations The last three chapters deal with Curve Fitting, Eigen Values and Eigen Vectors of a Matrix and Regression Analysis. Each chapter is supplemented with a number of worked-out examples as well as number of problems to be solved by the students. This would help in the better understanding of the subject. Contents: Errors Solution of Algebraic and Transcendental Equations Finite Differences Interpolation with Equal Intervals Interpolation with Unequal Int...

  17. Numerical analysis

    CERN Document Server

    Jacques, Ian

    1987-01-01

    This book is primarily intended for undergraduates in mathematics, the physical sciences and engineering. It introduces students to most of the techniques forming the core component of courses in numerical analysis. The text is divided into eight chapters which are largely self-contained. However, with a subject as intricately woven as mathematics, there is inevitably some interdependence between them. The level of difficulty varies and, although emphasis is firmly placed on the methods themselves rather than their analysis, we have not hesitated to include theoretical material when we consider it to be sufficiently interesting. However, it should be possible to omit those parts that do seem daunting while still being able to follow the worked examples and to tackle the exercises accompanying each section. Familiarity with the basic results of analysis and linear algebra is assumed since these are normally taught in first courses on mathematical methods. For reference purposes a list of theorems used in the t...

  18. Real analysis

    CERN Document Server

    DiBenedetto, Emmanuele

    2016-01-01

    The second edition of this classic textbook presents a rigorous and self-contained introduction to real analysis with the goal of providing a solid foundation for future coursework and research in applied mathematics. Written in a clear and concise style, it covers all of the necessary subjects as well as those often absent from standard introductory texts. Each chapter features a “Problems and Complements” section that includes additional material that briefly expands on certain topics within the chapter and numerous exercises for practicing the key concepts. The first eight chapters explore all of the basic topics for training in real analysis, beginning with a review of countable sets before moving on to detailed discussions of measure theory, Lebesgue integration, Banach spaces, functional analysis, and weakly differentiable functions. More topical applications are discussed in the remaining chapters, such as maximal functions, functions of bounded mean oscillation, rearrangements, potential theory, a...

  19. Clustering analysis

    International Nuclear Information System (INIS)

    Romli

    1997-01-01

    Cluster analysis is the name of group of multivariate techniques whose principal purpose is to distinguish similar entities from the characteristics they process.To study this analysis, there are several algorithms that can be used. Therefore, this topic focuses to discuss the algorithms, such as, similarity measures, and hierarchical clustering which includes single linkage, complete linkage and average linkage method. also, non-hierarchical clustering method, which is popular name K -mean method ' will be discussed. Finally, this paper will be described the advantages and disadvantages of every methods

  20. Convex analysis

    CERN Document Server

    Rockafellar, Ralph Tyrell

    2015-01-01

    Available for the first time in paperback, R. Tyrrell Rockafellar's classic study presents readers with a coherent branch of nonlinear mathematical analysis that is especially suited to the study of optimization problems. Rockafellar's theory differs from classical analysis in that differentiability assumptions are replaced by convexity assumptions. The topics treated in this volume include: systems of inequalities, the minimum or maximum of a convex function over a convex set, Lagrange multipliers, minimax theorems and duality, as well as basic results about the structure of convex sets and

  1. Numerical analysis

    CERN Document Server

    Brezinski, C

    2012-01-01

    Numerical analysis has witnessed many significant developments in the 20th century. This book brings together 16 papers dealing with historical developments, survey papers and papers on recent trends in selected areas of numerical analysis, such as: approximation and interpolation, solution of linear systems and eigenvalue problems, iterative methods, quadrature rules, solution of ordinary-, partial- and integral equations. The papers are reprinted from the 7-volume project of the Journal of Computational and Applied Mathematics on '/homepage/sac/cam/na2000/index.html<

  2. Reentry analysis

    International Nuclear Information System (INIS)

    Biehl, F.A.

    1984-05-01

    This paper presents the criteria, previous nuclear experience in space, analysis techniques, and possible breakup enhancement devices applicable to an acceptable SP-100 reentry from space. Reactor operation in nuclear-safe orbit will minimize the radiological risk; the remaining safeguards criteria need to be defined. A simple analytical point mass reentry technique and a more comprehensive analysis method that considers vehicle dynamics and orbit insertion malfunctions are presented. Vehicle trajectory, attitude, and possible breakup enhancement devices will be integrated in the simulation as required to ensure an adequate representation of the reentry process

  3. Outlier analysis

    CERN Document Server

    Aggarwal, Charu C

    2013-01-01

    With the increasing advances in hardware technology for data collection, and advances in software technology (databases) for data organization, computer scientists have increasingly participated in the latest advancements of the outlier analysis field. Computer scientists, specifically, approach this field based on their practical experiences in managing large amounts of data, and with far fewer assumptions- the data can be of any type, structured or unstructured, and may be extremely large.Outlier Analysis is a comprehensive exposition, as understood by data mining experts, statisticians and

  4. Cluster analysis

    CERN Document Server

    Everitt, Brian S; Leese, Morven; Stahl, Daniel

    2011-01-01

    Cluster analysis comprises a range of methods for classifying multivariate data into subgroups. By organizing multivariate data into such subgroups, clustering can help reveal the characteristics of any structure or patterns present. These techniques have proven useful in a wide range of areas such as medicine, psychology, market research and bioinformatics.This fifth edition of the highly successful Cluster Analysis includes coverage of the latest developments in the field and a new chapter dealing with finite mixture models for structured data.Real life examples are used throughout to demons

  5. Elementary analysis

    CERN Document Server

    Snell, K S; Langford, W J; Maxwell, E A

    1966-01-01

    Elementary Analysis, Volume 2 introduces several of the ideas of modern mathematics in a casual manner and provides the practical experience in algebraic and analytic operations that lays a sound foundation of basic skills. This book focuses on the nature of number, algebraic and logical structure, groups, rings, fields, vector spaces, matrices, sequences, limits, functions and inverse functions, complex numbers, and probability. The logical structure of analysis given through the treatment of differentiation and integration, with applications to the trigonometric and logarithmic functions, is

  6. Risk analysis

    International Nuclear Information System (INIS)

    Baron, J.H.; Nunez McLeod, J.; Rivera, S.S.

