Ethiopian health care professionals' knowledge, attitude, and interests toward pharmacogenomics.

Pharmgenomics Pers Med. 2017;10:279-285

Authors: Abdela OA, Bhagavathula AS, Gebreyohannes EA, Tegegn HG

Abstract
Background: Pharmacogenomics is a field of science which studies the impact of inheritance on individual variation in medication therapy response.
Aim: We assessed healthcare professionals' knowledge, attitude, and interest toward pharmacogenomics.
Methods: A cross-sectional survey was conducted using a 32-item questionnaire among physicians, nurses, and pharmacists who were working at the University of Gondar Referral and Teaching Hospital in northwest Ethiopia. Descriptive statistics was applied, and the categorical variables were summarized as frequency and percentages. An analysis of variance (ANOVA) test was performed to compare mean scores among health professionals. A p-value of <0.05 was considered as statistically significant.
Results: Of 292 health professionals who responded, the majority were male (60%) and the mean age of study participants was 27.00 (±4.85 SD) years. The mean knowledge scores of all participants, pharmacists, physicians, and nurses were 2.343±1.109, 2.671±1.059, 2.375±1.093, and 2.173±1.110, respectively. Based on the ANOVA test, a statistically significant difference was noted in mean knowledge score between pharmacists and nurses (p=0.002). More than two-thirds (67.33%) of nurses, 42.86% of pharmacists, and 40.27% of physicians who participated did not know that genetic variations can account for as much as 95% of the variability in drug disposition and effects. The ability to accurately apply their knowledge to drug therapy selection, dosing, or monitoring parameter was reported by 35.3% of the participants. More than two-thirds (69.2%) of participants thought that pharmacogenomic testing will allow the identification of the right drug with less side effects. Most of the participants (83.2%) also requested to have training on pharmacogenomics.
Conclusion: Participants showed limited knowledge, but they had positive attitude toward pharmacogenomics. Educational programs focusing on pharmacogenomic testing and its clinical application need to be emphasized.

PMID: 29255371 [PubMed]

Impact of DNA repair, folate and glutathione gene polymorphisms on risk of non small cell lung cancer.

Pathol Res Pract. 2017 Nov 21;:

Authors: Pérez-Ramírez C, Cañadas-Garre M, Alnatsha A, Villar E, Delgado JR, Calleja-Hernández MÁ, Faus-Dáder MJ

Abstract
Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC. No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC.

PMID: 29254785 [PubMed - as supplied by publisher]

Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma.

Br J Cancer. 2017 Dec 05;117(12):1819-1827

Authors: Lièvre A, Ouine B, Canet J, Cartier A, Amar Y, Cacheux W, Mariani O, Guimbaud R, Selves J, Lecomte T, Guyetant S, Bieche I, Berger F, de Koning L

Abstract
BACKGROUND: Metastatic colorectal cancer (mCRC) patients with mutant KRAS or NRAS are ineligible for anti-epidermal growth factor receptor (anti-EGFR) therapy, as RAS mutations activate downstream pathways independently of EGFR and induce primary resistance. However, even among RAS wild-type (WT) patients, only a fraction responds to anti-EGFR therapy, suggesting that other mechanisms of resistance exist. We hypothesise that different (epi)genetic alterations can lead to primary anti-EGFR resistance and that the crucial end point is the activation of protein signalling pathways.
METHODS: We analysed the expression and activation of proteins involved in cell signalling, using reverse phase protein arrays, on a multicentre French cohort of RAS WT mCRC treated with anti-EGFR treatment.
RESULTS: We identify activated EGFR and HER3 as protein biomarkers predictive for better overall survival. Active EGFR signalling and downstream PI3K, but not MAPK, pathway activation are associated with response to anti-EGFR treatment. Left-sided mCRC displays active ErbB2/3 and Wnt pathways and a better response to anti-EGFR therapy compared to right-sided mCRC.
CONCLUSIONS: We identify active EGFR and PI3K signalling as a key factor for response to anti-EGFR treatment in mCRC and highlight the importance of developing these biomarkers in clinical practice for the selection of RAS WT mCRC patients that would benefit from anti-EGFR treatment.

PMID: 29024937 [PubMed - indexed for MEDLINE]

Concise Review: Induced Pluripotent Stem Cell Research in the Era of Precision Medicine.

