Role of Cytochrome P450 2B6 Pharmacogenomics in Determining Efavirenz-Mediated Central Nervous System Toxicity, Treatment Outcomes, and Dosage Adjustments in Patients with Human Immunodeficiency Virus Infection.

Pharmacotherapy. 2016 Oct 25;:

Authors: Vo TT, Varghese Gupta S

Abstract
For treatment-naïve patients with human immunodeficiency virus infection, efavirenz (EFV) together with tenofovir and emtricitabine were once widely prescribed given its efficacy and ease of administration in a combination pill. However, the high rate of central nervous system toxicities from EFV prompted the United States Department of Health and Human Services to move the EFV-based regimen from the recommended to the alternative category. For patients who do meet the criteria for newer recommended antiretroviral treatments, EFV is a viable option and is often the mainstay of treatment outside the United States, as newer antiretroviral treatments are more expensive. Central nervous system (CNS) toxicity occurring with the recommended standard dose of EFV remains a challenge and may in part be attributable to polymorphisms in cytochrome P450 (CYP) 2B6, the enzyme involved in the major metabolic pathway for converting EFV to inactive metabolites. Functionally deficient alleles of CYP2B6 such as CYP2B6*6, *18, and *22 may be responsible for significantly higher therapeutic concentrations of EFV at a standard dose of 600 mg daily. To elucidate the relationship between polymorphisms in CYP2B6 with adverse events and treatment response-including virologic suppression, immunologic response, resistance, and discontinuation of treatment-we conducted a review of the literature. Compelling evidence exists to support the case for CYP2B6 genotype-guided EFV therapy while acknowledging the need for prospective, controlled, clinical trials to evaluate its clinical utility. This article is protected by copyright. All rights reserved.

PMID: 27779789 [PubMed - as supplied by publisher]

The global spectrum of protein-coding pharmacogenomic diversity.

Pharmacogenomics J. 2016 Oct 25;:

Authors: Wright GE, Carleton B, Hayden MR, Ross CJ

Abstract
Differences in response to medications have a strong genetic component. By leveraging publically available data, the spectrum of such genomic variation can be investigated extensively. Pharmacogenomic variation was extracted from the 1000 Genomes Project Phase 3 data (2504 individuals, 26 global populations). A total of 12 084 genetic variants were found in 120 pharmacogenes, with the majority (90.0%) classified as rare variants (global minor allele frequency <0.5%), with 52.9% being singletons. Common variation clustered individuals into continental super-populations and 23 pharmacogenes contained highly differentiated variants (FST>0.5) for one or more super-population comparison. A median of three clinical variants (PharmGKB level 1A/B) was found per individual, and 55.4% of individuals carried loss-of-function variants, varying by super-population (East Asian 60.9%>African 60.1%>South Asian 60.3%>European 49.3%>Admixed 39.2%). Genome sequencing can therefore identify clinical pharmacogenomic variation, and future studies need to consider rare variation to understand the spectrum of genetic diversity contributing to drug response.The Pharmacogenomics Journal advance online publication, 25 October 2016; doi:10.1038/tpj.2016.77.

PMID: 27779249 [PubMed - as supplied by publisher]

Association of CTH variant with sinusoidal obstruction syndrome in children receiving intravenous busulfan and cyclophosphamide before hematopoietic stem cell transplantation.

Pharmacogenomics J. 2016 Oct 25;:

Authors: Huezo-Diaz Curtis P, Uppugunduri CR, Muthukumaran J, Rezgui MA, Peters C, Bader P, Duval M, Bittencourt H, Krajinovic M, Ansari M

