Genetic Predisposition to Neuroblastoma.

Children (Basel). 2018 Aug 31;5(9):

Authors: Barr EK, Applebaum MA

Abstract
Neuroblastoma is the most common solid tumor in children under the age of one. It displays remarkable phenotypic heterogeneity, resulting in differences in outcomes that correlate with clinical and biologic features at diagnosis. While neuroblastoma accounts for approximately 5% of all cancer diagnoses in pediatrics, it disproportionately results in about 9% of all childhood deaths. Research advances over the decades have led to an improved understanding of neuroblastoma biology. However, the initiating events that lead to the development of neuroblastoma remain to be fully elucidated. It has only been recently that advances in genetics and genomics have allowed researchers to unravel the predisposing factors enabling the development of neuroblastoma and fully appreciate the interplay between the genetics of tumor and host. In this review, we outline the current understanding of familial neuroblastoma and highlight germline variations that predispose children to sporadic disease. We also discuss promising future directions in neuroblastoma genomic research and potential clinical applications for these advances.

PMID: 30200332 [PubMed]

Toward the Synthesis and Improved Biopotential of an N-methylated Analog of a Proline-Rich Cyclic Tetrapeptide from Marine Bacteria.

Mar Drugs. 2018 Aug 30;16(9):

Authors: Dahiya R, Kumar S, Khokra SL, Gupta SV, Sutariya VB, Bhatia D, Sharma A, Singh S, Maharaj S

Abstract
An N-methylated analog of a marine bacteria-derived natural proline-rich tetracyclopeptide was synthesized by coupling the deprotected dipeptide fragments Boc-l-prolyl-l-N-methylleucine-OH and l-prolyl-l-N-methylphenylalanine-OMe. A coupling reaction was accomplished utilizing N,N'-Dicyclohexylcarbodidimde (DCC) and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC·HCl) as coupling agents and Triethylamine (TEA) or N-methylmorpholine (NMM) as the base in the presence of the racemization suppressing agent. This was followed by the cyclization of the linear tetrapeptide fragment under alkaline conditions. The structure of the synthesized cyclooligopeptide was confirmed using quantitative elemental analysis, FTIR (Fourier-transform infrared spectroscopy), ¹H NMR (Nuclear magnetic resonance spectroscopy), 13C NMR, and mass spectrometry. From the bioactivity results, it was clear that the newly synthesized proline-rich tetracyclopeptide exhibited better anthelmintic potential against Megascoplex konkanensis, Pontoscotex corethruses, and Eudrilus eugeniae at a concentration of 2 mg/mL as well as improved antifungal activity against pathogenic dermatophytes Trichophyton mentagrophytes and Microsporum audouinii at a concentration of 6 μg/mL, as compared to non-methylated tetracyclopeptide. Moreover, N-methylated tetracyclopeptide displayed significant activity against pathogenic Candida albicans.

PMID: 30200225 [PubMed - in process]

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pharmacogenomics

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A Metabolomics Approach to Pharmacotherapy Personalization.

J Pers Med. 2018 Sep 05;8(3):

Authors: Balashova EE, Maslov DL, Lokhov PG

Abstract
The optimization of drug therapy according to the personal characteristics of patients is a perspective direction in modern medicine. One of the possible ways to achieve such personalization is through the application of "omics" technologies, including current, promising metabolomics methods. This review demonstrates that the analysis of pre-dose metabolite biofluid profiles allows clinicians to predict the effectiveness of a selected drug treatment for a given individual. In the review, it is also shown that the monitoring of post-dose metabolite profiles could allow clinicians to evaluate drug efficiency, the reaction of the host to the treatment, and the outcome of the therapy. A comparative description of pharmacotherapy personalization (pharmacogenomics, pharmacoproteomics, and therapeutic drug monitoring) and personalization based on the analysis of metabolite profiles for biofluids (pharmacometabolomics) is also provided.

PMID: 30189667 [PubMed]

A new design for the review and appraisal of semi-solid dosage forms: Semi-solid Control Diagram (SSCD).