    1997-01-01

    This book contains a selection of research works performed in the CEDIAC Institute (Cuyo National University) in the area of Risk Analysis, with specific orientations to the subjects of uncertainty and sensitivity studies, software reliability, severe accident modeling, etc. This volume presents important material for all those researches who want to have an insight in the risk analysis field, as a tool to solution several problems frequently found in the engineering and applied sciences field, as well as for the academic teachers who want to keep up to date, including the new developments and improvements continuously arising in this field [es

  7. Watershed analysis

    Science.gov (United States)

    Alan Gallegos

    2002-01-01

    Watershed analyses and assessments for the Kings River Sustainable Forest Ecosystems Project were done on about 33,000 acres of the 45,500-acre Big Creek watershed and 32,000 acres of the 85,100-acre Dinkey Creek watershed. Following procedures developed for analysis of cumulative watershed effects (CWE) in the Pacific Northwest Region of the USDA Forest Service, the...

  8. Regression Analysis

    CERN Document Server

    Freund, Rudolf J; Sa, Ping

    2006-01-01

    The book provides complete coverage of the classical methods of statistical analysis. It is designed to give students an understanding of the purpose of statistical analyses, to allow the student to determine, at least to some degree, the correct type of statistical analyses to be performed in a given situation, and have some appreciation of what constitutes good experimental design

  9. Relativistic analysis

    International Nuclear Information System (INIS)

    Unterberger, A.

    1987-01-01

    We study the Klein-Gordon symbolic calculus of operators acting on solutions of the free Klein-Gordon equation. It contracts to the Weyl calculus as c→∞. Mathematically, it may also be considered as a pseudodifferential analysis on the unit ball of R n [fr

  10. Consequence analysis

    International Nuclear Information System (INIS)

    Woodard, K.

    1985-01-01

    The objectives of this paper are to: Provide a realistic assessment of consequences; Account for plant and site-specific characteristics; Adjust accident release characteristics to account for results of plant-containment analysis; Produce conditional risk curves for each of five health effects; and Estimate uncertainties

  11. Domain analysis

    DEFF Research Database (Denmark)

    Hjørland, Birger

    2017-01-01

    The domain-analytic approach to knowledge organization (KO) (and to the broader field of library and information science, LIS) is outlined. The article reviews the discussions and proposals on the definition of domains, and provides an example of a domain-analytic study in the field of art studies....... Varieties of domain analysis as well as criticism and controversies are presented and discussed....

  12. IWS analysis

    International Nuclear Information System (INIS)

    Rhoades, W.A.; Dray, B.J.

    1970-01-01

    The effect of Gadolinium-155 on the prompt kinetic behavior of a zirconium hydride reactor has been deduced, using experimental data from the SNAPTRAN machine. The poison material makes the temperature coefficient more positive, and the Type IV sleeves were deduced to give a positive coefficient above 1100 0 F. A thorough discussion of the data and analysis is included. (U.S.)

  13. Analysis report

    International Nuclear Information System (INIS)

    Saadi, Radouan; Marah, Hamid

    2014-01-01

    This report presents results related to Tritium analysis carried out at the CNESTEN DASTE in Rabat (Morocco), on behalf of Senegal, within the framework of the RAF7011 project. It describes analytical method and instrumentation including general uncertainty estimation: Electrolytic enrichment and liquid scintillation counting; The results are expressed in Tritium Unit (TU); Low Limit Detection: 0.02 TU

  14. Survival Analysis

    CERN Document Server

    Miller, Rupert G

    2011-01-01

    A concise summary of the statistical methods used in the analysis of survival data with censoring. Emphasizes recently developed nonparametric techniques. Outlines methods in detail and illustrates them with actual data. Discusses the theory behind each method. Includes numerous worked problems and numerical exercises.

  15. Genetic analysis

    NARCIS (Netherlands)

    Koornneef, M.; Alonso-Blanco, C.; Stam, P.

    2006-01-01

    The Mendelian analysis of genetic variation, available as induced mutants or as natural variation, requires a number of steps that are described in this chapter. These include the determination of the number of genes involved in the observed trait's variation, the determination of dominance

  16. Poetic Analysis

    DEFF Research Database (Denmark)

    Nielsen, Kirsten

    2010-01-01

    The first part of this article presents the characteristics of Hebrew poetry: features associated with rhythm and phonology, grammatical features, structural elements like parallelism, and imagery and intertextuality. The second part consists of an analysis of Psalm 121. It is argued that assonan...

  17. Models of Economic Analysis

    OpenAIRE

    Adrian Ioana; Tiberiu Socaciu

    2013-01-01

    The article presents specific aspects of management and models for economic analysis. Thus, we present the main types of economic analysis: statistical analysis, dynamic analysis, static analysis, mathematical analysis, psychological analysis. Also we present the main object of the analysis: the technological activity analysis of a company, the analysis of the production costs, the economic activity analysis of a company, the analysis of equipment, the analysis of labor productivity, the anal...

  18. Trend analysis

    International Nuclear Information System (INIS)

    Smith, M.; Jones, D.R.

