Comparison of genome sequencing and clinical genotyping for pharmacogenes.

Clin Pharmacol Ther. 2016 Jun 17;

Authors: Yang W, Wu G, Broeckel U, Smith CA, Turner V, Haidar CE, Wang S, Carter R, Karol SE, Neale G, Crews K, Yang JJ, Mullighan CG, Downing JR, Evans WE, Relling MV

Abstract
We compared whole exome sequencing (WES, n=176 patients) and whole genome sequencing (WGS, n=68) and clinical genotyping (DMET array-based approach) for interrogating thirteen genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. We focused on 127 CPIC important variants: 103 single nucleotide variations (SNV), 21 insertion/deletions (Indel), HLA-B alleles, and two CYP2D6 structural variations. WES and WGS provided interrogation of non-overlapping sets of 115 SNV/Indels with call rate >98%. Among 68 loci interrogated by both WES and DMET, 64 loci (94.1%, CI:85.6-98.4%) showed no discrepant genotyping calls. Among 66 loci interrogated by both WGS and DMET, 63 loci (95.5%, CI:87.2-99.0%) showed no discrepant genotyping calls. In conclusion, even without optimization to interrogate pharmacogenetic variants, WES and WGS displayed potential to provide reliable interrogation of most pharmacogenes and further validation of genome sequencing in a clinical lab setting is warranted. This article is protected by copyright. All rights reserved.

PMID: 27311679 [PubMed - as supplied by publisher]

Progress and prospects in pharmacogenetics of antidepressant drugs.

Expert Opin Drug Metab Toxicol. 2016 Jun 16;

Authors: Fabbri C, Crisafulli C, Calabrò M, Spina E, Serretti A

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

PMID: 27310483 [PubMed - as supplied by publisher]

Identification of genetic polymorphisms of CYP2W1 in the three main Chinese ethnicities: Han, Tibetan, and Uighur.

Drug Metab Dispos. 2016 Jun 15;

Authors: Li YW, Kang X, Yang G, Dai PG, Chen C, Wang HJ

Abstract
CYP2W1 is an orphan member of the cytochrome P450 (CYP) superfamily. Recently, CYP2W1 has gained great research interest because of its unknown enzymatic function and tumor-specific expression property. This study aims to investigate the genetic polymorphisms of the CYP2W1 gene in Chinese populations and explore the functions of the detected variants. All the nine exons and exon-intron junction regions of the CYP2W1 gene were sequenced in 150 Chinese subjects, including 50 Han Chinese, 50 Tibetans, and 50 Uighurs. A total of 26 genetic variants were identified in this study, and 19 polymorphisms were detected in each population. Frequency comparison between populations showed that nine variants exhibited significantly different allelic distributions. A total of 12 different haplotypes were inferred from 150 samples by using the genotype data of nine exonic variants found in this study. CYP2W1*1A, *1B, *2, *4, and *6 were detected as the main alleles/haplotypes. Moreover, one, three, and two ethnically specific haplotypes were observed in the Han, Tibetan and Uighur samples, respectively. Then, the effects of four detected missense mutations (Ala181Thr, Gly376Ser, Val432Ile, and Pro488Leu) on the CYP2W1 protein function were predicted using three in-silico tools, namely, PolyPhen-2, SIFT, and MutationTaster. The results showed that Gly376Ser and Pro488Leu may have deleterious effects. In summary, this study showed that the genetic pattern of CYP2W1 is inter-ethnically different among the three Chinese populations, and this finding can extend our understanding of population genetics of CYP2W1 in the Chinese population.

PMID: 27307299 [PubMed - as supplied by publisher]

Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.