PLoS One. 2018;13(9):e0201643

Authors: Nardi-Ricart A, Linares MJ, Villca-Pozo F, Pérez-Lozano P, Suñé-Negre JM, Bachs-deMiquel L, Roig-Carreras M, Suñé-Pou M, Nofrerias-Roig I, García-Montoya E

Abstract
The Semi-solid Control Diagram (SSCD) is a new tool designed for the study of different excipients and different semi-solid dosage forms. It can be used to review and evaluate different formulations and/or batches and facilitate the selection of one of them that will present the most suitable galenic characteristics for topical application. It is also useful to track stability studies by comparing the diagrams, which allows to measure the impact of subjecting the formulation to different conditions and times to be examined. In this study, the Semi-solid Control Diagram (SSCD) is used as an instrument for studying and evaluating semi-solid pharmaceutical dosage forms, by comparing several different semisolid preparations (lipogels). With these results, the tool is validated and the best formulation has been discriminated from the others.

PMID: 30192759 [PubMed - in process]

Pharmacogenetics-based population pharmacokinetic analysis of gabapentin in patients with chronic pain: effect of OCT2 and OCTN1 gene polymorphisms.

Basic Clin Pharmacol Toxicol. 2018 Sep 07;:

Authors: Yamamoto PA, Benzi JRL, Azeredo FJ, Dach F, Júnior EI, Zanelli CF, de Moraes NV

Abstract
Gabapentin (GAB) is eliminated unchanged in urine, and organic cation transporters (OCT2 and OCTN1) have been shown to play a role at GAB renal excretion. This prospective clinical study aimed to evaluate the genetic polymorphisms effect on GAB pharmacokinetic (PK) variability using a population pharmacokinetic approach. Data were collected from fifty-three patients with chronic pain receiving multiple doses of GAB. Patients were genotyped for SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms. Both polymorphisms' distribution followed the Hardy-Weinberg equilibrium. A one-compartment model with first-order absorption and linear elimination best described the data. The absorption rate constant, volume of distribution and clearance estimated were 0.44 h-1 , 86 L and 17.3×(estimated glomerular filtration ratio/89.58)1.04 L/h, respectively. The genetic polymorphism SLC22A4 c.1507C>T did not have a significant influence on GAB absorption, distribution or elimination. Due to the low minor allelic frequency of SLC22A2 c.808G>T, further studies require higher number of participants to confirm its effect on GAB renal elimination. In conclusion, GAB clinical pharmacokinetics are strongly influenced by renal function and absorption process, but not by the OCTN1 (SLC22A4 c.1507C>T) polymorphism. This article is protected by copyright. All rights reserved.

PMID: 30192429 [PubMed - as supplied by publisher]

No Clinical Impact of CYP3A5 Gene Polymorphisms on the Pharmacokinetics and/or Efficacy of Maraviroc in Healthy Volunteers and HIV-1-Infected Subjects.

J Clin Pharmacol. 2018 Sep 07;:

Authors: Vourvahis M, McFadyen L, Nepal S, Valluri SR, Fang A, Fate GD, Wood LS, Marshall JC, Chan PLS, Nedderman A, Haynes J, Savage ME, Clark A, Smith KY, Heera J

Abstract
Maraviroc is a C-C chemokine receptor type-5 antagonist approved for the treatment of HIV-1. Previous studies show that cytochrome P450 3A5 (CYP3A5) plays a role in maraviroc metabolism. CYP3A5 is subject to a genetic polymorphism. The presence of 2 functional alleles (CYP3A5*1/*1) confers the extensive metabolism phenotype, which is rare in whites but common in blacks. The effect of CYP3A5 genotype on maraviroc and/or metabolite pharmacokinetics was evaluated in 2 clinical studies: a post hoc analysis from a phase 2b/3 study (NCT00098293) conducted in 494 HIV-1-infected subjects (study 1) in which the impact on maraviroc efficacy in 303 subjects was also assessed, and a study conducted in 47 healthy volunteers (study 2). In study 2 (NCT02625207), extensive metabolizers had 26% to 37% lower mean area under the concentration-time curve compared with poor metabolizers (no CYP3A5*1 alleles). This effect diminished to 17% in the presence of potent CYP3A inhibition. The effect of CYP3A5 genotype was greatest in the formation of the metabolite (1S,2S)-2-hydroxymaraviroc. In study 1, the CYP3A5*1/*1 genotype unexpectedly had higher maraviroc area under the curve predictions (20%) compared with those with no CYP3A5*1 alleles. The reason for this disparity remains unclear. The proportions of subjects with viral loads <50 and <400 copies/mL for maraviroc were comparable among all 3 CYP3A5 genotypes. In both studies maraviroc exposures were in the range of near-maximal viral inhibition in the majority of subjects. These results demonstrate that although CYP3A5 contributes to the metabolism of maraviroc, CYP3A5 genotype does not affect the clinical response to maraviroc in combination treatment of HIV-1 infection at approved doses.