    1991-01-01

    The goal of exploration is to find reserves that will earn an adequate rate of return on the capital invested. Neither exploration nor economics is an exact science. The authors must therefore explore in those trends (plays) that have the highest probability of achieving this goal. Trend analysis is a technique for organizing the available data to make these strategic exploration decisions objectively and is in conformance with their goals and risk attitudes. Trend analysis differs from resource estimation in its purpose. It seeks to determine the probability of economic success for an exploration program, not the ultimate results of the total industry effort. Thus the recent past is assumed to be the best estimate of the exploration probabilities for the near future. This information is combined with economic forecasts. The computer software tools necessary for trend analysis are (1) Information data base - requirements and sources. (2) Data conditioning program - assignment to trends, correction of errors, and conversion into usable form. (3) Statistical processing program - calculation of probability of success and discovery size probability distribution. (4) Analytical processing - Monte Carlo simulation to develop the probability distribution of the economic return/investment ratio for a trend. Limited capital (short-run) effects are analyzed using the Gambler's Ruin concept in the Monte Carlo simulation and by a short-cut method. Multiple trend analysis is concerned with comparing and ranking trends, allocating funds among acceptable trends, and characterizing program risk by using risk profiles. In summary, trend analysis is a reality check for long-range exploration planning

  19. Image Analysis

    DEFF Research Database (Denmark)

    The 19th Scandinavian Conference on Image Analysis was held at the IT University of Copenhagen in Denmark during June 15-17, 2015. The SCIA conference series has been an ongoing biannual event for more than 30 years and over the years it has nurtured a world-class regional research and development...... area within the four participating Nordic countries. It is a regional meeting of the International Association for Pattern Recognition (IAPR). We would like to thank all authors who submitted works to this year’s SCIA, the invited speakers, and our Program Committee. In total 67 papers were submitted....... The topics of the accepted papers range from novel applications of vision systems, pattern recognition, machine learning, feature extraction, segmentation, 3D vision, to medical and biomedical image analysis. The papers originate from all the Scandinavian countries and several other European countries...

  20. Harmonic analysis

    CERN Document Server

    Helson, Henry

    2010-01-01

    This second edition has been enlarged and considerably rewritten. Among the new topics are infinite product spaces with applications to probability, disintegration of measures on product spaces, positive definite functions on the line, and additional information about Weyl's theorems on equidistribution. Topics that have continued from the first edition include Minkowski's theorem, measures with bounded powers, idempotent measures, spectral sets of bounded functions and a theorem of Szego, and the Wiener Tauberian theorem. Readers of the book should have studied the Lebesgue integral, the elementary theory of analytic and harmonic functions, and the basic theory of Banach spaces. The treatment is classical and as simple as possible. This is an instructional book, not a treatise. Mathematics students interested in analysis will find here what they need to know about Fourier analysis. Physicists and others can use the book as a reference for more advanced topics.

  1. Geometric analysis

    CERN Document Server

    Bray, Hubert L; Mazzeo, Rafe; Sesum, Natasa

    2015-01-01

    This volume includes expanded versions of the lectures delivered in the Graduate Minicourse portion of the 2013 Park City Mathematics Institute session on Geometric Analysis. The papers give excellent high-level introductions, suitable for graduate students wishing to enter the field and experienced researchers alike, to a range of the most important areas of geometric analysis. These include: the general issue of geometric evolution, with more detailed lectures on Ricci flow and Kähler-Ricci flow, new progress on the analytic aspects of the Willmore equation as well as an introduction to the recent proof of the Willmore conjecture and new directions in min-max theory for geometric variational problems, the current state of the art regarding minimal surfaces in R^3, the role of critical metrics in Riemannian geometry, and the modern perspective on the study of eigenfunctions and eigenvalues for Laplace-Beltrami operators.

  2. Complex analysis

    CERN Document Server

    Freitag, Eberhard

    2005-01-01

    The guiding principle of this presentation of ``Classical Complex Analysis'' is to proceed as quickly as possible to the central results while using a small number of notions and concepts from other fields. Thus the prerequisites for understanding this book are minimal; only elementary facts of calculus and algebra are required. The first four chapters cover the essential core of complex analysis: - differentiation in C (including elementary facts about conformal mappings) - integration in C (including complex line integrals, Cauchy's Integral Theorem, and the Integral Formulas) - sequences and series of analytic functions, (isolated) singularities, Laurent series, calculus of residues - construction of analytic functions: the gamma function, Weierstrass' Factorization Theorem, Mittag-Leffler Partial Fraction Decomposition, and -as a particular highlight- the Riemann Mapping Theorem, which characterizes the simply connected domains in C. Further topics included are: - the theory of elliptic functions based on...

  3. Spectrographic analysis

    International Nuclear Information System (INIS)

    Quinn, C.A.

    1983-01-01

    The article deals with spectrographic analysis and the analytical methods based on it. The theory of spectrographic analysis is discussed as well as the layout of a spectrometer system. The infrared absorption spectrum of a compound is probably its most unique property. The absorption of infrared radiation depends on increasing the energy of vibration and rotation associated with a covalent bond. The infrared region is intrinsically low in energy thus the design of infrared spectrometers is always directed toward maximising energy throughput. The article also considers atomic absorption - flame atomizers, non-flame atomizers and the source of radiation. Under the section an emission spectroscopy non-electrical energy sources, electrical energy sources and electrical flames are discussed. Digital computers form a part of the development on spectrographic instrumentation

  4. Wavelet analysis

    CERN Document Server

    Cheng, Lizhi; Luo, Yong; Chen, Bo

    2014-01-01

    This book could be divided into two parts i.e. fundamental wavelet transform theory and method and some important applications of wavelet transform. In the first part, as preliminary knowledge, the Fourier analysis, inner product space, the characteristics of Haar functions, and concepts of multi-resolution analysis, are introduced followed by a description on how to construct wavelet functions both multi-band and multi wavelets, and finally introduces the design of integer wavelets via lifting schemes and its application to integer transform algorithm. In the second part, many applications are discussed in the field of image and signal processing by introducing other wavelet variants such as complex wavelets, ridgelets, and curvelets. Important application examples include image compression, image denoising/restoration, image enhancement, digital watermarking, numerical solution of partial differential equations, and solving ill-conditioned Toeplitz system. The book is intended for senior undergraduate stude...