Abstract
Sinusoidal obstruction syndrome (SOS) is a severe complication of hematopoietic stem cell transplantation (HSCT) that can be fatal, often attributed to the conditioning regimen prior to HSCT. We evaluated the association of SOS risk with gene variants in cystathionase (CTH), an enzyme involved in glutathione synthesis, in 76 children receiving intravenous busulfan (Bu) before HSCT. Our results indicated an association with CTHc.1364 G>T (ORTT=10.6, 95% confidence interval (CI)=2.16, 51.54) and SOS risk, which was sex dependent (female patients, ORTT=21.82, 95% CI=3.590-132.649). The interaction between CTHc.1364 G>T and another risk variant (GSTA1*B) was explored. A recessive model with the use of GSTA1*B*B and CTH c.1364 TT genotypes proved to be useful at predicting SOS occurrence, indicating the possibility of using these gene variants as markers of SOS occurrence and to further individualize preemptive treatment aimed at reducing SOS incidence.The Pharmacogenomics Journal advance online publication, 25 October 2016; doi:10.1038/tpj.2016.65.

PMID: 27779248 [PubMed - as supplied by publisher]

Association between DRD2 and DRD3 gene polymorphisms and gastrointestinal symptoms induced by levodopa therapy in Parkinson's disease.

Pharmacogenomics J. 2016 Oct 25;:

Authors: Rieck M, Schumacher-Schuh AF, Altmann V, Callegari-Jacques SM, Rieder CR, Hutz MH

Abstract
Levodopa is the most used drug to treat motor symptoms in Parkinson's disease (PD). However, dopaminergic side effects such as nausea and vomiting may occur. Several evidences indicate a major role for dopamine receptors D2 (DRD2) and D3 (DRD3) in emetic activity. The aim of this study was to investigate the relationship of DRD2 rs1799732 and DRD3 rs6280 gene polymorphisms with gastrointestinal (GI) symptoms induced by levodopa in PD patients. Two hundred and seventeen PD patients on levodopa therapy were investigated. DRD2 rs1799732 and DRD3 rs6280 polymorphisms were genotyped by PCR-based methods. Multiple Poisson regression method with robust variance estimators was performed to assess the association between polymorphisms and gastrointestinal symptoms. The analyses showed that DRD2 Ins/Ins (prevalence ratio (PR)=2.374, 95% confidence interval (CI): 1.105-5.100; P=0.027) and DRD3 Ser/Ser genotypes (PR=1.677, 95% CI 1.077-2.611; P=0.022) were independent and predictors of gastrointestinal symptoms associated with levodopa therapy. Despite all the efforts to alleviate GI symptoms, this adverse effect still occurs in PD patients. Pharmacogenetic studies of GI symptoms induced by levodopa therapy have the potential to display new ways to better understand the molecular mechanisms involved in these side effects.The Pharmacogenomics Journal advance online publication, 25 October 2016; doi:10.1038/tpj.2016.79.

PMID: 27779245 [PubMed - as supplied by publisher]

Predictive value of ATP7b, BRCA1, BRCA2, PARP1, UIMC1 (RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) genes in patients with epithelial ovarian cancer who received platinum-taxane first-line therapy.

Pharmacogenomics J. 2016 Oct 25;:

Authors: Pontikakis S, Papadaki C, Tzardi M, Trypaki M, Sfakianaki M, Koinis F, Lagoudaki E, Giannikaki L, Kalykaki A, Kontopodis E, Saridaki Z, Malamos N, Georgoulias V, Souglakos J

Abstract
To evaluate the predictive value of genes involved in resistance to platinum-taxane chemotherapy in patients with epithelial ovarian cancer (EOC). Microdissected formalin-fixed tumoral samples from 187 EOC patients' primary tumors (90 and 97 samples from matched patients in the experimental and validation sets, respectively) were analyzed. All specimens were analyzed for ATP7b, BRCA1, BRCA2, PARP1, UIMC1(RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) mRNA expression by quantitative real-time PCR. Most of the patients (172 out of 187) received front-line carboplatin-paclitaxel regimen. Expression levels were correlated with overall (OS) and progression-free (PFS) survival by multivariate analysis. Patients with high TXN and THBS1 expression presented longer PFS (P=0.001 and P<0.001, respectively) and OS (P=0.024 and P<0.001, respectively). High TXR1 expression was associated with decreased PFS (P<0.001) and OS (P<0.001). Multivariate analysis demonstrated that high PRR13/low THBS1 expression was an independent factor for decreased PFS (hazards ratio: 1.94; 95% confidence interval (CI): 1.48-2.92; P=0.008) and OS (hazard ratio: 3.89; 95% CI: 2.16-6.87; P<0.001), whereas low TXN expression was correlated with decreased PFS (hazard ratio: 1.44; 95% CI: 1.05-2.84; P=0.043) and OS (hazard ratio: 2.38; 95% CI: 1.78-2.77; P=0.009). These findings indicate that PRR13/THBS1 and TXN expression could be used for the prediction of resistance to treatment of EOC patients and, therefore, merit to be further evaluated.The Pharmacogenomics Journal advance online publication, 25 October 2016; doi:10.1038/tpj.2016.63.