PMID: 30192390 [PubMed - as supplied by publisher]

Genetic risk factors for VIPN in childhood acute lymphoblastic leukemia patients identified using whole-exome sequencing.

Pharmacogenomics. 2018 Sep 07;:

Authors: Abaji R, Ceppi F, Patel S, Gagné V, Xu CJ, Spinella JF, Colombini A, Parasole R, Buldini B, Basso G, Conter V, Cazzaniga G, Leclerc JM, Laverdière C, Sinnett D, Krajinovic M

Abstract
AIM: To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia.
PATIENTS & METHODS: Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN. Genotyping was then performed for top-ranked signals (n = 237), followed by validation in independent replication group (n = 405).
RESULTS: Minor alleles of rs2781377/SYNE2 (p = 0.01) and rs10513762/MRPL47 (p = 0.01) showed increased risk, whereas that of rs3803357/BAHD1 had a protective effect (p = 0.007). Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p = 0.003). The addition of rs1135989/ACTG1 further enhanced model performance (p = 0.0001).
CONCLUSION: Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia.

PMID: 30191766 [PubMed - as supplied by publisher]

Late stent thrombosis in a patient with CYP2C19 *3/*17 genotype and clopidogrel high on-treatment platelet reactivity.

Pharmacogenomics. 2018 Sep 07;:

Authors: Ning Tan SS, Koh KT, Tiong LL, Ong TK, Yip Fong AY

Abstract
AIM: Recurrent thrombotic events still occur despite dual antiplatelet therapy in patient's post percutaneous coronary intervention (PCI) could be attributed to high on-treatment platelet reactivity.
METHODS: A 44-year-old male, who had staged PCI to left anterior descending (LAD) 2 weeks after an anterior MI, with a drug-coated stent was readmitted with new anterior STEMI 35 days later. Coronary angiogram revealed mid-stent thrombus in situ. He had further uncomplicated PCI. Platelet function testing and genotyping showed clopidogrel high on-treatment platelet reactivity and CYP2C19 *3/*17 genotype. Ticagrelor was commenced.
RESULTS & CONCLUSION: This case study is the first reported in Malaysia to document a patient with a CYP2C19 *3/*17 genotype presenting with a stent thrombosis after an uncomplicated index PCI procedure.

PMID: 30191759 [PubMed - as supplied by publisher]

Multiplex analysis of genetic polymorphisms within UGT1A9, a gene involved in phase II of Δ9-THC metabolism.

Int J Legal Med. 2018 Sep 06;:

Authors: Schneider JS, Gasse A, Schürenkamp M, Sibbing U, Banken S, Pfeiffer H, Schürenkamp J, Vennemann M

Abstract
We present a novel multiplex assay for the simultaneous detection of 12 polymorphisms within the UGT1A9 sequence, which codes for enzymes involved in phase II biotransformation. The assay combines a multiplexed amplification step with single-base extension sequencing. The method described here is fast, cost-effective, and easy-to-use, combining the relevant features of screening methods for research and diagnostics in pharmacogenetics. To validate the assay, we tested reproducibility and sensitivity and analysed allele frequencies of 110 Caucasian individuals. Furthermore, we describe combining genetic information of individuals consuming Cannabis sativa products with respective plasma concentrations of a metabolite.

PMID: 30191314 [PubMed - as supplied by publisher]

Epigenetic predictive biomarkers for response or outcome to platinum-based chemotherapy in non-small cell lung cancer, current state-of-art.

Pharmacogenomics J. 2018 Sep 07;:

Authors: Szejniuk WM, Robles AI, McCulloch T, Falkmer UGI, Røe OD

Abstract
Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC). However, its efficacy is limited and no molecular biomarkers that predict response are available. In this review, we summarize current knowledge concerning potential epigenetic predictive markers for platinum-based chemotherapy response in NSCLC. A systematic search of PubMed and ClinicalTrials.gov using keywords "non-small cell lung cancer" combined with "chemotherapy predictive biomarkers", "chemotherapy epigenetics biomarkers", "chemotherapy microRNA biomarkers", "chemotherapy DNA methylation" and "chemotherapy miRNA biomarkers" revealed 1740 articles from PubMed and 36 clinical trials. Finally, 22 papers and no trials fulfilled the review criteria. Among miRNA, combination of miR-1290, miR-196b and miR-135a in tumor tissue, and miR-21, miR-25, miR27b, and miR-326 in plasma were predictive for response to platinum-based chemotherapy in advanced NSCLC. RASSF1A methylation measured in tumor or blood was predictive for response to neoadjuvant chemotherapy. These biomarkers remain experimental and none have been tested in a prospective trial.