PLoS One. 2015;10(10):e0140496

Authors: Bis JC, Sitlani C, Irvin R, Avery CL, Smith AV, Sun F, Evans DS, Musani SK, Li X, Trompet S, Krijthe BP, Harris TB, Quibrera PM, Brody JA, Demissie S, Davis BR, Wiggins KL, Tranah GJ, Lange LA, Sotoodehnia N, Stott DJ, Franco OH, Launer LJ, Stürmer T, Taylor KD, Cupples LA, Eckfeldt JH, Smith NL, Liu Y, Wilson JG, Heckbert SR, Buckley BM, Ikram MA, Boerwinkle E, Chen YD, de Craen AJ, Uitterlinden AG, Rotter JI, Ford I, Hofman A, Sattar N, Slagboom PE, Westendorp RG, Gudnason V, Vasan RS, Lumley T, Cummings SR, Taylor HA, Post W, Jukema JW, Stricker BH, Whitsel EA, Psaty BM, Arnett D

Abstract
BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).
RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

PMID: 26516778 [PubMed - indexed for MEDLINE]

Pharmacogenomic Testing and Warfarin Management.

Oncol Nurs Forum. 2015 Sep;42(5):563-5

Authors: Maluso A

Abstract
Warfarin has been used for the prevention of thrombosis for more than 50 years and is the most frequently prescribed vitamin K antagonist in North America (Gage & Eby, 2003). Its mode of action is to prevent vitamin K from converting to vitamin KH2, thereby inhibiting clotting factors (Johnson & Cavallari, 2015). Warfarin metabolism is affected by variations in the cytochrome P450 2C9 (CYP2C9) and the vitamin K epoxide reductase complex 1 (VKORC1) genotypes. CYP2C9 affects the drug's pharmacokinetics, or metabolism, whereas VKORC1, the target protein of warfarin, affects the drug's pharmacodynamics, or its impact on cell proteins
.

PMID: 26302287 [PubMed - indexed for MEDLINE]

Dihydropyrimidinase and β-ureidopropionase gene variation and severe fluoropyrimidine-related toxicity.

Pharmacogenomics. 2015;16(12):1367-77

Authors: Kummer D, Froehlich TK, Joerger M, Aebi S, Sistonen J, Amstutz U, Largiadèr CR

Abstract
AIMS: To assess the association of DPYS and UPB1 genetic variation, encoding the catabolic enzymes downstream of dihydropyrimidine dehydrogenase, with early-onset toxicity from fluoropyrimidine-based chemotherapy.
PATIENTS & METHODS: The coding and exon-flanking regions of both genes were sequenced in a discovery subset (164 patients). Candidate variants were genotyped in the full cohort of 514 patients.
RESULTS & CONCLUSIONS: Novel rare deleterious variants in DPYS (c.253C > T and c.1217G > A) were detected once each in toxicity cases and may explain the occurrence of severe toxicity in individual patients, and associations of common variants in DPYS (c.1-1T > C: p(adjusted) = 0.003; OR = 2.53; 95% CI: 1.39-4.62, and c.265-58T > C: p(adjusted) = 0.039; OR = 0.61; 95% CI: 0.38-0.97) with 5-fluorouracil toxicity were replicated.

PMID: 26244261 [PubMed - indexed for MEDLINE]

DMETTM (Drug Metabolism Enzymes and Transporters): a Pharmacogenomic platform for precision medicine.

Oncotarget. 2016 Jun 9;

Authors: Arbitrio M, Di Martino MT, Scionti F, Agapito G, Guzzi PH, Cannataro M, Tassone P, Tagliaferri P

Abstract
In the era of personalized medicine, high-throughput technologies have allowed the investigation of genetic variations underlying the inter-individual variability in drug pharmacokinetics/pharmacodynamics. Several studies have recently moved from a candidate gene-based pharmacogenetic approach to genome-wide pharmacogenomic analyses to identify biomarkers for selection of patient-tailored therapies. In this aim, the identification of genetic variants affecting the individual drug metabolism is relevant for the definition of more active and less toxic treatments. This review focuses on the potentiality, reliability and limitations of the DMETTM (Drug Metabolism Enzymes and Transporters) Plus as pharmacogenomic drug metabolism multi-gene panel platform for selecting biomarkers in the final aim to optimize drugs use and characterize the individual genetic background.