  5. Electrochemical analysis

    International Nuclear Information System (INIS)

    Hwang, Hun

    2007-02-01

    This book explains potentiometry, voltametry, amperometry and basic conception of conductometry with eleven chapters. It gives the specific descriptions on electrochemical cell and its mode, basic conception of electrochemical analysis on oxidation-reduction reaction, standard electrode potential, formal potential, faradaic current and faradaic process, mass transfer and overvoltage, potentiometry and indirect potentiometry, polarography with TAST, normal pulse and deferential pulse, voltammetry, conductometry and conductometric titration.

  6. Survival analysis

    International Nuclear Information System (INIS)

    Badwe, R.A.

    1999-01-01

    The primary endpoint in the majority of the studies has been either disease recurrence or death. This kind of analysis requires a special method since all patients in the study experience the endpoint. The standard method for estimating such survival distribution is Kaplan Meier method. The survival function is defined as the proportion of individuals who survive beyond certain time. Multi-variate comparison for survival has been carried out with Cox's proportional hazard model

  7. Elastodynamic Analysis

    DEFF Research Database (Denmark)

    Andersen, Lars

    This book contains the lecture notes for the 9th semester course on elastodynamics. The first chapter gives an overview of the basic theory of stress waves propagating in viscoelastic media. In particular, the effect of surfaces and interfaces in a viscoelastic material is studied, and different....... Thus, in Chapter 3, an alternative semi-analytic method is derived, which may be applied for the analysis of layered half-spaces subject to moving or stationary loads....

  8. Cluster analysis

    OpenAIRE

    Mucha, Hans-Joachim; Sofyan, Hizir

    2000-01-01

    As an explorative technique, duster analysis provides a description or a reduction in the dimension of the data. It classifies a set of observations into two or more mutually exclusive unknown groups based on combinations of many variables. Its aim is to construct groups in such a way that the profiles of objects in the same groups are relatively homogenous whereas the profiles of objects in different groups are relatively heterogeneous. Clustering is distinct from classification techniques, ...

  9. Water analysis

    International Nuclear Information System (INIS)

    Garbarino, J.R.; Steinheimer, T.R.; Taylor, H.E.

    1985-01-01

    This is the twenty-first biennial review of the inorganic and organic analytical chemistry of water. The format of this review differs somewhat from previous reviews in this series - the most recent of which appeared in Analytical Chemistry in April 1983. Changes in format have occurred in the presentation of material concerning review articles and the inorganic analysis of water sections. Organic analysis of water sections are organized as in previous reviews. Review articles have been compiled and tabulated in an Appendix with respect to subject, title, author(s), citation, and number of references cited. The inorganic water analysis sections are now grouped by constituent using the periodic chart; for example, alkali, alkaline earth, 1st series transition metals, etc. Within these groupings the references are roughly grouped by instrumental technique; for example, spectrophotometry, atomic absorption spectrometry, etc. Multiconstituent methods for determining analytes that cannot be grouped in this manner are compiled into a separate section sorted by instrumental technique. References used in preparing this review were compiled from nearly 60 major journals published during the period from October 1982 through September 1984. Conference proceedings, most foreign journals, most trade journals, and most government publications are excluded. References cited were obtained using the American Chemical Society's Chemical Abstracts for sections on inorganic analytical chemistry, organic analytical chemistry, water, and sewage waste. Cross-references of these sections were also included. 860 references

  10. Economic analysis

    Energy Technology Data Exchange (ETDEWEB)

    None

    1980-06-01

    The Energy Policy and Conservation Act (EPCA) mandated that minimum energy efficiency standards be established for classes of refrigerators and refrigerator-freezers, freezers, clothes dryers, water heaters, room air conditioners, home heating equipment, kitchen ranges and ovens, central air conditioners, and furnaces. EPCA requires that standards be designed to achieve the maximum improvement in energy efficiency that is technologically feasible and economically justified. Following the introductory chapter, Chapter Two describes the methodology used in the economic analysis and its relationship to legislative criteria for consumer product efficiency assessment; details how the CPES Value Model systematically compared and evaluated the economic impacts of regulation on the consumer, manufacturer and Nation. Chapter Three briefly displays the results of the analysis and lists the proposed performance standards by product class. Chapter Four describes the reasons for developing a baseline forecast, characterizes the baseline scenario from which regulatory impacts were calculated and summarizes the primary models, data sources and assumptions used in the baseline formulations. Chapter Five summarizes the methodology used to calculate regulatory impacts; describes the impacts of energy performance standards relative to the baseline discussed in Chapter Four. Also discussed are regional standards and other program alternatives to performance standards. Chapter Six describes the procedure for balancing consumer, manufacturer, and national impacts to select standard levels. Details of models and data bases used in the analysis are included in Appendices A through K.