PMID: 30190521 [PubMed - as supplied by publisher]

An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity.

J Immunol Res. 2018;2018:6431694

Authors: Chen CB, Abe R, Pan RY, Wang CW, Hung SI, Tsai YG, Chung WH

Abstract
Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

PMID: 29651444 [PubMed - indexed for MEDLINE]

Paeonol Ameliorates Ovalbumin-Induced Asthma through the Inhibition of TLR4/NF-κB and MAPK Signaling.

Evid Based Complement Alternat Med. 2018;2018:3063145

Authors: Tang Y, Huang W, Song Q, Zheng X, He R, Liu J

Abstract
Asthma is a chronic inflammatory disease of the airways, with complex signaling pathways involved in its pathogenesis. It was reported that paeonol attenuated airway inflammation of ovalbumin (OVA)-induced mice. Therefore, it is of importance to further investigate the underlying mechanism. BALB/c mice were challenged with OVA for the asthma model, which was validated by the changed levels of IL-4, IFN-γ, and IgE. The elevation of IL-4 and the decreasing of IFN-γ were significantly in middle (p<0.05) or high (p<0.01) paeonol dose groups compared with OVA group. MIP-1β in bronchoalveolar lavage fluid (BALF) also decreased significantly in middle and high paeonol group compared with OVA group (p<0.01), which is similar to the change of its mRNA in lung tissues. Moreover, the inflammatory cells infiltration and collagen deposition were attenuated by paeonol and montelukast sodium via histology examination. At last the immune blot of the protein extracted from lung tissues demonstrated that paeonol decreased the expression of TLR4 and the nuclear translocation of NF-κB, as well as the phosphorylation levels of P38 and ERK in asthma model. In conclusion, paeonol ameliorated OVA-induced asthma through the TLR4/NF-κB and mitogen-activated protein kinase (MAPK) signaling.

PMID: 30186353 [PubMed]

Genetic variants in major depressive disorder: From pathophysiology to therapy.

Pharmacol Ther. 2018 Sep 03;:

Authors: Gonda X, Petschner P, Eszlari N, Baksa D, Edes A, Antal P, Juhasz G, Bagdy G

Abstract
In spite of promising preclinical results there is a decreasing number of new registered medications in major depression. The main reason behind this fact is the lack of confirmation in clinical studies for the assumed, and in animals confirmed, therapeutic results. This suggests low predictive value of animal studies for central nervous system disorders. One solution for identifying new possible targets is the application of genetics and genomics, which may pinpoint new targets based on the effect of genetic variants in humans. The present review summarizes such research focusing on depression and its therapy. The inconsistency between most genetic studies in depression suggests, first of all, a significant role of environmental stress. Furthermore, effect of individual genes and polymorphisms is weak, therefore gene x gene interactions or complete biochemical pathways should be analyzed. Even genes encoding target proteins of currently used antidepressants remain non-significant in genome-wide case control investigations suggesting no main effect in depression, but rather an interaction with stress. The few significant genes in GWASs are related to neurogenesis, neuronal synapse, cell contact and DNA transcription and as being nonspecific for depression are difficult to harvest pharmacologically. Most candidate genes in replicable GxE interactions, on the other hand, are connected to the regulation of stress and the HPA axis and thus could serve as drug targets for a depression subgroups characterized by stress-sensitivity and anxiety while other risk polymorphisms such as those related to prominent cognitive symptoms in depression may help to identify additional subgroups and their distinct treatment. Until these new targets find their way in the therapy, the optimization of current medications can be approached by pharmacogenomics, where metabolizing enzyme polymorphisms remain prominent determinants of therapeutic success.

PMID: 30189291 [PubMed - as supplied by publisher]

Pharmacogenetic and clinical predictors of response to clopidogrel plus aspirin after acute coronary syndrome in Egyptians.