PMID: 27779244 [PubMed - as supplied by publisher]

Pharmacogenomic implications of the evolutionary history of infectious diseases in Africa.

Pharmacogenomics J. 2016 Oct 25;:

Authors: Baker JL, Shriner D, Bentley AR, Rotimi CN

Abstract
As the common birthplace of all human populations, modern humans have lived longer on the African continent than in any other geographical region of the world. This long history, along with the evolutionary need to adapt to environmental challenges such as exposure to infectious agents, has led to greater genetic variation in Africans. The vast genetic variation in Africans also extends to genes involved in the absorption, distribution, metabolism and excretion of pharmaceuticals. Ongoing cataloging of these clinically relevant variants reveals huge allele-frequency differences within and between African populations. Here, we examine Africa's large burden of infectious disease, discuss key examples of known genetic variation modulating disease risk, and provide examples of clinically relevant variants critical for establishing dosing guidelines. We propose that a more systematic characterization of the genetic diversity of African ancestry populations is required if the current benefits of precision medicine are to be extended to these populations.The Pharmacogenomics Journal advance online publication, 25 October 2016; doi:10.1038/tpj.2016.78.

PMID: 27779243 [PubMed - as supplied by publisher]

New treatment strategies for HIV-positive cancer patients undergoing antiblastic chemotherapy.

Expert Opin Pharmacother. 2016 Oct 22;

Authors: Berretta M, Di Francia R, Stanzione B, Facchini G, LLeshi A, De Paoli P, Spina M, Tirelli U

Abstract
INTRODUCTION: The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the outcome of HIV-infected patients by prolonging their survival. The increase in life expectancy has led to an increased risk of non-AIDS-related mortality and morbidity, including cardiovascular diseases, neurocognitive diseases, neuroendocrine dysfunctions and cancer. Areas Covered: The GICAT (Italian Cooperation Group on AIDS and Tumors) has demonstrated that patients who receive a multidisciplinary approach with the combination of anticancer agents (AC) and HAART can achieve better responses and survival rates than patients who receive AC alone. The first obstacle for the oncologist to plan treatment for cancer HIV-patients is the preliminary evaluation of drug-drug interactions between AC and HAART. Recent progress in pharmacogenomics could provide a new approach for personalized treatments. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, to maximize the efficacy of both concomitant therapy and to minimize the risk of DDIs, a currently useful list of pharmacogenomic markers of key metabolic enzymes is provided. Expert opinion: In this scenario, the importance of cooperation between oncologists and other health specialists (i.e., infectivologists, pharmacists, genetics and lab specialists) must not be underestimated in the management of these patients with the aim of planning an individual treatment strategy.

PMID: 27771974 [PubMed - as supplied by publisher]

THE CHALLENGES IN USING ELECTRONIC HEALTH RECORDS FOR PHARMACOGENOMICS AND PRECISION MEDICINE RESEARCH.