  11. Vector analysis

    CERN Document Server

    Newell, Homer E

    2006-01-01

    When employed with skill and understanding, vector analysis can be a practical and powerful tool. This text develops the algebra and calculus of vectors in a manner useful to physicists and engineers. Numerous exercises (with answers) not only provide practice in manipulation but also help establish students' physical and geometric intuition in regard to vectors and vector concepts.Part I, the basic portion of the text, consists of a thorough treatment of vector algebra and the vector calculus. Part II presents the illustrative matter, demonstrating applications to kinematics, mechanics, and e

  12. Vector analysis

    CERN Document Server

    Brand, Louis

    2006-01-01

    The use of vectors not only simplifies treatments of differential geometry, mechanics, hydrodynamics, and electrodynamics, but also makes mathematical and physical concepts more tangible and easy to grasp. This text for undergraduates was designed as a short introductory course to give students the tools of vector algebra and calculus, as well as a brief glimpse into these subjects' manifold applications. The applications are developed to the extent that the uses of the potential function, both scalar and vector, are fully illustrated. Moreover, the basic postulates of vector analysis are brou

  13. Understanding analysis

    CERN Document Server

    Abbott, Stephen

    2015-01-01

    This lively introductory text exposes the student to the rewards of a rigorous study of functions of a real variable. In each chapter, informal discussions of questions that give analysis its inherent fascination are followed by precise, but not overly formal, developments of the techniques needed to make sense of them. By focusing on the unifying themes of approximation and the resolution of paradoxes that arise in the transition from the finite to the infinite, the text turns what could be a daunting cascade of definitions and theorems into a coherent and engaging progression of ideas. Acutely aware of the need for rigor, the student is much better prepared to understand what constitutes a proper mathematical proof and how to write one. Fifteen years of classroom experience with the first edition of Understanding Analysis have solidified and refined the central narrative of the second edition. Roughly 150 new exercises join a selection of the best exercises from the first edition, and three more project-sty...

  14. Consensus analysis:

    DEFF Research Database (Denmark)

    Moore, R; Brødsgaard, I; Miller, ML

    1997-01-01

    A quantitative method for validating qualitative interview results and checking sample parameters is described and illustrated using common pain descriptions among a sample of Anglo-American and mandarin Chinese patients and dentists matched by age and gender. Assumptions were that subjects were ...... of covalidating questionnaires that reflect results of qualitative interviews are recommended in order to estimate sample parameters such as intersubject agreement, individual subject accuracy, and minimum required sample sizes.......A quantitative method for validating qualitative interview results and checking sample parameters is described and illustrated using common pain descriptions among a sample of Anglo-American and mandarin Chinese patients and dentists matched by age and gender. Assumptions were that subjects were...... of consistency in use of descriptors within groups, validity of description, accuracy of individuals compared with others in their group, and minimum required sample size were calculated using Cronbach's alpha, factor analysis, and Bayesian probability. Ethnic and professional differences within and across...

  15. Failure Analysis

    International Nuclear Information System (INIS)

    Iorio, A.F.; Crespi, J.C.

    1987-01-01

    After ten years of operation at the Atucha I Nuclear Power Station a gear belonging to a pressurized heavy water reactor refuelling machine, failed. The gear box was used to operate the inlet-outlet heavy-water valve of the machine. Visual examination of the gear device showed an absence of lubricant and that several gear teeth were broken at the root. Motion was transmitted with a speed-reducing device with controlled adjustable times in order to produce a proper fitness of the valve closure. The aim of this paper is to discuss the results of the gear failure analysis in order to recommend the proper solution to prevent further failures. (Author)

  16. Nuclear analysis

    International Nuclear Information System (INIS)

    1988-01-01

    In a search for correlations between the elemental composition of trace elements in human stones and the stone types with relation to their growth pattern, a combined PIXE and x-ray diffraction spectrometry approach was implemented. The combination of scanning PIXE and XRD has proved to be an advance in the methodology of stone analysis and may point to the growth pattern in the body. The exact role of trace elements in the formation and growth of urinary stones is not fully understood. Efforts are thus continuing firstly to solve the analytical problems concerned and secondly to design suitable experiments that would provide information about the occurrence and distribution of trace elements in urine. 1 fig., 1 ref

  17. Ferrous analysis

    International Nuclear Information System (INIS)

    Straub, W.A.

    1987-01-01

    This review is the seventh in the series compiled by using the Dialog on-line CA Search facilities at the Information Resource Center of USS Technical Center covering the period from Oct. 1984 to Nov. 1, 1986. The quest for better surface properties, through the application of various electrochemical and other coating techniques, seems to have increased and reinforces the notion that only through the value added to a steel by proper finishing steps can a major supplier hope to compete profitably. The detection, determination, and control of microalloying constituents has also been generating a lot of interest as evidenced by the number of publications devoted to this subject in the last few years. Several recent review articles amplify on the recent trends in the application of modern analytical technology to steelmaking. Another review has been devoted to the determination of trace elements and the simultaneous determination of elements in metals by mass spectrometry, atomic absorption spectrometry, and multielement emission spectrometry. Problems associated with the analysis of electroplating wastewaters have been reviewed in a recent publication that has described the use of various spectrophotometric methods for this purpose. The collection and treatment of analytical data in the modern steel making environment have been extensively reviewed emphasis on the interaction of the providers and users of the analytical data, its quality, and the cost of its collection. Raw material treatment and beneficiation was the dominant theme

  18. Matrix analysis

    CERN Document Server

    Bhatia, Rajendra

    1997-01-01

    A good part of matrix theory is functional analytic in spirit. This statement can be turned around. There are many problems in operator theory, where most of the complexities and subtleties are present in the finite-dimensional case. My purpose in writing this book is to present a systematic treatment of methods that are useful in the study of such problems. This book is intended for use as a text for upper division and gradu­ ate courses. Courses based on parts of the material have been given by me at the Indian Statistical Institute and at the University of Toronto (in collaboration with Chandler Davis). The book should also be useful as a reference for research workers in linear algebra, operator theory, mathe­ matical physics and numerical analysis. A possible subtitle of this book could be Matrix Inequalities. A reader who works through the book should expect to become proficient in the art of deriving such inequalities. Other authors have compared this art to that of cutting diamonds. One first has to...