Pharmacogenet Genomics. 2018 Sep 04;:

Authors: Fathy S, Shahin MH, Langaee T, Khalil BM, Saleh A, Sabry NA, Schaalan MF, El Wakeel LL, Cavallari LH

Abstract
OBJECTIVES: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the risk for recurrent cardiovascular events after acute coronary syndrome (ACS). However, there is significant variation in response to DAPT that may be influenced by both genetic and nongenetic factors. This study aimed to assess the effect of genetic polymorphisms in PON-1, PEAR-1, P2Y12, CES1, and CYP2C19, along with clinical, demographic, and social factors, on variation in response to DAPT in Egyptians.
PARTICIPANTS AND METHODS: This study included 230 Egyptians treated with clopidogrel 75 mg/day and aspirin 81 mg/day for at least 12 months following their first ACS. Simple and multivariable logistic regression analyses were carried out to identify factors associated with major adverse cardiovascular events (MACE), defined as the occurrence of recurrent ACS, ischemic stroke, stent-related revascularization, or death, in clopidogrel-treated participants.
RESULTS: Using multivariable logistic regression analysis, the CYP2C19*2 polymorphism was the only genetic predictor of MACE [odds ratio (OR): 2.23, 95% confidence interval (CI): 1.15-4.33, P=0.01]. In addition, proton pump inhibitor use (OR: 4.77, 95% CI: 1.47-15.54, P=0.009) and diabetes (OR: 1.83, 95% CI: 1.03-3.26, P=0.03) were associated with higher cardiovascular risk, whereas statin use was associated with lower risk (OR: 0.43, 95% CI: 0.25-0.76, P=0.003). The contribution of these four genetic and nongenetic factors explained 19% of the variability in risk for MACE in Egyptians treated with DAPT.
CONCLUSIONS: These results highlight that CYP2C19*2, along with diabetes, and use of proton pump inhibitor and statin are important factors jointly associated with variability in clinical response to DAPT following ACS in Egyptians.

PMID: 30188374 [PubMed - as supplied by publisher]

Bendamustine alone or with rituximab modifies expression of apoptosis-regulating genes and proteins of CLL cells, depending on IGVH mutational status.

Leuk Lymphoma. 2018 Sep 06;:1-11

Authors: Ziolkowska E, Wolowiec D, Karpinski P, Blonski JZ, Lech-Maranda E, Borowiec M, Balcerczak E, Sasiadek M, Robak T, Korycka-Wolowiec A

Abstract
We studied whether bendamustine (BENDA) alone or with rituximab (RIT) modifies in vitro expression of apoptosis-involved genes and proteins of chronic lymphocytic leukemia (CLL) cells depending on IGVH mutational status. Circulating lymphocytes from 34 untreated patients (18 IGVH-MUT and 16 IGVH-UNMUT) were incubated with above drugs to evaluate proteins expression. Microarray analysis of 93 genes was performed in 14 patients. BENDA and BENDA + RIT increased expression of BAX and BBC3 in IGVH-MUT and IGVH-UNMUT groups, and significant differences in expression of above genes after BENDA + RIT were observed between both groups. Additionally, BENDA + RIT decreased NFκB and BCL-2 genes in IGVH-UNMUT patients and increased expression of P53, BAX and PUMA proteins in IGVH-MUT and UNMUT subjects. However, no significant differences were found between these groups. In conclusion, BENDA + RIT modified gene expression profile in CLL cells and affected expression of some apoptosis-regulating proteins in vitro. Expression of BAX and BBC3 depends on action of drugs and IGVH mutational status.

PMID: 30187811 [PubMed - as supplied by publisher]

Management of adverse events associated with idelalisib treatment in chronic lymphocytic leukemia and follicular lymphoma: A multidisciplinary position paper.

Hematol Oncol. 2018 Sep 05;:

Authors: Cuneo A, Barosi G, Danesi R, Fagiuoli S, Ghia P, Marzano A, Montillo M, Poletti V, Viale P, Zinzani PL

Abstract
The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), including the new kinase inhibitor idelalisib, has changed the therapeutic landscape of these diseases. However, the use of idelalisib is associated with a peculiar profile of side effects, which require an optimization of the current approach to prophylaxis and supportive treatment. Moving from the recognition that the abovementioned issue represents an unmet need in CLL and FL, a multidisciplinary panel of experts was convened to produce a consensus document aiming to provide practical recommendations for the management of the side effects during idelalisib therapy for CLL and FL. The present publication represents a consensus document from a series of meetings held during 2017. The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process and explored 4 domains, ie, diarrhea/colitis, transaminitis, pneumonitis, and infectious complications. Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib.