Pac Symp Biocomput. 2016;21:369-80

Authors: Laper SM, Restrepo NA, Crawford DC

Abstract
Access and utilization of electronic health records with extensive medication lists and genetic profiles is rapidly advancing discoveries in pharmacogenomics. In this study, we analyzed ~116,000 variants on the Illumina Metabochip for response to antihypertensive and lipid lowering medications in African American adults from BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records. Our study population included individuals who were prescribed an antihypertensive or lipid lowering medication, and who had both pre- and post-medication blood pressure or low-density lipoprotein cholesterol (LDL-C) measurements, respectively. Among those with pre- and post-medication systolic and diastolic blood pressure measurements (n=2,268), the average change in systolic and diastolic blood pressure was -0.6 mg Hg and -0.8 mm Hg, respectively. Among those with pre- and post-medication LDL-C measurements (n=1,244), the average change in LDL-C was -26.3 mg/dL. SNPs were tested for an association with change and percent change in blood pressure or blood levels of LDL-C. After adjustment for multiple testing, we did not observe any significant associations, and we were not able to replicate previously reported associations, such as in APOE and LPA, from the literature. The present study illustrates the benefits and challenges with using electronic health records linked to biorepositories for pharmacogenomic studies.

PMID: 26776201 [PubMed - indexed for MEDLINE]

Economic analysis of pharmacogenomic-guided clopidogrel treatment in Serbian patients with myocardial infarction undergoing primary percutaneous coronary intervention.

Pharmacogenomics. 2016 Oct 21;

Authors: Mitropoulou C, Fragoulakis V, Rakicevic LB, Novkovic MM, Vozikis A, Matic DM, Antonijevic NM, Radojkovic DP, van Schaik RH, Patrinos GP

Abstract
INTRODUCTION: Clopidogrel, which is activated by the CYP2C19 enzyme, is among the drugs for which all major regulatory agencies recommend genetic testing to be performed to identify a patient's CYP2C19 genotype in order to determine the optimal antiplatelet therapeutic scheme. The CYP2C19*2 and CYP2C19*3 variants are loss-of-function alleles, leading to abolished CYP2C19 function and thus have the risk of thrombotic events for carriers of these alleles on standard dosages, while the CYP2C19*17 allele results in CYP2C19 hyperactivity.
AIMS: Here, we report our findings from a retrospective study to assess whether genotyping for the CYP2C19*2 allele was cost effective for myocardial infarction patients receiving clopidogrel treatment in the Serbian population compared with the nongenotype-guided treatment.
RESULTS: We found that 59.3% of the CYP2C19*1/*1 patients had a minor or major bleeding event versus 42.85% of the CYP2C19*1/*2 and *2/*2, while a reinfarction event occurred only in 2.3% of the CYP21C9*1/*1 patients, compared with 11.2% of the CYP2C19*1/*2 and CYP2C19*2/*2 patients. There were subtle differences between the two patient groups, as far as the duration of hospitalization and rehabilitation is concerned, in favor of the CYP2C19*1/*1 group. The mean cost for the CYP2C19*1/*1 patients was estimated at €2547 versus €2799 in the CYP2C19*1/*2 and CYP2C19*2/*2 patients. Furthermore, based on the overall CYP2C19*1/*2 genotype frequencies in the Serbian population, a break-even point analysis indicated that performing the genetic test prior to drug prescription represents a cost-saving option, saving €13 per person on average.
CONCLUSION: Overall, our data demonstrate that pharmacogenomics-guided clopidogrel treatment may represent a cost-saving approach for the management of myocardial infarction patients undergoing primary percutaneous coronary intervention in Serbia.

PMID: 27767438 [PubMed - as supplied by publisher]

Addressing ethical challenges at the intersection of pharmacogenomics and primary care using deliberative consultations.

Pharmacogenomics. 2016 Oct 21;

Authors: Longo C, Rahimzadeh V, O'Doherty K, Bartlett G

Abstract
AIM: Primary care physicians will play a central role in the successful implementation of pharmacogenomics (PGx); however, important challenges remain. We explored the perspectives of stakeholders on key challenges of the PGx translation process in primary care using deliberative consultations.
METHODS: Primary care physicians, patients and policy-makers attended deliberations, where they discussed four ethical questions raised by PGx research and implementation in the primary care context.
RESULTS: Stakeholders voiced skepticism regarding PGx funding, commercialization, regulation, maintenance of an equal access healthcare system and restructuring of health research incentives and priorities in the public sector.
CONCLUSION: Deliberants developed governing principles for a PGx-specific charter of ethics, aiming to protect the interests of patients, and outlined recommendations for the future of PGx in primary care.