  19. Uncertainty analysis

    International Nuclear Information System (INIS)

    Thomas, R.E.

    1982-03-01

    An evaluation is made of the suitability of analytical and statistical sampling methods for making uncertainty analyses. The adjoint method is found to be well-suited for obtaining sensitivity coefficients for computer programs involving large numbers of equations and input parameters. For this purpose the Latin Hypercube Sampling method is found to be inferior to conventional experimental designs. The Latin hypercube method can be used to estimate output probability density functions, but requires supplementary rank transformations followed by stepwise regression to obtain uncertainty information on individual input parameters. A simple Cork and Bottle problem is used to illustrate the efficiency of the adjoint method relative to certain statistical sampling methods. For linear models of the form Ax=b it is shown that a complete adjoint sensitivity analysis can be made without formulating and solving the adjoint problem. This can be done either by using a special type of statistical sampling or by reformulating the primal problem and using suitable linear programming software

  20. Experimental modal analysis

    Energy Technology Data Exchange (ETDEWEB)

    Ibsen, Lars Bo; Liingaard, M.

    2006-12-15

    This technical report concerns the basic theory and principles for experimental modal analysis. The sections within the report are: Output-only modal analysis software, general digital analysis, basics of structural dynamics and modal analysis and system identification. (au)

  1. Theoretical numerical analysis a functional analysis framework

    CERN Document Server

    Atkinson, Kendall

    2005-01-01

    This textbook prepares graduate students for research in numerical analysis/computational mathematics by giving to them a mathematical framework embedded in functional analysis and focused on numerical analysis. This helps the student to move rapidly into a research program. The text covers basic results of functional analysis, approximation theory, Fourier analysis and wavelets, iteration methods for nonlinear equations, finite difference methods, Sobolev spaces and weak formulations of boundary value problems, finite element methods, elliptic variational inequalities and their numerical solu

  2. Analysis of Heat Transfer

    International Nuclear Information System (INIS)

    2003-08-01

    This book deals with analysis of heat transfer which includes nonlinear analysis examples, radiation heat transfer, analysis of heat transfer in ANSYS, verification of analysis result, analysis of heat transfer of transition with automatic time stepping and open control, analysis of heat transfer using arrangement of ANSYS, resistance of thermal contact, coupled field analysis such as of thermal-structural interaction, cases of coupled field analysis, and phase change.

  3. Information security risk analysis

    CERN Document Server

    Peltier, Thomas R

    2001-01-01

    Effective Risk AnalysisQualitative Risk AnalysisValue AnalysisOther Qualitative MethodsFacilitated Risk Analysis Process (FRAP)Other Uses of Qualitative Risk AnalysisCase StudyAppendix A: QuestionnaireAppendix B: Facilitated Risk Analysis Process FormsAppendix C: Business Impact Analysis FormsAppendix D: Sample of ReportAppendix E: Threat DefinitionsAppendix F: Other Risk Analysis OpinionsIndex

  4. System analysis and design

    International Nuclear Information System (INIS)

    Son, Seung Hui

    2004-02-01

    This book deals with information technology and business process, information system architecture, methods of system development, plan on system development like problem analysis and feasibility analysis, cases for system development, comprehension of analysis of users demands, analysis of users demands using traditional analysis, users demands analysis using integrated information system architecture, system design using integrated information system architecture, system implementation, and system maintenance.

  5. Identification of genetic variants in pharmacogenetic genes associated with type 2 diabetes in a Mexican-Mestizo population.

    Science.gov (United States)

    Rodríguez-Rivera, Nidia Samara; Cuautle-Rodríguez, Patricia; Castillo-Nájera, Fernando; Molina-Guarneros, Juan Arcadio

    2017-07-01

    Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic pathologies in the world. In developing countries, such as Mexico, its prevalence represents an important public health and research issue. Determining factors triggering T2DM are environmental and genetic. While diet, exercise and proper weight control are the first measures recommended to improve the quality of life and life expectancy of patients, pharmacological treatment is usually the next step. Within every population there are variations in interindividual drug response, which may be due to genetic background. Some of the most frequent first line T2DM treatments in developing countries are sulfonylureas (SU), whose targets are ATP-sensitive potassium channels (K ATP ). Single nucleotide polymorphisms (SNPs) of the K ATP coding genes, potassium voltage-gated channel subfamily J member 11 ( KCNJ11 ) and ATP binding cassette subfamily C member 8 ( ABCC8 ) have been associated with SU response variability. To date, there is little information regarding the mechanism by which these SNPs work within Mexican populations. The present study describes the distribution of three SNPs [KCNJ11 rs5219 (E23K), ABCC8 rs757110 (S1369A) and rs1799854 (-3C/T)] among Mestizo Mexican (MM) T2DM patients, and compares it with published data on various healthy subjects and T2DM populations. Through this comparison, no difference in the KCNJ11 rs5219 and ABCC8 rs757110 allelic and genotypic frequencies in MM were observed compared with the majority of the reported populations of healthy and diabetic individuals among other ethnic groups; except for African and Colombian individuals. By contrast, ABCC8 rs1799854 genomic and allelic frequencies among MM were observed to be significantly different from those reported by the 1000 Genomes Project, and from diabetic patients within other populations reported in the literature, such as the European, Asian and Latin-American individuals [T=0.704, G=0.296; CC=0.506, CT=0.397, TT=0.097; 95% confidence interval (CI); P≤0.05]; except for South Asian and Iberian populations, which may reflect the admixture origins of the present Mexican population. This genetic similarity has not been observed in the other Latin-American groups. To the best of our knowledge, this is the first study of ABCC8 rs757110 and rs1799854 SNP frequencies in any Mexican population and, specifically with diabetic Mexicans. Knowledge of the genetic structure of different populations is key to understanding the interindividual responses to drugs, such as SU and whether genotypic differences affect clinical outcome.

