The ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24-25, 2015. Workshop Report.

Clin Sarcoma Res. 2016;6:3

Authors: Kager L, Whelan J, Dirksen U, Hassan B, Anninga J, Bennister L, Bovée JV, Brennan B, Broto JM, Brugières L, Cleton-Jansen AM, Copland C, Dutour A, Fagioli F, Ferrari S, Fiocco M, Fleuren E, Gaspar N, Gelderblom H, Gerrand C, Gerß J, Gonzato O, van der Graaf W, Hecker-Nolting S, Herrero-Martín D, Klco-Brosius S, Kovar H, Ladenstein R, Lancia C, LeDeley MC, McCabe MG, Metzler M, Myklebost O, Nathrath M, Picci P, Potratz J, Redini F, Richter GH, Reinke D, Rutkowski P, Scotlandi K, Strauss S, Thomas D, Tirado OM, Tirode F, Vassal G, Bielack SS

Abstract
This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas.

PMID: 27315524 [PubMed - as supplied by publisher]

CYP3A pharmacogenetics and tacrolimus disposition in adult heart transplant recipients.

Clin Transplant. 2016 Jun 17;

Authors: Deininger KM, Vu A, Page RL, Ambardekar AV, Lindenfeld J, Aquilante CL

Abstract
BACKGROUND: Cytochrome P450 (CYP) 3A polymorphisms are associated with variable CYP3A metabolizing enzyme activity and tacrolimus pharmacokinetics. We sought to determine the singular and combined impact of CYP3A4*22 and CYP3A5*3 variants on tacrolimus drug disposition in adult heart transplant recipients.
METHODS: The retrospective study included n=76 patients greater than one year post-heart transplant and receiving tacrolimus. Patients were genotyped for CYP3A4*22 and CYP3A5*3, and combined genotypes were classified as: extensive metabolizers (EM, CYP3A4*1/*1+CYP3A5*1 carriers); intermediate metabolizers (IM, CYP3A4*1/*1+CYP3A5*3/*3, or CYP3A4*22 carriers+CYP3A5*1 carriers), and poor metabolizers (PM, CYP3A4*22 carriers+CYP3A5*3/*3). The primary outcome was tacrolimus dose-adjusted trough concentration (C0 /D, ng/ml per mg/day).
RESULTS: In singular analysis, tacrolimus C0 /D did not differ significantly between CYP3A4*22 genotype groups. However, tacrolimus C0 /D was 1.8-fold lower (p<0.001) in CYP3A5 expressers versus nonexpressers. When combined CYP3A genotype was evaluated, tacrolimus C0 /D was 1.8-fold lower in EMs versus IMs (p<0.001) and EMs versus PMs (p=0.001). Tacrolimus C0 /D did not differ significantly between CYP3A IMs versus PMs.
CONCLUSION: Combined CYP3A genotype was associated with tacrolimus drug disposition in adult heart transplant recipients, but the effect was largely driven by CYP3A5*3. These data suggest that CYP3A4*22 and combined CYP3A genotype are unlikely to provide additional information beyond CYP3A5 genotype. This article is protected by copyright. All rights reserved.

PMID: 27314545 [PubMed - as supplied by publisher]

Implementation of Clinical Pharmacogenomics within a Large Health System: From Electronic Health Record Decision Support to Consultation Services.

Pharmacotherapy. 2016 Jun 17;

Authors: Hicks JK, Stowe D, Willner MA, Wai M, Daly T, Gordon SM, Lashner BA, Parikh S, White R, Teng K, Moss T, Erwin A, Chalmers J, Eng C, Knoer S

Abstract
The number of clinically relevant, gene-based guidelines and recommendations pertaining to drug prescribing continues to grow. Incorporating gene-drug interaction information into the drug prescribing process can help optimize pharmacotherapy outcomes and improve patient safety. However, pharmacogenomic implementation barriers exist such as integration of pharmacogenomic results into electronic health records (EHRs), development and deployment of pharmacogenomic decision-support tools to EHRs, and feasible models for establishing ambulatory pharmacogenomic clinics. We describe the development of pharmacist-managed pharmacogenomic services within a large health system. The Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B*57:01-abacavir, HLA-B*15:02-carbamazepine, and TPMT-thiopurines (i.e., azathioprine, mercaptopurine, and thioguanine) were systematically integrated into patient care. Sixty-three custom rules and alerts (20 for TPMT-thiopurines, 8 for HLA-B*57:01-abacavir, and 35 for HLA-B*15:02-anticonvulsants) were developed and deployed to the EHR for the purpose of providing point-of-care pharmacogenomic decision support. In addition, a pharmacist and physician-geneticist collaboration established a pharmacogenomics ambulatory clinic. This clinic provides genetic testing when warranted, result interpretation along with pharmacotherapy recommendations, and patient education. Our processes for developing these pharmacogenomic services and solutions for addressing implementation barriers are presented. This article is protected by copyright. All rights reserved.