PMID: 27767407 [PubMed - as supplied by publisher]

Correlation of SIN3A genomic variants with β-hemoglobinopathies disease severity and hydroxyurea treatment efficacy.

Pharmacogenomics. 2016 Oct 21;

Authors: Gravia A, Chondrou V, Kolliopoulou A, Kourakli A, John A, Symeonidis A, Ali BR, Sgourou A, Papachatzopoulou A, Katsila T, Patrinos GP

Abstract
AIMS: Hemoglobinopathies, particularly β-thalassemia and sickle cell disease, are characterized by great phenotypic variability in terms of disease severity, while notable differences have been observed in hydroxyurea treatment efficacy. In both cases, the observed phenotypic diversity is mostly dependent on the elevated fetal hemoglobin levels, resulting from the persistent fetal globin gene expression in the adult erythroid stage orchestrated by intricate mechanisms that still remain only partly understood. We have previously shown that several protein factors act as modifiers of fetal hemoglobin production, exerting their effect via different pathways.
MATERIALS & METHODS: Here, we explored whether SIN3A could act as a modifier of fetal globin gene expression, as it interacts with KLF10, a known modifier of fetal hemoglobin production.
RESULTS: We show that SIN3A genomic variants are associated both with β-thalassemia disease severity (rs11072544) as well as hydroxyurea treatment response (rs7166737) in β-hemoglobinopathies patients.
CONCLUSION: Our findings further underline that fetal hemoglobin production is the result of a complex interplay in which several human globin gene cluster variants interact with protein factors encoded by modifier genes to produce the observed clinical outcome.

PMID: 27767389 [PubMed - as supplied by publisher]

The effect of SNPs in CYP450 in chloroquine/primaquine Plasmodium vivax malaria treatment.

Pharmacogenomics. 2016 Oct 21;

Authors: Sortica VA, Lindenau JD, Cunha MG, Ohnishi MD, Ventura AM, Ribeiro-Dos-Santos ÂK, Santos SE, Guimarães LS, Hutz MH

Abstract
BACKGROUND: Chloroquine/primaquine is the current therapy to eliminate Plasmodium vivax infection in the Amazon region.
AIMS: This study investigates CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 genetic polymorphisms influence on cloroquine/primaquine treatment.
PATIENTS & METHODS: Generalized estimating equations analyses were performed to determine the genetic influence in parasitemia and/or gametocytemia clearance over treatment time in 164 patients.
RESULTS: An effect of CYP2C8 low-activity alleles on treatment was observed (p = 0.01). From baseline to first day of treatment, wild-type individuals achieved greater reduction of gametocytes than low-activity allele carriers. CYP2C9 and CYP3A5 genes showed a trend for gametocytemia and parasitemia clearance rates.
CONCLUSION: Future studies should be performed to access the extent of CYP2C8, CYP2C9 and CYP3A5 gene polymorphisms influence on cloroquine/primaquine treatment.

PMID: 27767381 [PubMed - as supplied by publisher]

Pharmacogenomics and histone deacetylase inhibitors.

Pharmacogenomics. 2016 Oct 21;

Authors: Goey AK, Sissung TM, Peer CJ, Figg WD

Abstract
The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping.

PMID: 27767376 [PubMed - as supplied by publisher]

Theory based PKPD of S- and R-warfarin and effects on INR: influence of body size, composition and genotype in cardiac surgery patients.