Stem Cells. 2017 Mar;35(3):545-550

Authors: Hamazaki T, El Rouby N, Fredette NC, Santostefano KE, Terada N

Abstract
Recent advances in DNA sequencing technologies are revealing how human genetic variations associate with differential health risks, disease susceptibilities, and drug responses. Such information is now expected to help evaluate individual health risks, design personalized health plans and treat patients with precision. It is still challenging, however, to understand how such genetic variations cause the phenotypic alterations in pathobiologies and treatment response. Human induced pluripotent stem cell (iPSC) technologies are emerging as a promising strategy to fill the knowledge gaps between genetic association studies and underlying molecular mechanisms. Breakthroughs in genome editing technologies and continuous improvement in iPSC differentiation techniques are particularly making this research direction more realistic and practical. Pioneering studies have shown that iPSCs derived from a variety of monogenic diseases can faithfully recapitulate disease phenotypes in vitro when differentiated into disease-relevant cell types. It has been shown possible to partially recapitulate disease phenotypes, even with late onset and polygenic diseases. More recently, iPSCs have been shown to validate effects of disease and treatment-related single nucleotide polymorphisms identified through genome wide association analysis. In this review, we will discuss how iPSC research will further contribute to human health in the coming era of precision medicine. Stem Cells 2017;35:545-550.

PMID: 28100040 [PubMed - indexed for MEDLINE]

Autoimmune manifestations in aged mice arise from early-life immune dysregulation.

Sci Transl Med. 2016 Oct 19;8(361):361ra137

Authors: Mahmoud TI, Wang J, Karnell JL, Wang Q, Wang S, Naiman B, Gross P, Brohawn PZ, Morehouse C, Aoyama J, Wasserfall C, Carter L, Atkinson MA, Serreze DV, Braley-Mullen H, Mustelin T, Kolbeck R, Herbst R, Ettinger R

Abstract
Autoantibodies can be present years to decades before the onset of disease manifestations in autoimmunity. This finding suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. We show that Sjögren's syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren's pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks of age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology, including anti-muscarinic receptor antibodies. Microarray profiling of the salivary gland characterized the expression pattern of genes that increased with disease progression and showed that early anti-CD40L greatly repressed B cell function while having a broader effect on multiple biological pathways, including interleukin-12 and interferon signaling. A single prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and nonobese diabetic mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest that early peripheral immune dysregulation gives rise to autoimmune manifestations later in life, and for diseases predated by autoantibodies, early prophylactic intervention with biologics may prove efficacious.

PMID: 27798262 [PubMed - indexed for MEDLINE]

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

Pharmacol Res. 2016 Sep;111:877-884

Authors: Pérez-Ramírez C, Cañadas-Garre M, Alnatsha A, Villar E, Delgado JR, Faus-Dáder MJ, Calleja-Hernández MŸ

Abstract
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.

PMID: 27498158 [PubMed - indexed for MEDLINE]

Discovering Biology in Periodic Data through Phase Set Enrichment Analysis (PSEA).

J Biol Rhythms. 2016 Jun;31(3):244-57

Authors: Zhang R, Podtelezhnikov AA, Hogenesch JB, Anafi RC

Abstract
Several tools use prior biological knowledge to interpret gene expression data. However, existing enrichment tools assume that variables are monotonic and incorrectly measure the distance between periodic phases. As a result, these tools are poorly suited for the analysis of the cell cycle, circadian clock, or other periodic systems. Here, we develop Phase Set Enrichment Analysis (PSEA) to incorporate prior knowledge into the analysis of periodic data. PSEA identifies biologically related gene sets showing temporally coordinated expression. Using synthetic gene sets of various sizes generated from von Mises (circular normal) distributions, we benchmarked PSEA alongside existing methods. PSEA offered enhanced sensitivity over a broad range of von Mises distributions and gene set sizes. Importantly, and unlike existing tools, the sensitivity of PSEA is independent of the mean expression phase of the set. We applied PSEA to 4 published datasets. Application of PSEA to the mouse circadian atlas revealed that several pathways, including those regulating immune and cell-cycle function, demonstrate temporal orchestration across multiple tissues. We then applied PSEA to the phase shifts following a restricted feeding paradigm. We found that this perturbation disrupts intraorgan metabolic synchrony in the liver, altering the timing between anabolic and catabolic pathways. Reanalysis of expression data using custom gene sets derived from recent ChIP-seq results revealed circadian transcriptional targets bound exclusively by CLOCK, independently of BMAL1, differ from other exclusive circadian output genes and have well-synchronized phases. Finally, we used PSEA to compare 2 cell-cycle datasets. PSEA increased the apparent biological overlap while also revealing evidence of cell-cycle dysregulation in these cancer cells. To encourage its use by the community, we have implemented PSEA as a Java application. In sum, PSEA offers a powerful new tool to investigate large-scale, periodic data for biological insight.

