PGWD: Integrating Personal Genome for Warfarin Dosing.

Interdiscip Sci. 2016 Mar;8(1):23-7

Authors: Pan Y, Cheng R, Li Z, Zhao Y, He J

Abstract
Warfarin is a drug normally used in the prevention of thrombosis and the formation of blood clots. The dosage of warfarin is strongly affected by genetic variants of CYP2C9 and VKORC1 genes. Current technologies for detecting the variants of these genes are mainly based on real-time PCR. In recent years, due to the rapidly dropping cost of whole genome sequencing and genotyping, more and more people get their whole genome sequenced or genotyped. However, current software for warfarin dosing prediction is based on low-throughput genetic information from either real-time PCR or melting curve methods. There is no bioinformatics tool available that can take the high-throughput genome sequencing data as input and determine the accurate dosage of warfarin. Here, we present PGWD, a web tool that analyzes personal genome sequencing data and integrates with clinical information for warfarin dosing.

PMID: 26267707 [PubMed - indexed for MEDLINE]

Bringing clinical pharmacogenomics information to pharmacists: A qualitative study of information needs and resource requirements.

Int J Med Inform. 2016 Feb;86:54-61

Authors: Romagnoli KM, Boyce RD, Empey PE, Adams S, Hochheiser H

Abstract
INTRODUCTION: As key experts in supporting medication-decision making, pharmacists are well-positioned to support the incorporation of pharmacogenomics into clinical care. However, there has been little study to date of pharmacists' information needs regarding pharmacogenomics. Understanding those needs is critical to design information resources that help pharmacists effectively apply pharmacogenomics information.
OBJECTIVES: We sought to understand the pharmacogenomics information needs and resource requirements of pharmacists.
METHODS: We conducted qualitative inquiries with 14 pharmacists representing 6 clinical environments, and used the results of those inquiries to develop a model of pharmacists' pharmacogenomics information needs and resource requirements.
RESULTS: The inquiries identified 36 pharmacogenomics-specific and pharmacogenomics-related information needs that fit into four information needs themes: background information, patient information, medication information, and guidance information. The results of the inquiries informed a model of pharmacists' pharmacogenomics resource requirements, with 3 themes: structure of the resource, perceptions of the resource, and perceptions of the information.
CONCLUSION: Responses suggest that pharmacists anticipate an imminently growing role for pharmacogenomics in their practice. Participants value information from trust-worthy resources like FDA product labels, but struggle to find relevant information quickly in labels. Specific information needs include clinically relevant guidance about genotypes, phenotypes, and how to care for their patients with known genotypes. Information resources supporting the goal of incorporating complicated genetic information into medication decision-making goals should be well-designed and trustworthy.

PMID: 26725696 [PubMed - indexed for MEDLINE]

Genetic polymorphisms of pharmacogenomic VIP variants in the lhoba population of southwest China.

Int J Clin Exp Pathol. 2015;8(10):13293-303

Authors: He Y, Yang H, Geng T, Feng T, Yuan D, Kang L, Luo M, Jin T

Abstract
BACKGROUND: It is well-established that differences among ethnic groups in drug responses are primarily due to the genetic diversity of pharmacogenes. A number of genes or variants that play a crucial role in drug responses have been designated Very Important Pharmacogenes (VIP) by the PharmGKB database. Clarifying the polymorphic distribution of VIPs in different ethnic groups will aid in personalized medicine for specific populations.
METHODS: We sequenced 85 VIP variants in the Lhoba population based on the PharmGKB database. The polymorphic distribution of the 85 VIP variants in 100 Lhoba subjects was determined and compared with that of 11 major HapMap populations, including ASW, CEU, CHB, CHD, GIH, JPT, LWK, MEX, MKK, TSI, and YRI. We used χ(2) tests to identify significantly different loci between these populations. We downloaded SNP allele frequencies from the ALlele FREquency Database to observe the global genetic variation distribution for these specific loci. And then we used Structure software to perform the genetic structure analysis of 12 populations.
RESULTS: Based on comparisons of selected available loci, we found that 23, 28, 16, 10, 20, 16, 24, 19, 22, 21 and 36 of the selected VIP variant genotype frequencies in the Lhoba population differed from those of the ASW, CEU, CHB, CHD, GIH, JPT, LWK, MEX, MKK, TSI, and YRI populations, respectively. In addition, Pairwise FST values and clustering analyses also showed the VIP variants in Lhoba exhibited a close genetic affinity with CHD, CHB and JPT populations.
CONCLUSION: Our results complement pharmacogenomic data on the Lhoba ethnic group and may be helpful in the diagnosis of certain diseases in minorities.