  6. Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer

    DEFF Research Database (Denmark)

    Bergmann, Troels K; Gréen, Henrik; Andersen, Charlotte Brasch

    2011-01-01

    Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindiv......Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia...

  7. Pharmacogenetic Aspects of the Interaction of AT1 Receptor Antagonists With ATP-Binding Cassette Transporter ABCG2

    Directory of Open Access Journals (Sweden)

    Anne Ripperger

    2018-05-01

    Full Text Available The ATP-binding cassette transporter ABCG2 (BCRP and MXR is involved in the absorption, distribution, and elimination of numerous drugs. Thus, drugs that are able to reduce the activity of ABCG2, e.g., antihypertensive AT1 receptor antagonists (ARBs, may cause drug-drug interactions and compromise drug safety and efficacy. In addition, genetic variability within the ABCG2 gene may influence the ability of the transporter to interact with ARBs. Thus, the aim of this study was to characterize the ARB-ABCG2 interaction in the light of naturally occurring variations (F489L, R482G or amino acid substitutions with in silico-predicted relevance for the ARB-ABCG2 interaction (Y469A; M483F; Y570A. For this purpose, ABCG2 variants were expressed in HEK293 cells and the impact of ARBs on ABCG2 activity was studied in vitro using the pheophorbide A (PhA efflux assay. First, we demonstrated that both the F489L and the Y469A substitution, respectively, reduced ABCG2 protein levels in these cells. Moreover, both substitutions enhanced the inhibitory effect of candesartan cilexetil, irbesartan, losartan, and telmisartan on ABCG2-mediated PhA efflux, whereas the R482G substitution blunted the inhibitory effect of candesartan cilexetil and telmisartan in this regard. In contrast, the ARB-ABCG2 interaction was not altered in cells expressing either the M483F or the Y570A variant, respectively. In conclusion, our data indicate that the third transmembrane helix and adjacent regions of ABCG2 may be of major importance for the interaction of ARBs with the ABC transporter. Moreover, we conclude from our data that individuals carrying the F489L polymorphism may be at increased risk of developing ABCG2-related drug-drug interactions in multi-drug regimens involving ARBs.

  8. Evaluation of the iPLEX® ADME PGx Pro Panel and allele frequencies of pharmacogenetic markers in Danes

    DEFF Research Database (Denmark)

    Jensen, Line; Børsting, Claus; Dalhoff, Kim

    2016-01-01

    of this study was to perform a technical evaluation of the iPlex® ADME PGx Pro Panel by genotyping 50 unrelated Danes and estimate preliminary genotype frequencies among Danes. DESIGN AND METHODS: The investigations were performed by the use of PCR, single base extension (SBE) and Matrix Assisted Laser...

  9. Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients.

    Science.gov (United States)

    Sarfo, Fred S; Zhang, Yuan; Egan, Deirdre; Tetteh, Lambert A; Phillips, Richard; Bedu-Addo, George; Sarfo, Maame Anima; Khoo, Saye; Owen, Andrew; Chadwick, David R

    2014-02-01

    Efavirenz is widely used in first-line antiretroviral therapy in sub-Saharan Africa. However, exposure to efavirenz shows marked interindividual variability that is genetically mediated with potential for important pharmacodynamic consequences. The aims of this study were to assess the frequencies of CYP2B6, CYP2A6, UGT2B7 and CAR single nucleotide polymorphisms (SNPs) and their impact on plasma efavirenz concentration and clinical/immunological responses in Ghanaian patients. Genomic DNA from 800 HIV-infected patients was genotyped for selected SNPs by real-time PCR-based allelic discrimination. Mid-dose plasma efavirenz concentrations were measured for 521 patients using HPLC with UV detection. Clinical outcomes in 299 patients on efavirenz were retrospectively assessed. Univariate and multivariate linear regression were performed using best subset selection. Time-to-event outcomes were analysed using a Cox proportional hazards regression model. The variant allele frequencies for CYP2B6 516G>T (rs3745274), CYP2B6 983T>C (rs28399499), CYP2A6 -48T>G (CYP2B6*9B; rs28399433), UGT2B7 802C>T (UGT2B7*2; rs7439366), UGT2B7 735A>G (UGT2B7*1c; rs28365062) and CAR 540C>T (rs2307424) were 48%, 4%, 3%, 23%, 15% and 7%, respectively. CYP2B6 516G>T, CYP2B6 983T>C and CYP2A6 -48T>G were associated with significantly elevated efavirenz concentrations. A trend towards association between plasma efavirenz concentration and CAR 540C>T was observed. CYP2B6 516G homozygosity was associated with immunological failure [adjusted hazards ratio compared with T homozygosity, 1.70 (1.04-2.76); P = 0.03]. CYP2B6 and CYP2A6 SNPs were associated with higher plasma efavirenz concentrations due to reduction in major and minor phase I routes of elimination, respectively. Further prospective studies are needed to validate the pharmacodynamic correlates of these polymorphisms in this population.