PMID: 26955841 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/12/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/12/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Metabolic analysis of Panax notoginseng saponins with gut microbiota-mediated biotransformation by HPLC-DAD-Q-TOF-MS/MS.

J Pharm Biomed Anal. 2017 Dec 07;150:199-207

Authors: Chen MY, Shao L, Zhang W, Wang CZ, Zhou HH, Huang WH, Yuan CS

Abstract
Saponins such as notoginsenosides and ginsenosides from Panax notoginseng are responsible for the herb's clinical applications. Unfortunately, there is poor oral bioavailability of saponins. However, gut microbiota can transform saponins to yield the metabolites that are potential bioactive substances. In this study, we aimed to characterize the metabolic profiles of P. notoginseng saponins (PNS) by incubating them with human gut microbiota. The notoginsenosides, ginsenosides and related metabolites were separated and identified using a highly sensitive and selective high-performance liquid chromatography coupled with diode array detection/quadrupole tandem time-of-flight mass spectrometry (HPLC-DAD-Q-TOF-MS/MS). The results showed that the most abundant metabolites, ginsenoside F1, protopanaxatriol (PPT), ginsenoside Rh2, ginsenoside compound K (GCK) and protopanaxadiol (PPD), were reported to possess stronger related pharmacological activities when compared with parent ginsenosides. These metabolites were identified among a total of 45 other metabolites. Furthermore, it was elucidated that deglycosylation is the main metabolic pathway which saponins are split off from glycosyl moieties by the enzymes secreted from gut microbiota. The gut microbiota may play a significant role in mediating the bioactivities of PNS.

PMID: 29245089 [PubMed - as supplied by publisher]

Comparative Performance of Pharmacogenetics-based Warfarin Dosing Algorithms Derived from Caucasian, Asian and Mixed Races in Thai Population.

Cardiovasc Ther. 2017 Dec 15;:

Authors: Chumnumwat S, Yi K, Lucksiri A, Nosoongnoen W, Chindavijak B, Chulavatnatol S, Sarapakdi A, Nathisuwan S

Abstract
AIM: This study was conducted to compare predictive accuracy of the available pharmacogenetics (PGx)-guided warfarin-dosing algorithms derived from Caucasian, Asian and mixed population to identify a suitable algorithm for Thai population.
METHODS: Ten warfarin-dosing algorithms derived from different population including Caucasian, East Asian, Southeast Asian and mixed races were selected and tested with clinical and genetic data of Thai patients. Comparative performances of these algorithms were tested using mean dose error (MDE) between actual warfarin maintenance dose (AWMD) and predicted dose generated by each dosing algorithm, and percentage of ideal dose prediction (IDP). Sensitivity analysis for predictive accuracy was also conducted by stratifying patients into low (AWMD ≤21mg/week), intermediate (AWMD >21 - <49 mg/week) and high maintenance dose (AWMD ≥49mg/week) groups.
RESULTS: Data of 165 patients were included for the analyses. Mean actual warfarin dose of the study population was 25.03 ± 10.53 mg/week. Large variability of MDE, ranging from -12.11 to 11.24 mg/week, among algorithms was observed. International Warfarin Pharmacogenetics Consortium, Gage, et al and Ohno, et al algorithms had comparable performances to Sangviroon,et al algorithm, as observed by MDE of <1 mg/week with percentage of IDP ≥40%. Further sensitivity analyses among patients requiring low and intermediate maintenance doses confirmed such findings with IDP percentage ranging from 37.8% to 59.2%. Among high dose group, only Ohno, et al and Sarapakdi, et al algorithms had acceptable performance.
CONCLUSIONS: Warfarin PGx-guided dosing algorithms derived from large, mixed population performed comparably to Sangviroon, et alalgorithm. Certain algorithms should be avoided due to significant dose prediction error. This article is protected by copyright. All rights reserved.

PMID: 29243335 [PubMed - as supplied by publisher]

CYP2D6 drug-gene and drug-drug-gene interactions among patients prescribed pharmacogenetically actionable opioids.