PMID: 27304055 [PubMed - as supplied by publisher]

Personalized medicine. Closing the gap between knowledge and clinical practice.

Autoimmun Rev. 2016 Jun 11;

Authors: Anaya JM, Duarte-Rey C, Sarmiento-Monroy JC, Bardey D, Castiblanco J, Rojas-Villarraga A

Abstract
Personalized medicine encompasses a broad and evolving field informed by a patient distinctive information and biomarker profile. Although terminology is evolving and some semantic interpretations exist (e.g., personalized, individualized, precision), in a broad sense personalized medicine can be coined as: "To practice medicine as it once used to be in the past using the current biotechnological tools." A humanized approach to personalized medicine would offer the possibility of exploiting systems biology and its concept of P5 medicine, where predictive factors for developing a disease should be examined within populations in order to establish preventive measures on at-risk individuals, for whom healthcare should be personalized and participatory. Herein, the process of personalized medicine is presented together with the options that can be offered in health care systems with limited resources for diseases like rheumatoid arthritis and type 1 diabetes.

PMID: 27302209 [PubMed - as supplied by publisher]

Creating a scalable clinical pharmacogenomics service with automated interpretation and medical record result integration - experience from a pediatric tertiary care facility.

J Am Med Inform Assoc. 2016 Jun 14;

Authors: Manzi SF, Fusaro VA, Chadwick L, Brownstein C, Clinton C, Mandl KD, Wolf WA, Hawkins JB

Abstract
OBJECTIVE: This paper outlines the implementation of a comprehensive clinical pharmacogenomics (PGx) service within a pediatric teaching hospital and the integration of clinical decision support in the electronic health record (EHR).
MATERIALS AND METHODS: An approach to clinical decision support for medication ordering and dispensing driven by documented PGx variant status in an EHR is described. A web-based platform was created to automatically generate a clinical report from either raw assay results or specified diplotypes, able to parse and combine haplotypes into an interpretation for each individual and compared to the reference lab call for accuracy.
RESULTS: Clinical decision support rules built within an EHR provided guidance to providers for 31 patients (100%) who had actionable PGx variants and were written for interacting medications. A breakdown of the PGx alerts by practitioner service, and alert response for the initial cohort of patients tested is described. In 90% (355/394) of the cases, thiopurine methyltranferase genotyping was ordered pre-emptively.
DISCUSSION: This paper outlines one approach to implementing a clinical PGx service in a pediatric teaching hospital that cares for a heterogeneous patient population. There is a focus on incorporation of PGx clinical decision support rules and a program to standardize report text within the electronic health record with subsequent exploration of clinician behavior in response to the alerts.
CONCLUSION: The incorporation of PGx data at the time of prescribing and dispensing, if done correctly, has the potential to impact the incidence of adverse drug events, a significant cause of morbidity and mortality.

PMID: 27301749 [PubMed - as supplied by publisher]

Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children.

Pharmacogenomics. 2015;16(10):1065-76

Authors: Visscher H, Rassekh SR, Sandor GS, Caron HN, van Dalen EC, Kremer LC, van der Pal HJ, Rogers PC, Rieder MJ, Carleton BC, Hayden MR, Ross CJ, CPNDS consortium

Abstract
AIM: To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model.
PATIENTS & METHODS: Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes.
RESULTS: Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]).
CONCLUSION: Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification.

PMID: 26230641 [PubMed - indexed for MEDLINE]

Progress in understanding the genomic basis for adverse drug reactions: a comprehensive review and focus on the role of ethnicity.

Pharmacogenomics. 2015;16(10):1161-78

Authors: Chan SL, Jin S, Loh M, Brunham LR

Abstract
A major goal of the field of pharmacogenomics is to identify the genomic causes of serious adverse drug reactions (ADRs). Increasingly, genome-wide association studies (GWAS) have been used to achieve this goal. In this article, we review recent progress in the identification of genetic variants associated with ADRs using GWAS and discuss emerging themes from these studies. We also compare aspects of GWAS for ADRs to GWAS for common diseases. In the second part of the article, we review progress in performing pharmacogenomic research in multi-ethnic populations and discuss the challenges and opportunities of investigating genetic causes of ADRs in ethnically diverse patient populations.