PMID: 26722533 [PubMed - indexed for MEDLINE]

Physician perspectives of CYP2C19 and clopidogrel drug-gene interaction active clinical decision support alerts.

Int J Med Inform. 2016 Feb;86:117-25

Authors: Nishimura AA, Shirts BH, Salama J, Smith JW, Devine B, Tarczy-Hornoch P

Abstract
OBJECTIVE: To determine if physicians find clinical decision support alerts for pharmacogenomic drug-gene interactions useful and assess their perceptions of usability aspects that impact usefulness.
MATERIALS AND METHODS: 52 physicians participated in an online simulation and questionnaire involving a prototype alert for the clopidogrel and CYP2C19 drug-gene interaction.
RESULTS: Only 4% of participants stated they would override the alert. 92% agreed that the alerts were useful. 87% found the visual interface appropriate, 91% felt the timing of the alert was appropriate and 75% were unfamiliar with the specific drug-gene interaction. 80% of providers preferred the ability to order the recommended medication within the alert. Qualitative responses suggested that supplementary information is important, but should be provided as external links, and that the utility of pharmacogenomic alerts depends on the broader ecosystem of alerts.
PRINCIPAL CONCLUSIONS: Pharmacogenomic alerts would be welcomed by many physicians, can be built with minimalist design principles, and are appropriately placed at the end of the prescribing process. Since many physicians lack familiarity with pharmacogenomics but have limited time, information and educational resources within the alert should be carefully selected and presented in concise ways.

PMID: 26642939 [PubMed - indexed for MEDLINE]

Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine.

Genomics Proteomics Bioinformatics. 2016 Oct 8;:

Authors: Ahmed S, Zhou Z, Zhou J, Chen SQ

Abstract
The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual's particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.

PMID: 27729266 [PubMed - as supplied by publisher]

Targeted next-generation sequencing for comprehensive genetic profiling of pharmacogenes.

Clin Pharmacol Ther. 2016 Oct 11;:

Authors: Han SM, Park J, Lee JH, Lee SS, Kim H, Han H, Kim Y, Yi S, Cho JY, Jang IJ, Lee MG

Abstract
Phenotypic differences in drug responses have been associated with known pharmacogenomic loci, but many remain to be characterized. We therefore developed next-generation sequencing (NGS) panels to enable broad and unbiased inspection of genes that are involved in pharmacokinetics (PK) and pharmacodynamics (PD). These panels feature repetitively optimized probes to capture up to 114 PK/PD-related genes with high coverage (99.6%) and accuracy (99.9%). Sequencing of a Korean cohort (n = 376) with the panels enabled profiling of actionable variants as well as rare variants of unknown functional consequences. Notably, variants that occurred at low frequency were enriched with likely protein-damaging variants and previously unreported variants. Furthermore, in vitro evaluation of four pharmacogenes including CYP2C19 confirmed that many of these rare variants have considerable functional impact. The present study suggests that targeted NGS panels are readily applicable platforms to facilitate comprehensive profiling of pharmacogenes, including common but also rare variants that warrant screening for personalized medicine. This article is protected by copyright. All rights reserved.

PMID: 27727443 [PubMed - as supplied by publisher]

Harnessing Knowledge on Very Important Pharmacogenes CYP2C9 and CYP2C19 Variation for Precision Medicine in Resource-Limited Global Conflict Zones.

OMICS. 2016 Oct;20(10):604-609

Authors: Barlas İÖ, Sezgin O, Dandara C, Türköz G, Yengel E, Cindi Z, Ankaralı H, Şardaş S