Appl Nurs Res. 2017 Dec;38:107-110

Authors: Knisely MR, Carpenter JS, Draucker CB, Skaar T, Broome ME, Holmes AM, Von Ah D

Abstract
PURPOSE: When codeine and tramadol are used for pain management, it is imperative that nurses are able to assess for potential drug-gene and drug-drug-gene interactions that could adversely impact drug metabolism and ultimately pain relief. Both drugs are metabolized through the CYP2D6 metabolic pathway which can be affected by medications as well the patient's own pharmacogenotype. The purpose of this brief report is to identify drug-gene and drug-drug-gene interactions in 30 adult patients prescribed codeine or tramadol for pain.
METHODS: We used three data sources: (1) six months of electronic health record data on the number and types of medications prescribed to each patient; (2) each patient's CYP2D6 pharmacogenotype, and (3) published data on known CYP2D6 gene-drug and drug-drug-gene interactions.
RESULTS: Ten patients (33%) had possible drug-gene or drug-drug-gene interactions. Five patients had CYP2D6 drug-gene interactions indicating they were not good candidates for codeine or tramadol. In addition, five patients had potential CYP2D6 drug-drug-gene interactions with either codeine or tramadol.
CONCLUSION: Our findings from this exploratory study underscores the importance of assessing and accounting for drug-gene and drug-drug-gene interactions in patients prescribed codeine or tramadol.

PMID: 29241501 [PubMed - in process]

Validation of the 17-item Hamilton Depression Rating Scale definition of response for adults with major depressive disorder using equipercentile linking to Clinical Global Impression scale ratings: analysis of Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) data.

Hum Psychopharmacol. 2016 May;31(3):185-92

Authors: Bobo WV, Angleró GC, Jenkins G, Hall-Flavin DK, Weinshilboum R, Biernacka JM

Abstract
OBJECTIVE: The study aimed to define thresholds of clinically significant change in 17-item Hamilton Depression Rating Scale (HDRS-17) scores using the Clinical Global Impression-Improvement (CGI-I) Scale as a gold standard.
METHODS: We conducted a secondary analysis of individual patient data from the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study, an 8-week, single-arm clinical trial of citalopram or escitalopram treatment of adults with major depression. We used equipercentile linking to identify levels of absolute and percent change in HDRS-17 scores that equated with scores on the CGI-I at 4 and 8 weeks. Additional analyses equated changes in the HDRS-7 and Bech-6 scale scores with CGI-I scores.
RESULTS: A CGI-I score of 2 (much improved) corresponded to an absolute decrease (improvement) in HDRS-17 total score of 11 points and a percent decrease of 50-57%, from baseline values. Similar results were observed for percent change in HDRS-7 and Bech-6 scores. Larger absolute (but not percent) decreases in HDRS-17 scores equated with CGI-I scores of 2 in persons with higher baseline depression severity.
CONCLUSIONS: Our results support the consensus definition of response based on HDRS-17 scores (>50% decrease from baseline). A similar definition of response may apply to the HDRS-7 and Bech-6. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 26999588 [PubMed - indexed for MEDLINE]

Natural Compounds as Epigenetic Regulators of Human Dendritic Cell-mediated Immune Function.

J Immunother. 2017 Dec 12;:

Authors: Mirza S, Shah K, Patel S, Jain N, Rawal R

Abstract
Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) and are poised to capture antigen, migrate to draining lymphoid organs, and postmaturation process. Recent evidences have suggested that tumor microenvironment has an effect on DCs by inactivating various components of the immune system responsible for tumor clearance, eventually leading to tumorigenesis. This inactivation is owed to the epigenetic modifications [ie, microRNA (miRNA)] at the posttranscriptional level, thus regulating the differentiation patterns and functional behavior of DCs. Thus, need of the hour is to develop protocols for ex vivo generation of DCs which may provide a foundation for designing and developing DC-based vaccination for treatment of solid tumors. To achieve this, it is crucial to modulate DCs by identifying miRNAs which may increase the efficacy of DC-based vaccines by reprogramming the immunosuppressive nature of tumor microenvironment. Furthermore, it would be an interesting aspect to check the immunomodulatory potential of natural compounds in reprogramming the immune responses through DCs. Thus, this review aims to improvise the understanding of DC immune biology and miRNAs at genetic level in cancer which can be pivotal for designing novel or improved therapeutic approaches that will allow proper functioning of DCs in patient care. Furthermore, we have highlighted the candidate target molecules and signaling mechanisms having a vital role in the immune-modulatory activities of natural compounds and its derived phytocompounds. This review also establishes a link between miRNA expressions and biological roles of natural compounds modulating the activity of DCs.

PMID: 29239917 [PubMed - as supplied by publisher]

Welcome to the 19th volume of Pharmacogenomics.