Br J Clin Pharmacol. 2016 Oct 20;:

Authors: Xue L, Holford N, Ding XL, Shen ZY, Huang CR, Zhang H, Zhang JJ, Guo ZN, Xie C, Zhou L, Chen ZY, Liu LS, Miao LY

Abstract
AIMS: The aims of this study are to apply a theory based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin.
METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population pharmacokinetic parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction-corrected visual predictive checks.
RESULTS: The warfarin PK had been described using one-compartment model. CYP2C9 *1/*3 genotype had reduced clearance (CL) for S-warfarin, but increased CL for R-warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory based values (A = 1, B = 0). There was a small difference between healthy subjects and patients. A sigmoid Emax pharmacodynamic model inhibiting PCA synthesis as a function of S-warfarin concentration predicted INR. Small R-warfarin effects was described by competitive antagonism of S-warfarin inhibition. Patients with VKORC1 AA and CYP4F2 CC or CT genotypes had lower C50 for S-warfarin.
CONCLUSION: A theory based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory based allometric scaling of PK parameters was identified. R-warfarin had a minor effect compared with S-warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo.

PMID: 27763679 [PubMed - as supplied by publisher]

Pharmacogenomics of genes involved in antifolate drug response and toxicity in osteosarcoma.

Expert Opin Drug Metab Toxicol. 2016 Oct 19;:1-13

Authors: Hattinger CM, Tavanti E, Fanelli M, Vella S, Picci P, Serra M

Abstract
INTRODUCTION: Antifolates are structural analogs of folates, which have been used as antitumor drugs for more than 60 years. The antifolate drug most commonly used for treating human tumors is methotrexate (MTX), which is utilized widely in first-line treatment protocols of high-grade osteosarcoma (HGOS). In addition to MTX, two other antifolates, trimetrexate and pemetrexed, have been tested in clinical settings for second-line treatment of recurrent HGOS with patients unfortunately showing modest activity. Areas covered: There is clinical evidence which suggsest that, like other chemotherapeutic agents, not all HGOS patients are equally responsive to antifolates and do not have the same susceptibility to experience adverse drug-related toxicities. Here, we summarize the pharmacogenomic information reported so far for genes involved in antifolate metabolism and transport and in MTX-related toxicity in HGOS patients. Expert opinion: Identification and validation of genetic biomarkers that significantly impact clinical antifolate treatment response and related toxicity may provide the basis for a future treatment modulation based on the pharmacogenetic and pharmacogenomic features of HGOS patients.

PMID: 27758143 [PubMed - as supplied by publisher]

Pharmacogenomics of statins: understanding susceptibility to adverse effects.

Pharmgenomics Pers Med. 2016;9:97-106

Authors: Kitzmiller JP, Mikulik EB, Dauki AM, Murkherjee C, Luzum JA

Abstract
Statins are a cornerstone of the pharmacologic treatment and prevention of atherosclerotic cardiovascular disease. Atherosclerotic disease is a predominant cause of mortality and morbidity worldwide. Statins are among the most commonly prescribed classes of medications, and their prescribing indications and target patient populations have been significantly expanded in the official guidelines recently published by the American and European expert panels. Adverse effects of statin pharmacotherapy, however, result in significant cost and morbidity and can lead to nonadherence and discontinuation of therapy. Statin-associated muscle symptoms occur in ~10% of patients on statins and constitute the most commonly reported adverse effect associated with statin pharmacotherapy. Substantial clinical and nonclinical research effort has been dedicated to determining whether genetics can provide meaningful insight regarding an individual patient's risk of statin adverse effects. This contemporary review of the relevant clinical research on polymorphisms in several key genes that affect statin pharmacokinetics (eg, transporters and metabolizing enzymes), statin efficacy (eg, drug targets and pathways), and end-organ toxicity (eg, myopathy pathways) highlights several promising pharmacogenomic candidates. However, SLCO1B1 521C is currently the only clinically relevant pharmacogenetic test regarding statin toxicity, and its relevance is limited to simvastatin myopathy.

PMID: 27757045 [PubMed - in process]

Effects of Using Personal Genotype Data on Student Learning and Attitudes in a Pharmacogenomics Course.