PMID: 25978008 [PubMed - indexed for MEDLINE]

Review on Pharmacogenetics and Pharmacogenomics Applied to the Study of Asthma.

Methods Mol Biol. 2016;1434:255-272

Authors: Sánchez-Martín A, García-Sánchez A, Isidoro-García M

Abstract
Nearly one-half of asthmatic patients do not respond to the most common therapies. Evidence suggests that genetic factors may be involved in the heterogeneity in therapeutic response and adverse events to asthma therapies. We focus on the three major classes of asthma medication: β-adrenergic receptor agonist, inhaled corticosteroids, and leukotriene modifiers. Pharmacogenetics and pharmacogenomics studies have identified several candidate genes associated with drug response.In this chapter, the main pharmacogenetic and pharmacogenomic studies in addition to the future perspectives in personalized medicine will be reviewed. The ideal treatment of asthma would be a tailored approach to health care in which adverse effects are minimized and the therapeutic benefit for an individual asthmatic is maximized leading to a more cost-effective care.

PMID: 27300544 [PubMed - as supplied by publisher]

Verification of five pharmacogenomics-based warfarin administration models.

Indian J Pharmacol. 2016 May-Jun;48(3):258-63

Authors: Lin M, Yu L, Qiu H, Wang Q, Zhang J, Song H

Abstract
OBJECTIVE: This study aims to screen and validate five individual warfarin dosing models (four Asian model algorithms, namely, Ohno, Wen, Miao, Huang, and the algorithm of International Warfarin Pharmacogenetic Consortium, namely IWPC algorithm) with the aim of evaluating their accuracy, practicality, and safety.
MATERIALS AND METHODS: Patients' CYP2C9*3 and VKORC1-1639G >A genes were genotyped, and patient-related information and steady warfarin doses were recorded. The difference between the predicted dose and actual maintenance dose of each model was compared.
RESULTS: The prediction accuracies of the Huang and Wen models were the highest. In terms of clinical practicality, the Huang model rated the highest for the low-dose group, whereas the Ohno and IWPC models rated the highest for the middle-dose group. The models tended to markedly overpredict the doses in the low-dose group, especially the IWPC model. The Miao model tended to severely underpredict the doses in the middle-dose group, whereas no model exhibited severe overprediction.
CONCLUSIONS: Since none of the models ranked high for all the three criteria considered, the impact of various factors should be thoroughly considered before selecting the most appropriate model for the region's population.

PMID: 27298494 [PubMed - in process]

Individualized network-based drug repositioning infrastructure for precision oncology in the panomics era.

Brief Bioinform. 2016 Jun 12;

Authors: Cheng F, Hong H, Yang S, Wei Y

Abstract
Advances in next-generation sequencing technologies have generated the data supporting a large volume of somatic alterations in several national and international cancer genome projects, such as The Cancer Genome Atlas and the International Cancer Genome Consortium. These cancer genomics data have facilitated the revolution of a novel oncology drug discovery paradigm from candidate target or gene studies toward targeting clinically relevant driver mutations or molecular features for precision cancer therapy. This focuses on identifying the most appropriately targeted therapy to an individual patient harboring a particularly genetic profile or molecular feature. However, traditional experimental approaches that are used to develop new chemical entities for targeting the clinically relevant driver mutations are costly and high-risk. Drug repositioning, also known as drug repurposing, re-tasking or re-profiling, has been demonstrated as a promising strategy for drug discovery and development. Recently, computational techniques and methods have been proposed for oncology drug repositioning and identifying pharmacogenomics biomarkers, but overall progress remains to be seen. In this review, we focus on introducing new developments and advances of the individualized network-based drug repositioning approaches by targeting the clinically relevant driver events or molecular features derived from cancer panomics data for the development of precision oncology drug therapies (e.g. one-person trials) to fully realize the promise of precision medicine. We discuss several potential challenges (e.g. tumor heterogeneity and cancer subclones) for precision oncology. Finally, we highlight several new directions for the precision oncology drug discovery via biotherapies (e.g. gene therapy and immunotherapy) that target the 'undruggable' cancer genome in the functional genomics era.