Pharmacogenomics. 2018 Jan;19(1):1-2

Authors: Jones S

PMID: 29239278 [PubMed - in process]

Pharmacogenetic landscape of DPYD variants in south Asian populations by integration of genome-scale data.

Pharmacogenomics. 2017 Dec 14;:

Authors: Hariprakash JM, Vellarikkal SK, Keechilat P, Verma A, Jayarajan R, Dixit V, Ravi R, Senthivel V, Kumar A, Sehgal P, Sonakar AK, Ambawat S, Giri AK, Philip A, Sivadas A, Faruq M, Bharadwaj D, Sivasubbu S, Scaria V

Abstract
AIM: Adverse drug reactions to 5-Fluorouracil(5-FU) is frequent and largely attributable to genetic variations in the DPYD gene, a rate limiting enzyme that clears 5-FU. The study aims at understanding the pharmacogenetic landscape of DPYD variants in south Asian populations.
MATERIALS & METHODS: Systematic analysis of population scale genome wide datasets of over 3000 south Asians was performed. Independent evaluation was performed in a small cohort of patients.
RESULTS: Our analysis revealed significant differences in the the allelic distribution of variants in different ethnicities.
CONCLUSIONS: This is the first and largest genetic map the DPYD variants associated with adverse drug reaction to 5-FU in south Asian population. Our study highlights ethnic differences in allelic frequencies.

PMID: 29239269 [PubMed - as supplied by publisher]

Association of HLA-A and HLA-B Alleles with Lamotrigine-Induced Cutaneous Adverse Drug Reactions in the Thai Population.

Front Pharmacol. 2017;8:879

Authors: Koomdee N, Pratoomwun J, Jantararoungtong T, Theeramoke V, Tassaneeyakul W, Klaewsongkram J, Rerkpattanapipat T, Santon S, Puangpetch A, Intusoma U, Tempark T, Deesudchit T, Satapornpong P, Visudtibhan A, Sukasem C

Abstract
Background: Lamotrigine (LTG) is commonly used for treatment of epilepsy and bipolar disorder. It is one of the common cause of cutaneous adverse drug reactions (CADR). Clinical symptoms of LTG-induced CADR range from maculopapular exanthema (MPE) to severe cutaneous adverse reactions (SCAR). This study aimed to determine the association of the LTG-induced CADR with human leukocyte antigen (HLA) alleles in Thai patients. Methods: Fifteen patients with LTG-induced CADR [10 MPE; 4 Stevens-Johnson syndrome; and 1 drug reaction with eosinophilia and systemic symptoms] and 50 LTG-tolerant controls were included in the study. HLA-A and HLA-B genotyping was performed using polymerase chain reaction-sequence-specific oligonucleotides probes. Results: The proportion of HLA-A∗02:07 and HLA-B∗15:02 allele carriers were significantly higher in the LTG-induced CADR group than in the tolerant controls [odds ratio (OR): 7.83; 95% confidence interval (CI): 1.60-38.25; P = 0.013, and OR: 4.89; 95% CI: 1.28-18.67; P = 0.014]. In addition, subjects with HLA-A∗33:03, HLA-B∗15:02, and HLA-B∗44:03 were significantly higher in the LTG-induced MPE group than in the tolerant controls (OR: 8.27; 95% CI: 1.83-37.41; P = 0.005, OR: 7.33; 95% CI: 1.63-33.02; P = 0.005; and OR: 10.29; 95% CI: 1.45-72.81; P = 0.029). In contrast to the LTG-induced MPE group, there were no significant differences between HLA alleles and LTG-induced SCAR group. Conclusion:HLA-A∗02:07 and HLA-B∗15:02 were associated with LTG-induced CADR in Thai patients. We also identified an association between HLA-A∗33:03, HLA-B∗15:02, and HLA-B∗44:03 and LTG-induced MPE in this population. These results suggest that these alleles could be useful screening markers for preventing CADR before LTG treatment in Thai patients, but further replication studies with larger sample sizes are needed.

PMID: 29238301 [PubMed]

Personalized Anticoagulation: Optimizing Warfarin Management Using Genetics and Simulated Clinical Trials.