Abstract
Pharmacogenomics harnesses the utility of a patient's genome (n = 1) in decisions on which therapeutic drugs and in what amounts should be administered. Often, patients with shared ancestry present with comparable genetic profiles that predict drug response. However, populations are not static, thus, often, population mobility through migration, especially enmasse as is seen for refugees, changes the pharmacogenetic profiles of resultant populations and therefore observed responses to commonly used therapeutic drugs. For example, in the aftermath of the Syrian civil war since 2011, millions have fled their homes to neighboring countries in the Middle East. The growing permanence of refugees and mass migrations is a call to shift our focus in the life sciences community from old models of pharmaceutical innovation. These seismic social changes demand faster decisions for "population-to-population bridging," whereby novel drugs developed in or for particular regions/countries can meet with rational regulatory decisions/approval in world regions impacted by migrant/refugee populations whose profiles are dynamic, such as in the Eastern Mediterranean region at present. Thus, it is important to characterize and report on the prevalence of pharmacogenes that affect commonly used medications and predict if population changes may call for attention to particular differences that may impact health of patients. Thus, we report here on four single-nucleotide polymorphism (SNP) variations in CYP2C9 and CYP2C19 genes among Mersin-Turkish healthy volunteers in the Mersin Province in the Eastern Mediterranean region that is currently hosting a vast number of migrant populations from Syria. Both CYP2C9 and CYP2C19 are very important pharmacogene molecular targets. We compare and report here on the observed SNP genetic variation in our sample with data on 12 world populations from dbSNP and discuss the feasibility of forecasting the pharmacokinetics of drugs utilized by migrant communities in Mersin and the Eastern Mediterranean region. This study can serve as a catalyst to invest in research in Syrian populations currently living in the Eastern Mediterranean. The findings have salience for rapid and rational regulatory decision-making for worldwide precision medicine and, specifically, "pharmacogenovigilance-guided bridging of pharmacokinetics" across world populations in the current era of planetary scale migration.

PMID: 27726640 [PubMed - in process]

Facile and Phase-Defined Determination of HLA Alleles with Morpholino-Functionalized Nanoparticle Probes.

Nanomedicine. 2016 Oct 5;:

Authors: Zu Y, Tan MH, Ee CR, Ying JY

Abstract
A number of human leukocyte antigen (HLA) gene alleles have been found to be genetic risk markers for immunologically mediated drug hypersensitivity. Clinical adoption of HLA pharmacogenomics requires facile and accurate allele screening assays. As HLA genes are highly polymorphic, currently available methods are usually labor-intensive and liable to generate false positives. Herein we report a general strategy for screening HLA alleles with nanoparticle probes. Specific HLA alleles can be identified by gauging three to five sequence variants. Single-polymerase chain reaction (PCR) and dual-PCR methods have been proposed to achieve phase-defined determination of the sequence variants. Morpholino-functionalized gold nanoparticle probes allow for colorimetric and highly specific detection. Assays for HLA-B*58:01 and HLA-B*15:02 have been developed and validated with 49 selected human genomic DNA samples. The facile nanoparticle probe-based assays can be implemented easily in molecular diagnostic laboratories for accurate and cost-effective screening of HLA alleles.

PMID: 27720927 [PubMed - as supplied by publisher]

Personalized Learning: From Neurogenetics of Behaviors to Designing Optimal Language Training.

Neuropsychologia. 2016 Oct 5;:

Authors: Wong PC, Vuong L, Liu K

Abstract
Variability in drug responsivity has prompted the development of Personalized Medicine, which has shown great promise in utilizing genotypic information to develop safer and more effective drug regimens for patients. Similarly, individual variability in learning outcomes has puzzled researchers who seek to create optimal learning environments for students. "Personalized Learning" seeks to identify genetic, neural and behavioral predictors of individual differences in learning and aims to use predictors to help create optimal teaching paradigms. Evidence for Personalized Learning can be observed by connecting research in pharmacogenomics, cognitive genetics and behavioral experiments across domains of learning, which provides a framework for conducting empirical studies from the laboratory to the classroom and holds promise for addressing learning effectiveness in the individual learners. Evidence can also be seen in the subdomain of speech learning, thus providing initial support for the applicability of Personalized Learning to language.

PMID: 27720749 [PubMed - as supplied by publisher]

Pharmacogenomics and adverse drug reactions: Primetime and not ready for primetime tests.

J Allergy Clin Immunol. 2016 Oct;138(4):943-955

Authors: Khan DA

Abstract
Adverse drug reactions (ADRs) are a relatively common cause of morbidity and mortality. Many factors can contribute to ADRs, including genetics. The degree to which genetics contributes to ADRs is not entirely clear and varies by drug, as well as the type of ADR. Pharmacogenetics and, more recently, pharmacogenomics have been applied to the field of ADRs for both predictable ADRs and hypersensitivity drug reactions. Evaluations for glucose-6-phosphate dehydrogenase and thiopurine S-methyltransferase are commonplace clinical tests to reduce hematologic problems associated with drugs, such as dapsone and azathioprine, respectively. Numerous pharmacogenetic associations have been discovered for immediate hypersensitivity reactions to β-lactams, aspirin, and nonsteroidal anti-inflammatory drugs; however, the clinical utility of testing for these genetic associations has not been established. In contrast, pharmacogenetic testing for HLA-B*1502 before carbamazepine in patients of certain Asian ethnicities and testing for HLA-B*5701 before abacavir treatment are recommended. This review will focus on pharmacogenetics and pharmacogenomics and their role in reducing ADRs, especially those caused by drug hypersensitivity reactions.