  10. Pharmacogenetics of telatinib, a VEGFR-2 and VEGFR-3 tyrosine kinase inhibitor, used in patients with solid tumors

    NARCIS (Netherlands)

    N. Steeghs (Neeltje); A.J. Gelderblom (Hans); J.A.M. Wessels (Judith); F.A.L.M. Eskens (Ferry); N. de Bont (Natasja); J.W. Nortier (Johan); H.J. Guchelaar (Henk Jan)

    2011-01-01

    textabstractSummary: Purpose Telatinib is an orally active small-molecule tyrosine kinase inhibitor of kinase insert domain receptor (KDR; VEGFR-2) and fms-related tyrosine kinase 4 (FLT4; VEGFR-3). This study aims at the identification of relationships between single nucleotide polymorphisms (SNPs)

  11. Why Research on the Pharmacogenetics of Atypical Antipsychotic-Induced Weight Gain in Individuals with Intellectual Disabilities Is Warranted

    Science.gov (United States)

    Sleister, Heidi M.; Valdovinos, Maria Gabriela

    2011-01-01

    Weight gain is an often-observed side effect of atypical antipsychotics (AAPs) and is particularly significant in individuals with intellectual disabilities (ID). The majority of individuals treated with AAPs will gain at least 10% of their initial body weight over the course of therapy (Umbricht & Kane, 1996). One's genetic constitution is an…

  12. Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

    International Nuclear Information System (INIS)

    Anthoney, D Alan; Miwa, Masanori; Twelves, Christopher; Evans, TRJ; Naik, Jay; MacPherson, Iain RJ; Crawford, Donna; Hartley, John M; Hartley, Janet A; Saito, Tomohisa; Abe, Masaichi; Jones, Keith

    2012-01-01

    A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m 2 . MTD was 10 mg/m 2 ; DLTs at 12 (2/4 patients) and 10 mg/m 2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhoea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and C max from 1–10 mg/m 2 . Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. TP300 had predictable hematologic toxicity, and diarrhoea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage. EU-CTR2006-001345-33

  13. Analysis of Project Finance | Energy Analysis | NREL

    Science.gov (United States)

    Analysis of Project Finance Analysis of Project Finance NREL analysis helps potential renewable energy developers and investors gain insights into the complex world of project finance. Renewable energy project finance is complex, requiring knowledge of federal tax credits, state-level incentives, renewable

  14. Safety analysis fundamentals

    International Nuclear Information System (INIS)

    Wright, A.C.D.

    2002-01-01

    This paper discusses the safety analysis fundamentals in reactor design. This study includes safety analysis done to show consequences of postulated accidents are acceptable. Safety analysis is also used to set design of special safety systems and includes design assist analysis to support conceptual design. safety analysis is necessary for licensing a reactor, to maintain an operating license, support changes in plant operations

  15. An example of multidimensional analysis: Discriminant analysis

    International Nuclear Information System (INIS)

    Lutz, P.

    1990-01-01

    Among the approaches on the data multi-dimensional analysis, lectures on the discriminant analysis including theoretical and practical aspects are presented. The discrimination problem, the analysis steps and the discrimination categories are stressed. Examples on the descriptive historical analysis, the discrimination for decision making, the demonstration and separation of the top quark are given. In the linear discriminant analysis the following subjects are discussed: Huyghens theorem, projection, discriminant variable, geometrical interpretation, case for g=2, classification method, separation of the top events. Criteria allowing the obtention of relevant results are included [fr

  16. Semen Analysis Test

    Science.gov (United States)

    ... Sources Ask Us Also Known As Sperm Analysis Sperm Count Seminal Fluid Analysis Formal Name Semen Analysis This ... semen Viscosity—consistency or thickness of the semen Sperm count—total number of sperm Sperm concentration (density)—number ...

  17. Handbook of Applied Analysis

    CERN Document Server

    Papageorgiou, Nikolaos S

    2009-01-01

    Offers an examination of important theoretical methods and procedures in applied analysis. This book details the important theoretical trends in nonlinear analysis and applications to different fields. It is suitable for those working on nonlinear analysis.

  18. Shape analysis in medical image analysis

    CERN Document Server

    Tavares, João

    2014-01-01

    This book contains thirteen contributions from invited experts of international recognition addressing important issues in shape analysis in medical image analysis, including techniques for image segmentation, registration, modelling and classification, and applications in biology, as well as in cardiac, brain, spine, chest, lung and clinical practice. This volume treats topics such as, anatomic and functional shape representation and matching; shape-based medical image segmentation; shape registration; statistical shape analysis; shape deformation; shape-based abnormity detection; shape tracking and longitudinal shape analysis; machine learning for shape modeling and analysis; shape-based computer-aided-diagnosis; shape-based medical navigation; benchmark and validation of shape representation, analysis and modeling algorithms. This work will be of interest to researchers, students, and manufacturers in the fields of artificial intelligence, bioengineering, biomechanics, computational mechanics, computationa...

  19. NCEP SST Analysis

    Science.gov (United States)

    Organization Search Go Search Polar Go MMAB SST Analysis Main page About MMAB Our Mission Our Personnel EMC Branches Global Climate & Weather Modeling Mesoscale Modeling Marine Modeling and Analysis Contact EMC (RTG_SST_HR) analysis For a regional map, click the desired area in the global SST analysis and anomaly maps

  20. Foundations of factor analysis

    CERN Document Server

    Mulaik, Stanley A

    2009-01-01

    Introduction Factor Analysis and Structural Theories Brief History of Factor Analysis as a Linear Model Example of Factor AnalysisMathematical Foundations for Factor Analysis Introduction Scalar AlgebraVectorsMatrix AlgebraDeterminants Treatment of Variables as Vectors Maxima and Minima of FunctionsComposite Variables and Linear Transformations Introduction Composite Variables Unweighted Composite VariablesDifferentially Weighted Composites Matrix EquationsMulti