PMID: 27296652 [PubMed - as supplied by publisher]

Pharmacogenetic considerations in the treatment of Alzheimer's disease.

Pharmacogenomics. 2016 Jun 13;

Authors: Cacabelos R, Torrellas C, Teijido O, Carril JC

Abstract
The practical pharmacogenetics of Alzheimer's disease (AD) is circumscribed to acetylcholinesterase inhibitors (AChEIs) and memantine. However, pharmacogenetic procedures should be applied to novel strategies in AD therapeutics including: novel AChEIs and neurotransmitter regulators, anti-Aβ treatments, anti-tau treatments, pleiotropic products, epigenetic drugs and combination therapies. Genes involved in the pharmacogenetic network are under the influence of the epigenetic machinery which regulates gene expression transcriptionally and post-transcriptionally, configuring the fundamentals of pharmacoepigenomics. Over 60% of AD patients present concomitant pathologies demanding additional treatments which increase the likelihood of drug-drug interactions. Lipid metabolism dysfunction is a pathogenic mechanism inherent to AD neurodegeneration. The therapeutic response to hypolipidemic compounds is influenced by the APOE and CYP genotypes. The development of novel compounds and the use of combination/multifactorial treatments require the implantation of pharmacogenomic procedures for the avoidance of ADRs and the optimization of therapeutics.

PMID: 27291247 [PubMed - as supplied by publisher]

Will personalized drugs for cardiovascular disease become an option? - Defining 'Evidence-based personalized medicine' for its implementation and future use.

Expert Opin Pharmacother. 2015;16(17):2549-52

Authors: de Denus S, Dubé MP, Tardif JC

Abstract
It is generally accepted that the implementation of pharmacogenomics and, more broadly, personalized medicine will have to be 'evidence-based'. However, there is a lack of consensus on the level of evidence required to justify the use of pharmacogenomic testing in clinical practice. In the cardiovascular field, this lack of agreement has led to somewhat contradicting recommendations by different organizations regarding the clinical utility and use of pharmacogenomic tests or information. Here, we argue that randomized, controlled trials are paramount in order to enable and accelerate the widespread implementation of pharmacogenomics, not only to demonstrate the clinical efficacy and cost-effectiveness of such tests, but because such level of evidence is required to support the considerable changes associated with the implantation of pharmacogenomics in clinical practice.

PMID: 26371722 [PubMed - indexed for MEDLINE]

Virtual Pharmacist: A Platform for Pharmacogenomics.

PLoS One. 2015;10(10):e0141105

Authors: Cheng R, Leung RK, Chen Y, Pan Y, Tong Y, Li Z, Ning L, Ling XB, He J

Abstract
We present Virtual Pharmacist, a web-based platform that takes common types of high-throughput data, namely microarray SNP genotyping data, FASTQ and Variant Call Format (VCF) files as inputs, and reports potential drug responses in terms of efficacy, dosage and toxicity at one glance. Batch submission facilitates multivariate analysis or data mining of targeted groups. Individual analysis consists of a report that is readily comprehensible to patients and practioners who have basic knowledge in pharmacology, a table that summarizes variants and potential affected drug response according to the US Food and Drug Administration pharmacogenomic biomarker labeled drug list and PharmGKB, and visualization of a gene-drug-target network. Group analysis provides the distribution of the variants and potential affected drug response of a target group, a sample-gene variant count table, and a sample-drug count table. Our analysis of genomes from the 1000 Genome Project underlines the potentially differential drug responses among different human populations. Even within the same population, the findings from Watson's genome highlight the importance of personalized medicine. Virtual Pharmacist can be accessed freely at http://www.sustc-genome.org.cn/vp or installed as a local web server. The codes and documentation are available at the GitHub repository (https://github.com/VirtualPharmacist/vp). Administrators can download the source codes to customize access settings for further development.