PMID: 27720019 [PubMed - in process]

A model to assess the cost-effectiveness of pharmacogenomics tests in chronic heart failure: the case of ivabradine.

Pharmacogenomics. 2016 Oct 10;:

Authors: Iliza AC, Matteau A, Guertin JR, Mitchell D, Fanton-Aita F, Dubois A, Dubé MP, Tardif JC, LeLorier J

Abstract
Pharmacogenomics (PGx) tests have the potential of improving the effectiveness of expensive new drugs by predicting the likelihood, for a particular patient, to respond to a treatment. The objective of this study was to develop a pharmacoeconomic model to determine the characteristics and the cost-effectiveness of a hypothetical PGx test, which would identify patients who are most likely to respond to an expensive treatment for chronic heart failure. For this purpose, we chose the example of ivabradine. Our results suggest that the use of a PGx test that could select a subgroup of patients to be treated with an expensive drug has the potential to provide more efficient drug utilization.

PMID: 27719379 [PubMed - as supplied by publisher]

Pharmacogenetics driving personalized medicine: analysis of genetic polymorphisms related to breast cancer medications in Italian isolated populations.

J Transl Med. 2016 Jan 22;14:22

Authors: Cocca M, Bedognetti D, La Bianca M, Gasparini P, Girotto G

Abstract
BACKGROUND: Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with equivalent regimens and novel targeted therapies. In this study, we performed a population based approach intersecting high-throughput genotype data from Friuli Venezia Giulia (FVG) isolated populations with publically available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way.
METHODS: A list of 80 variants reported to be related to the efficacy or toxicity of breast cancer drugs was obtained from PharmGKB database. Fourty-one were present in FVG, 1000G European (EUR) and ExAC (Non Finnish European) databases. Their frequency was extracted using PLINK software and the differences tested by Fisher's exact test.
RESULTS: Statistical analyses revealed that 13 out of the 41 (32 %) variants were significantly different in frequency in our sample as compared to the EUR/ExAC cohorts. For nine variants the available level of evidence (LOE) included polymorphisms related to cyclophosphamide, tamoxifen, doxorubicin, fluorpyrimidine and paclitaxel. In particular, for trastuzumab two variants were detected: (1) rs1801274-G within FCGR2A and associated with decreased efficacy (LOE 2B); (2) rs1136201-G located within ERBB2 and associated with increased toxicity (LOE 3). Both these two variants were underrepresented in the FVG population compared to EUR/ExAC population thus suggesting a high therapeutic index of this drug in our population. Moreover, as regards fluoropyrimidines, the frequency of two polymorphisms within the DPYD gene associated with drug toxicity (e.g., rs2297595-C allele and rs3918290-T allele, LOE 2A and 1, respectively) was extremely low in FVG population thus suggesting that a larger number of FVG patients could benefit from full dosage of fluoropyrimidine therapy.
CONCLUSIONS: All these findings increase the overall knowledge on the prevalence of specific variants related with breast cancer treatment responsiveness in FVG population and highlight the importance of assessing gene polymorphisms related with cancer medications in isolated communities.

PMID: 26801900 [PubMed - indexed for MEDLINE]

PGMD: a comprehensive manually curated pharmacogenomic database.

Pharmacogenomics J. 2016 Apr;16(2):124-8

Authors: Kaplun A, Hogan JD, Schacherer F, Peter AP, Krishna S, Braun BR, Nambudiry R, Nitu MG, Mallelwar R, Albayrak A

Abstract
The PharmacoGenomic Mutation Database (PGMD) is a comprehensive manually curated pharmacogenomics database. Two major sources of PGMD data are peer-reviewed literature and Food and Drug Administration (FDA) and European Medicines Agency (EMA) drug labels. PGMD curators capture information on exact genomic location and sequence changes, on resulting phenotype, drugs administered, patient population, study design, disease context, statistical significance and other properties of reported pharmacogenomic variants. Variants are annotated into functional categories on the basis of their influence on pharmacokinetics, pharmacodynamics, efficacy or clinical outcome. The current release of PGMD includes over 117 000 unique pharmacogenomic observations, covering all 24 disease superclasses and nearly 1400 drugs. Over 2800 genes have associated pharmacogenomic variants, including genes in proximity to intergenic variants. PGMD is optimized for use in annotating next-generation sequencing data by providing genomic coordinates for all covered variants, including Single Nucleotide Polymorphisms (SNPs), insertions, deletions, haplotypes, diplotypes, Variable Number Tandem Repeats (VNTR), copy number variations and structural variations.