PMID: 27312955 [PubMed - as supplied by publisher]

Association between Prolonged Neutropenia and Reduced Relapse Risk in Pediatric AML: A Report from the Children's Oncology Group.

Int J Cancer. 2016 Jun 16;

Authors: Sung L, Aplenc R, Alonzo TA, Gerbing RB, Wang YC, Meshinchi S, Gamis AS

Abstract
Objective was to describe the relationship between the number of sterile site infections and duration of neutropenia during the first four cycles of chemotherapy and the risk of recurrence and overall survival. AAML0531 was a Children's Oncology Group (COG) randomized phase 3 clinical trial that included 1022 children with de novo AML. For this analysis, we focused on non-Down syndrome favorable and standard risk patients who completed at least 4 cycles of chemotherapy without recurrence or withdrawal during protocol therapy. Those receiving hematopoietic stem cell transplantation in first remission were excluded. 569 patients were included; 274 (48.2%) were favorable risk. The median cumulative time with neutropenia between Induction II to completion of Intensification II was 96 (range 54-204) days. Number of sterile site infections did not influence the risk of relapse or overall survival. However, longer duration of neutropenia was associated with a lower risk of relapse (hazard ratio 0.81 per 20 days neutropenia, P=0.007). Longer duration of neutropenia was associated with a reduced risk of relapse for children with favorable and standard risk AML. Toxicity may be influenced by pharmacogenomics suggesting that individualized chemotherapy dosing may be an effective strategy. This article is protected by copyright. All rights reserved.

PMID: 27312107 [PubMed - as supplied by publisher]

MicroRNA hsa-miR-25-3p suppresses the expression and drug induction of CYP2B6 in human hepatocytes.

Biochem Pharmacol. 2016 Jun 13;

Authors: Jin Y, Yu D, Tolleson WH, Knox B, Wang Y, Chen S, Ren Z, Deng H, Guo Y, Ning B

Abstract
Cytochrome P450 2B6 (CYP2B6), mainly expressed in the liver and brain, is important for processing a number of widely used drugs. Variations in CYP2B6 expression are associated with decreased drug efficacy or adverse effects in some patients. Although CYP2B6 genetic variants are associated with its differential expression, epigenetic mechanisms affecting CYP2B6 gene regulation have not been established. Sequence analysis identified 29 domains in the CYP2B6 mRNA transcript that could be subject to regulation by microRNAs. Inverse correlations were found in human hepatocytes for the levels of the microRNAs hsa-miR-504-5p and hsa-miR-25-3p compared with CYP2B6 mRNA. Reporter gene assays showed that hsa-miR-25-3p suppresses CYP2B6 expression by targeting a specific sequence in the 3'-untranslated region of the mRNA transcript. Electrophoretic mobility shift assays confirmed that hsa-miR-25-3p forms stable complexes with its cognate mRNA sequence and that it recruits cellular factors, including Ago-4. Transfection of HepaRG cells with hsa-miR-25-3p mimics inhibited expression of the endogenous CYP2B6 gene and it also decreased rifampicin-dependent induction of CYP2B6 at the mRNA and protein levels. In summary, in sillico and in vitro analyses show that hsa-miR-25-3p suppresses CYP2B6 expression in human liver cells via an epigenetic mechanism.

PMID: 27311985 [PubMed - as supplied by publisher]

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]

Airway remodeling: Systems biology approach, from bench to bedside.

Technol Health Care. 2016 Jun 10;

Authors: Najafi A, Ghanei M, Jamalkandi SA

Abstract
Airway Remodeling, a patho-physiologic process, is considered as a key feature of chronic airway diseases. In recent years, our understanding of the complex diseases has increased significantly by the use of combined approaches, including systems biology, which may contribute to the development of personalized and predictive medicine approaches. Integrative analysis, along with the cooperation of clinicians, computer scientists, research scientists, and bench scientists, has become an important part of the experimental design and therapeutic strategies in the era of omics. The airway remodeling process is the result of the dysregulation of several signaling pathways that modulate the airway regeneration; therefore, high-throughput experiments and systems biology approach can help to understand this process better. The study reviews related literature and is consistent with the existing clinical evidence.