Am J Pharm Educ. 2016 Sep 25;80(7):122

Authors: Weitzel KW, McDonough CW, Elsey AR, Burkley B, Cavallari LH, Johnson JA

Abstract
Objective. To evaluate the impact of personal genotyping and a novel educational approach on student attitudes, knowledge, and beliefs regarding pharmacogenomics and genomic medicine. Methods. Two online elective courses (pharmacogenomics and genomic medicine) were offered to student pharmacists at the University of Florida using a flipped-classroom, patient-centered teaching approach. In the pharmacogenomics course, students could be genotyped and apply results to patient cases. Results. Thirty-four and 19 student pharmacists completed the pharmacogenomics and genomic medicine courses, respectively, and 100% of eligible students (n=34) underwent genotyping. Student knowledge improved after the courses. Seventy-four percent (n=25) of students reported better understanding of pharmacogenomics based on having undergone genotyping. Conclusions. Completion of a novel pharmacogenomics elective course sequence that incorporated personal genotyping and genomic medicine was associated with increased student pharmacist knowledge and improved clinical confidence with pharmacogenomics.

PMID: 27756930 [PubMed - in process]

Epigenetics of Aging and Alzheimer's Disease: Implications for Pharmacogenomics and Drug Response.

Int J Mol Sci. 2015 Dec 21;16(12):30483-543

Authors: Cacabelos R, Torrellas C

Abstract
Epigenetic variability (DNA methylation/demethylation, histone modifications, microRNA regulation) is common in physiological and pathological conditions. Epigenetic alterations are present in different tissues along the aging process and in neurodegenerative disorders, such as Alzheimer's disease (AD). Epigenetics affect life span and longevity. AD-related genes exhibit epigenetic changes, indicating that epigenetics might exert a pathogenic role in dementia. Epigenetic modifications are reversible and can potentially be targeted by pharmacological intervention. Epigenetic drugs may be useful for the treatment of major problems of health (e.g., cancer, cardiovascular disorders, brain disorders). The efficacy and safety of these and other medications depend upon the efficiency of the pharmacogenetic process in which different clusters of genes (pathogenic, mechanistic, metabolic, transporter, pleiotropic) are involved. Most of these genes are also under the influence of the epigenetic machinery. The information available on the pharmacoepigenomics of most drugs is very limited; however, growing evidence indicates that epigenetic changes are determinant in the pathogenesis of many medical conditions and in drug response and drug resistance. Consequently, pharmacoepigenetic studies should be incorporated in drug development and personalized treatments.

PMID: 26703582 [PubMed - indexed for MEDLINE]

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Using Pharmacogenomic Databases for Discovering Patient-Target Genes and Small Molecule Candidates to Cancer Therapy.

Front Pharmacol. 2016;7:312

Authors: Belizário JE, Sangiuliano BA, Perez-Sosa M, Neyra JM, Moreira DF

Abstract
With multiple omics strategies being applied to several cancer genomics projects, researchers have the opportunity to develop a rational planning of targeted cancer therapy. The investigation of such numerous and diverse pharmacogenomic datasets is a complex task. It requires biological knowledge and skills on a set of tools to accurately predict signaling network and clinical outcomes. Herein, we describe Web-based in silico approaches user friendly for exploring integrative studies on cancer biology and pharmacogenomics. We briefly explain how to submit a query to cancer genome databases to predict which genes are significantly altered across several types of cancers using CBioPortal. Moreover, we describe how to identify clinically available drugs and potential small molecules for gene targeting using CellMiner. We also show how to generate a gene signature and compare gene expression profiles to investigate the complex biology behind drug response using Connectivity Map. Furthermore, we discuss on-going challenges, limitations and new directions to integrate molecular, biological and epidemiological information from oncogenomics platforms to create hypothesis-driven projects. Finally, we discuss the use of Patient-Derived Xenografts models (PDXs) for drug profiling in vivo assay. These platforms and approaches are a rational way to predict patient-targeted therapy response and to develop clinically relevant small molecules drugs.

PMID: 27746730 [PubMed - in process]