Circ Cardiovasc Genet. 2017 Dec;10(6):

Authors: Ravvaz K, Weissert JA, Ruff CT, Chi CL, Tonellato PJ

Abstract
BACKGROUND: Clinical trials testing pharmacogenomic-guided warfarin dosing for patients with atrial fibrillation have demonstrated conflicting results. Non-vitamin K antagonist oral anticoagulants are expensive and contraindicated for several conditions. A strategy optimizing anticoagulant selection remains an unmet clinical need.
METHODS AND RESULTS: Characteristics from 14 206 patients with atrial fibrillation were integrated into a validated warfarin clinical trial simulation framework using iterative Bayesian network modeling and a pharmacokinetic-pharmacodynamic model. Individual dose-response for patients was simulated for 5 warfarin protocols-a fixed-dose protocol, a clinically guided protocol, and 3 increasingly complex pharmacogenomic-guided protocols. For each protocol, a complexity score was calculated using the variables predicting warfarin dose and the number of predefined international normalized ratio (INR) thresholds for each adjusted dose. Study outcomes included optimal time in therapeutic range ≥65% and clinical events. A combination of age and genotype identified different optimal protocols for various subpopulations. A fixed-dose protocol provided well-controlled INR only in normal responders ≥65, whereas for normal responders <65 years old, a clinically guided protocol was necessary to achieve well-controlled INR. Sensitive responders ≥65 and <65 and highly sensitive responders ≥65 years old required pharmacogenomic-guided protocols to achieve well-controlled INR. However, highly sensitive responders <65 years old did not achieve well-controlled INR and had higher associated clinical events rates than other subpopulations.
CONCLUSIONS: Under the assumptions of this simulation, patients with atrial fibrillation can be triaged to an optimal warfarin therapy protocol by age and genotype. Clinicians should consider alternative anticoagulation therapy for patients with suboptimal outcomes under any warfarin protocol.

PMID: 29237680 [PubMed - in process]

Cancer genomics guide clinical practice in personalized medicine.

Therapie. 2017 Sep;72(4):439-451

Authors: Lehmann-Che J, Poirot B, Boyer JC, Evrard A

Abstract
Targeted therapies have revolutionized the treatment of many cancers. Widely developed over the last decade, this new concept of precision medicine relies on the use of genomic technologies to analyze tumor samples in order to identify actionable targets and biomarkers of resistance. The goal is to optimize treatment by identifying which therapeutic approach is best for each patient, i.e. the treatment that is effective, has minimal adverse effects, and avoids unnecessary intervention and cost. The purpose of this review is to highlight, using a few seminal examples of therapeutic targets, the important contribution of appropriate analysis of key oncogenes or driver genes in making clinical decisions. Cancer genomics is now an indispensable part of clinical management. Furthermore, the development of next generation sequencing (NGS) will enable exploration of more and more genes of interest, leading to new treatment options for personalized medicine.

PMID: 28258721 [PubMed - indexed for MEDLINE]

Role of Preemptive Genotyping in Preventing Serious Adverse Drug Events in South Korean Patients.

Drug Saf. 2017 01;40(1):65-80

Authors: Kim GJ, Lee SY, Park JH, Ryu BY, Kim JH

Abstract
INTRODUCTION: Preemptive and multi-variant genotyping is suggested to improve the safety of patient drug therapy. The number of South Koreans who would benefit from this approach is unknown.
OBJECTIVE: We aimed to quantify the number of patients who may experience serious adverse drug events (ADEs) due to high-risk pharmacogenetic variants and who may benefit from preemptive genotyping.
METHODS: The health claims dataset of the Korean Health Insurance Review and Assessment service for 3 % of the South Korean population for year 2011 was used to calculate the number of patients exposed to 84 drugs covered by National Health Insurance with pharmacogenomic biomarkers. The product of ADE risk-conferring genotype prevalence, ADE prevalence rates, and genotype effect sizes in South Koreans or East Asians derived from published literature and the 1000 Genomes Project, and the drug exposure data were solved to estimate the number of South Koreans in whom preemptive genotyping may prevent serious ADEs.
RESULTS: Among 1,341,077 patients in the dataset with prescriptions, 47.4 % were prescribed a drug whose response was affected by genetic variants and 31.9 % were prescribed at least one drug with serious ADEs modulated by these variants. Without genetic testing, the number of South Korean patients predicted to experience serious ADEs due to their higher ADE risk genotypes was estimated at 729. Extrapolating this to the total South Korean population indicated that approximately 24,300 patients in 2011 might have benefitted from preemptive genotyping.
CONCLUSIONS: This study quantified the number of South Korean patients predicted to have serious ADEs and demonstrated the need for preemptive genotyping to assist safer drug therapy in South Korea.

PMID: 27638658 [PubMed - indexed for MEDLINE]