PMID: 27315153 [PubMed - as supplied by publisher]

Differential RNA-seq, Multi-Network Analysis and Metabolic Regulation Analysis of Kluyveromyces marxianus Reveals a Compartmentalised Response to Xylose.

PLoS One. 2016;11(6):e0156242

Authors: Schabort DT, Letebele PK, Steyn L, Kilian SG, du Preez JC

Abstract
We investigated the transcriptomic response of a new strain of the yeast Kluyveromyces marxianus, in glucose and xylose media using RNA-seq. The data were explored in a number of innovative ways using a variety of networks types, pathway maps, enrichment statistics, reporter metabolites and a flux simulation model, revealing different aspects of the genome-scale response in an integrative systems biology manner. The importance of the subcellular localisation in the transcriptomic response is emphasised here, revealing new insights. As was previously reported by others using a rich medium, we show that peroxisomal fatty acid catabolism was dramatically up-regulated in a defined xylose mineral medium without fatty acids, along with mechanisms to activate fatty acids and transfer products of β-oxidation to the mitochondria. Notably, we observed a strong up-regulation of the 2-methylcitrate pathway, supporting capacity for odd-chain fatty acid catabolism. Next we asked which pathways would respond to the additional requirement for NADPH for xylose utilisation, and rationalised the unexpected results using simulations with Flux Balance Analysis. On a fundamental level, we investigated the contribution of the hierarchical and metabolic regulation levels to the regulation of metabolic fluxes. Metabolic regulation analysis suggested that genetic level regulation plays a major role in regulating metabolic fluxes in adaptation to xylose, even for the high capacity reactions, which is unexpected. In addition, isozyme switching may play an important role in re-routing of metabolic fluxes in subcellular compartments in K. marxianus.

PMID: 27315089 [PubMed - as supplied by publisher]

Heterologous vaccine effects.

Vaccine. 2016 Jun 13;

Authors: Saadatian-Elahi M, Aaby P, Shann F, Netea MG, Levy O, Louis J, Picot V, Greenberg M, Warren W

Abstract
The heterologous or non-specific effects (NSEs) of vaccines, at times defined as "off-target effects" suggest that they can affect the immune response to organisms other than their pathogen-specific intended purpose. These NSEs have been the subject of clinical, immunological and epidemiological studies and are increasingly recognized as an important biological process by a growing group of immunologists and epidemiologists. Much remain to be learned about the extent and underlying mechanisms for these effects. The conference "Off-target effects of vaccination" held in Annecy-France (June 8-10 2015) intended to take a holistic approach drawing from the fields of immunology, systems biology, epidemiology, bioinformatics, public health and regulatory science to address fundamental questions of immunological mechanisms, as well as translational questions about vaccines NSEs. NSE observations were examined using case-studies on live attenuated vaccines and non-live vaccines followed by discussion of studies of possible biological mechanisms. Some possible pathways forward in the study of vaccines NSE were identified and discussed by the expert group.

PMID: 27312214 [PubMed - as supplied by publisher]

A Systems Biology Approach for Identifying Hepatotoxicant Groups Based on Similarity in Mechanisms of Action and Chemical Structure.

Methods Mol Biol. 2016;1425:339-59

Authors: Hebels DG, Rasche A, Herwig R, van Westen GJ, Jennen DG, Kleinjans JC

Abstract
When evaluating compound similarity, addressing multiple sources of information to reach conclusions about common pharmaceutical and/or toxicological mechanisms of action is a crucial strategy. In this chapter, we describe a systems biology approach that incorporates analyses of hepatotoxicant data for 33 compounds from three different sources: a chemical structure similarity analysis based on the 3D Tanimoto coefficient, a chemical structure-based protein target prediction analysis, and a cross-study/cross-platform meta-analysis of in vitro and in vivo human and rat transcriptomics data derived from public resources (i.e., the diXa data warehouse). Hierarchical clustering of the outcome scores of the separate analyses did not result in a satisfactory grouping of compounds considering their known toxic mechanism as described in literature. However, a combined analysis of multiple data types may hypothetically compensate for missing or unreliable information in any of the single data types. We therefore performed an integrated clustering analysis of all three data sets using the R-based tool iClusterPlus. This indeed improved the grouping results. The compound clusters that were formed by means of iClusterPlus represent groups that show similar gene expression while simultaneously integrating a similarity in structure and protein targets, which corresponds much better with the known mechanism of action of these toxicants. Using an integrative systems biology approach may thus overcome the limitations of the separate analyses when grouping liver toxicants sharing a similar mechanism of toxicity.