PMID: 26496198 [PubMed - indexed for MEDLINE]

Effects of CYP2B6 and CYP1A2 Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients.

OMICS. 2015 Sep;19(9):553-62

Authors: Mhandire D, Lacerda M, Castel S, Mhandire K, Zhou D, Swart M, Shamu T, Smith P, Musingwini T, Wiesner L, Stray-Pedersen B, Dandara C

Abstract
The extremely high prevalence of HIV/AIDS in sub-Saharan Africa and limitations of current antiretroviral medicines demand new tools to optimize therapy such as pharmacogenomics for person-to-person variations. African populations exhibit greater genetic diversity than other world populations, thus making it difficult to extrapolate findings from one population to another. Nevirapine, an antiretroviral medicine, displays large plasma concentration variability which adversely impacts therapeutic virological response. This study, therefore, aimed to identify sources of variability in nevirapine pharmacokinetics and pharmacodynamics, focusing on genetic variation in CYP2B6 and CYP1A2. Using a cross-sectional study design, 118 HIV-infected adult Zimbabwean patients on nevirapine-containing highly active antiretroviral therapy (HAART) were characterized for three key functional single nucleotide polymorphisms (SNPs), CYP2B6 c.516G>T (rs3745274), CYP2B6 c.983T>C (rs28399499), and CYP1A2 g.-163C>A (rs762551). We investigated whether genotypes at these loci were associated with nevirapine plasma concentration, a therapeutic biomarker, and CD4 cell count, a biomarker of disease progression. CYP2B6 and CYP1A2 were chosen as the candidate genes based on reports in literature, as well as their prominence in the metabolism of efavirenz, a drug in the same class with nevirapine. Nevirapine plasma concentration was determined using LC-MS/MS. The mean nevirapine concentration for CYP2B6 c.516T/T genotype differed significantly from that of 516G/G (p < 0.001) and 516G/T (p < 0.01) genotypes, respectively. There were also significant differences in mean nevirapine concentration between CYP2B6 c.983T > C genotypes (p = 0.04). Importantly, the CYP1A2 g.-163C>A SNP was significantly associated with the pharmacodynamics endpoint, the CD4 cell count (p = 0.012). Variant allele frequencies for the three SNPs observed in this Zimbabwean group were similar to other African population groups but different to observations among Caucasian and Asian populations. We conclude that CYP2B6 c.516G>T and CYP2B6 c.983T>C could be important sources of nevirapine pharmacokinetic variability that could be considered for dosage optimization, while CYP1A2 g.-163C>A seems to be associated with HIV disease progression. These inter- and intra-population pharmacokinetic and pharmacodynamics differences suggest that a single prescribed dosage may not be appropriate for the treatment of disease. Further research into a personalized nevirapine regimen is required.

PMID: 26348712 [PubMed - indexed for MEDLINE]

Genetic polymorphism of pharmacogenomic VIP variants in the Deng people from the Himalayas in Southeast Tibet.

Biomarkers. 2015;20(5):275-86

Authors: Shi X, Wang L, Du S, Wang H, Feng T, Jin T, Kang L

Abstract
Little is known about polymorphic distribution of pharmacogenes among ethnicities, including the Deng people. In this study, we recruited 100 unrelated, healthy Deng people and genotyped them with respect to 76 different single-nucleotide polymorphisms by the PharmGKB database. Our results first indicated that the polymorphic distribution of pharmacogenes of the Deng people is most similar to CHD, suggesting that Deng people have a closest genetic relationship with CHD. Our data will enrich the database of pharmacogenomics and provide a theoretical basis for safer drug administration and individualized treatment plans, promoting the development of personalized medicine.

PMID: 26329523 [PubMed - indexed for MEDLINE]

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