PMID: 25939485 [PubMed - indexed for MEDLINE]

Pharmacogenomics of Prostaglandin and Leukotriene Receptors.

Front Pharmacol. 2016;7:316

Authors: Cornejo-García JA, Perkins JR, Jurado-Escobar R, García-Martín E, Agúndez JA, Viguera E, Pérez-Sánchez N, Blanca-López N

Abstract
Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs), have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs) and leukotrienes (LTs) are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesized through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2); mast cell maturation, eosinophil recruitment, and allergic responses (PTGD2); vascular and respiratory smooth muscle contraction (PTGF2), and inhibition of platelet aggregation (PTGI2). LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs) (LTC4, LTD4, and LTE4) induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic.

PMID: 27708579 [PubMed - in process]

Precision medicine: from pharmacogenomics to pharmacoproteomics.

Clin Proteomics. 2016;13:25

Authors: Chambliss AB, Chan DW

Abstract
Disease progression and drug response may vary significantly from patient to patient. Fortunately, the rapid development of high-throughput 'omics' technologies has allowed for the identification of potential biomarkers that may aid in the understanding of the heterogeneities in disease development and treatment outcomes. However, mechanistic gaps remain when the genome or the proteome are investigated independently in response to drug treatment. In this article, we discuss the current status of pharmacogenomics in precision medicine and highlight the needs for concordant analysis at the proteome and metabolome levels via the more recently-evolved fields of pharmacoproteomics, toxicoproteomics, and pharmacometabolomics. Integrated 'omics' investigations will be critical in piecing together targetable mechanisms of action for both drug development and monitoring of therapy in order to fully apply precision medicine to the clinic.

PMID: 27708556 [PubMed - in process]

Genetic factors affecting patient responses to pancreatic cancer treatment.

Ann Gastroenterol. 2016 Oct-Dec;29(4):466-476

Authors: Fotopoulos G, Syrigos K, Saif MW

Abstract
Cancer of the exocrine pancreas is a malignancy with a high lethal rate. Surgical resection is the only possible curative mode of treatment. Metastatic pancreatic cancer is incurable with modest results from the current treatment options. New genomic information could prove treatment efficacy. An independent review of PubMed and ScienceDirect databases was performed up to March 2016, using combinations of terms such pancreatic exocrine cancer, chemotherapy, genomic profile, pancreatic cancer pharmacogenomics, genomics, molecular pancreatic pathogenesis, and targeted therapy. Recent genetic studies have identified new markers and therapeutic targets. Our current knowledge of pancreatic cancer genetics must be further advanced to elucidate the molecular basis and pathogenesis of the disease, improve the accuracy of diagnosis, and guide tailor-made therapies.

PMID: 27708512 [PubMed - in process]

Cancer Gene Profiling for Response Prediction.

Methods Mol Biol. 2016;1381:163-79

Authors: Ghadimi BM, Jo P

Abstract
The revolution of genomic technologies, including gene expression profiling, high-resolution mapping of genomic imbalances, and next-generation sequencing, allows us to establish molecular portraits of cancer cells with unprecedented accuracy. This generates hope and justifies anticipation that disease diagnosis, prognosis, and the choice of treatment will be adapted to the individual needs of patients based on molecular evidence. Preoperative treatment strategies are now recommended for a variety of human cancers. Unfortunately, the response of individual tumors to a preoperative treatment is not uniform, and ranges from complete regression to resistance. This poses a considerable clinical dilemma, as patients with a priori resistant tumors could either be spared exposure to radiation or DNA-damaging drugs, i.e., could be referred to primary surgery, or dose-intensified protocols could be pursued. Because the response of an individual tumor as well as therapy-induced side effects represent the major limiting factors of current treatment strategies, identifying molecular markers of response or for treatment toxicity has become exceedingly important. However, complex phenotypes such as tumor responsiveness to multimodal treatments probably do not depend on the expression levels of just one or a few genes and proteins. Therefore, methods that allow comprehensive interrogation of genetic pathways and networks hold great promise in delivering such tumor-specific signatures, since expression levels of thousands of genes can be monitored simultaneously. Over the past few years, microarray technology has emerged as a central tool in addressing pertinent clinical questions, the answers to which are critical for the realization of a personalized genomic medicine, in which patients will be treated based on the biology of their tumor and their genetic profile (Quackenbush, N Engl J Med 354:2463-72, 2006; Jensen et al., Curr Opin Oncol 18:374-380, 2006; Bol and Ebner, Pharmacogenomics 7:227-235, 2006; Nevins and Potti, Nat Rev Genet 8:601-609, 2007).