PMID: 30187496 [PubMed - as supplied by publisher]

A comparison of genome cohort participants' genetic knowledge and preferences to receive genetic results before and after a genetics workshop.

J Hum Genet. 2018 Sep 05;:

Authors: Yamamoto K, Shimizu A, Aizawa F, Kawame H, Tokutomi T, Fukushima A

Abstract
Several biobanks have begun returning genetic results to individuals, making the development of public genetic literacy an urgent task for their effective use. No research exists regarding the effects of genetic education on biobank participants, so we conducted genetics workshops with specialists, and surveyed differences in the participants' (n = 112) preferences to receive their own genetic information by disease categories and their genetic knowledge using questionnaires before and after the workshops. Almost 90% of our participants were over 60 years old, which was similar to our previous preference research. The preference to receive five of the six categories of genetic information (lifestyle diseases, pharmacogenetics, adult-onset non-clinically actionable diseases, non-clinically actionable multifactorial diseases, and all genetic information) was slightly but significantly decreased after the genetics workshop. More participants preferred to receive genetic results regarding lifestyle diseases, pharmacogenetics, and adult-onset clinically actionable diseases after the workshop, while less participants preferred to receive information regarding adult-onset non-clinically actionable diseases, non-clinically actionable multifactorial diseases, and all genetic information. Total genetic knowledge scores significantly increased after the workshop (before: 11.89, after: 13.30, p < 0.001). Our findings suggest that genetics workshops are useful to improve the genetic literacy of genome cohort participants.

PMID: 30185949 [PubMed - as supplied by publisher]

Knowledge, perceptions and confidence of physicians and pharmacists towards pharmacogenetics practice in Kuwait.

PLoS One. 2018;13(9):e0203033

Authors: Albassam A, Alshammari S, Ouda G, Koshy S, Awad A

Abstract
BACKGROUND: Pharmacogenetics practice has been successfully implemented in many developed countries to enhance personalized medicine and improve clinical and economic outcomes. An understanding of healthcare providers' knowledge, perceptions, confidence towards pharmacogenetics, and their active enrollment with pharmacogenetic testing is essential for test acceptance and utilization. This study was designed to assess physicians' and pharmacists' knowledge, perceptions, and confidence towards pharmacogenetics, determine the preferred learning format for their future education in pharmacogenetics, and identify the barriers to its application in their practice settings.
METHODS: A cross-sectional survey was conducted using a pretested self-administered questionnaire on a sample of 629 randomly selected physicians and pharmacists. Descriptive and comparative analyses were used in data analysis.
RESULTS: The response rate was 98.1%. Less than one-tenth of respondents were exposed to pharmacogenetics education or training (8.9%), applied pharmacogenetics testing in their practice (9.4%), or provided patient counselling on the results of the pharmacogenetic testing (9.1%), and over 90% of them were physicians. The overall respondents' mean (SD) total knowledge score percentage was low [45.0% (24)] and there was no significant difference between the physicians and pharmacists scores (p>0.05). Only 16.0% of participants indicated that they felt confident in applying pharmacogenetics in their practice settings. Despite these low levels of knowledge and self-confidence, 70.2% of participants expressed overall positive perceptions towards pharmacogenetics and its clinical implications. These positive overall perceptions were found to be significantly more common among pharmacists compared to physicians (p<0.05). The top two perceived barriers facing the implementation of pharmacogenetics in Kuwait were lack of education or training and clinical guidelines.
CONCLUSIONS: These findings highlight important concerns and will aid in the assessment of current pharmacogenetics practice. Also, they will provide further insight in designing future targeted multifaceted interventions to promote the adoption and utilization of pharmacogenetics testing in Kuwait.

PMID: 30183746 [PubMed - in process]

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

OMICS. 2018 Sep 05;:

Authors: Naranjo MG, Rodrigues-Soares F, Peñas-Lledó EM, Tarazona-Santos E, Fariñas H, Rodeiro I, Terán E, Grazina M, Moya GE, López-López M, Sarmiento AP, Calzadilla LR, Ramírez-Roa R, Ortiz-López R, Estévez-Carrizo FE, Sosa-Macías M, Barrantes R, LLerena A

Abstract
Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.

PMID: 30183544 [PubMed - as supplied by publisher]