PMID: 27311473 [PubMed - in process]

Molecular profiles to biology and pathways: a systems biology approach.

Chin J Cancer. 2016;35(1):53

Authors: Van Laere S, Dirix L, Vermeulen P

Abstract
Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific molecular processes. However, the shortcoming of interpreting gene lists by using predefined sets of genes has resulted in the development of novel methods that heavily rely on network-based concepts. These algorithms have the advantage that they allow a more holistic view of the signaling properties of the condition under study as well as that they are suitable for integrating different data types like gene expression, gene mutation, and even histological parameters.

PMID: 27311441 [PubMed - in process]

Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins.

PLoS One. 2015;10(12):e0144025

Authors: Yao C, Behring JB, Shao D, Sverdlov AL, Whelan SA, Elezaby A, Yin X, Siwik DA, Seta F, Costello CE, Cohen RA, Matsui R, Colucci WS, McComb ME, Bachschmid MM

Abstract
Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2), react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential cysteine thiolates. We previously found that cardiac-specific overexpression of catalase (Cat), an enzyme that detoxifies excess H2O2, protected from oxidative stress and delayed cardiac aging in mice. Using redox proteomics and systems biology, we sought to identify the cysteines that could play a key role in cardiac disease and aging. With a 'Tandem Mass Tag' (TMT) labeling strategy and mass spectrometry, we investigated differential reversible cysteine oxidation in the cardiac proteome of wild type and Cat transgenic (Tg) mice. Reversible cysteine oxidation was measured as thiol occupancy, the ratio of total available versus reversibly oxidized cysteine thiols. Catalase overexpression globally decreased thiol occupancy by ≥1.3 fold in 82 proteins, including numerous mitochondrial and contractile proteins. Systems biology analysis assigned the majority of proteins with differentially modified thiols in Cat Tg mice to pathways of aging and cardiac disease, including cellular stress response, proteostasis, and apoptosis. In addition, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and II, suggesting improved function of cardiac mitochondria. In conclusion, our data suggest that catalase may alleviate cardiac disease and aging by moderating global protein cysteine thiol oxidation.

PMID: 26642319 [PubMed - indexed for MEDLINE]

Systems biology of IL-6, IL-12 family cytokines.

Cytokine Growth Factor Rev. 2015 Oct;26(5):595-602

Authors: Dittrich A, Hessenkemper W, Schaper F

Abstract
Interleukin-6-type cytokines play important roles in the communication between cells of multicellular organisms. They are involved in the regulation of complex cellular processes such as proliferation and differentiation and act as key player during inflammation and immune response. A major challenge is to understand how these complex non-linear processes are connected and regulated. Systems biology approaches are used to tackle this challenge in an iterative process of quantitative experimental and mathematical analyses. Here we review quantitative experimental studies and systems biology approaches dealing with the function of Interleukin-6-type cytokines in physiological and pathophysiological conditions. These approaches cover the analyses of signal transduction on a cellular level up to pharmacokinetic and pharmacodynamic studies on a whole organism level.

PMID: 26187858 [PubMed - indexed for MEDLINE]

@MInter: Automated Text-mining of Microbial Interactions.

Bioinformatics. 2016 Jun 16;

Authors: Lim KM, Li C, Chng KR, Nagarajan N

Abstract
MOTIVATION: Microbial consortia are frequently defined by numerous interactions within the community that are key to understanding their function. While microbial interactions have been extensively studied experimentally, information regarding them is dispersed in the scientific literature. As manual collation is an infeasible option, automated data processing tools are needed to make this information easily accessible.
RESULTS: We present @MInter, an automated information extraction system based on Support Vector Machines to analyze paper abstracts and infer microbial interactions. @MInter was trained and tested on a manually curated gold standard dataset of 735 species interactions and 3,917 annotated abstracts, constructed as part of this study. Cross-validation analysis showed that @MInter is able to detect abstracts pertaining to one or more microbial interactions with high specificity (specificity = 95%, AUC = 0.97). Despite challenges in identifying specific microbial interactions in an abstract (interaction level recall = 95%, precision = 25%), @MInter was shown to reduce annotator workload 13-fold compared to alternate approaches. Applying @MInter to 175 bacterial species abundant on human skin, we identified a network of 357 literature-reported microbial interactions, demonstrating its utility for the study of microbial communities.
AVAILABILITY: @MInter is freely available at https://github.com/CSB5/atminter CONTACT: nagarajann@gis.a-star.edu.sg SUPPLEMENTARY INFORMATION: Supplementary data is available at Bioinformatics online.

PMID: 27312413 [PubMed - as supplied by publisher]

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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]