PMID: 26667460 [PubMed - indexed for MEDLINE]

How can we improve on the already impressive results in pediatric ALL?

Hematology Am Soc Hematol Educ Program. 2015;2015:414-9

Authors: Thomas A

Abstract
The past 70 years have seen childhood acute lymphoblastic leukemia move from a fatal disease with a survival of barely 4 months to a curable disease in >85% of patients. It has become clear that as treatment has intensified, more children are cured but at the expense of increased toxicity which for some can cause significant long-term morbidity and even mortality. The drive in more recent years has been to identify sensitive markers of disease and response to treatment to allow a reduction in therapy in those who do not require it and more intensive treatment in those who do. Clinical characteristics have been used to stratify patients into different risk groups and this, coupled with following response at a molecular level, has done much to tailor treatment to the patient. Considerable research has been focused on the molecular characteristics of the leukemia itself to elucidate the biologic mechanisms underlying both the disease and the comparative or absolute resistance of some types of leukemia. These molecular markers can also act as targets for novel therapies, which require newer trial methodologies to prove their utility. There has been less focus on the biology of the patient but it is clear that some patients are more susceptible to adverse events and toxicities than others. Through the use of pharmacogenomics, modification to therapy may be appropriate in certain patients based on their genetic profile. As novel therapies become available, suitable controlled trials in children are essential for their safe use in this population and will ensure that children are not denied timely access to advances in treatment.

PMID: 26637751 [PubMed - indexed for MEDLINE]

Genetic Polymorphisms Analysis of Pharmacogenomic VIP Variants in Miao Ethnic Group of Southwest China.

Med Sci Monit. 2015 Dec 03;21:3769-76

Authors: Jin T, Aikemu A, Zhang M, Geng T, Feng T, Kang L, Luo ML

Abstract
BACKGROUND Genetic polymorphisms have a potential clinical role in determining both inter-individual and inter-ethnic differences in drug efficacy, but we have not found any pharmacogenomics information regarding minorities, such as the Miao ethnic group. Our study aimed to screen numbers of the Miao ethnic group for genotype frequencies of VIP variants and to determine differences between the Miao and other human populations worldwide. MATERIAL AND METHODS In this study, we genotyped 66 Very Important Pharmacogene (VIP) variants selected from PharmGKB in 98 unrelated, healthy Miao individuals from the Guizhou province and compared our data with 12 other populations, including 11 populations from the HapMap data set and Xi'an Han Chinese. RESULTS Using the χ2 test, we found that the allele frequencies of the VDR rs1544410 and VKORC1 (rs9934438) variants in the Miao population are quite different from that in other ethnic groups. Furthermore, we found that genotype frequencies of rs1801133 (MTHFR) in the 13 selected populations are significantly different. Population structure and F-statistics (Fst) analysis show that the genetic background of the Miao is relatively close to that of Chinese in metropolitan Denver, CO, USA (CHD). CONCLUSIONS Our results help complete the information provided by the pharmacogenomics database of the Miao ethnic group and provide a theoretical basis for safer drug administration, which may be useful for diagnosing and treating diseases in this population.

PMID: 26632549 [PubMed - indexed for MEDLINE]

Pharmacogenomics of estrogens on changes in carotid artery intima-medial thickness and coronary arterial calcification: Kronos Early Estrogen Prevention Study.

Physiol Genomics. 2016 Jan;48(1):33-41

Authors: Miller VM, Jenkins GD, Biernacka JM, Heit JA, Huggins GS, Hodis HN, Budoff MJ, Lobo RA, Taylor HS, Manson JE, Black DM, Naftolin F, Harman SM, de Andrade M

Abstract
Prior to the initiation of menopausal hormone treatment (MHT), genetic variations in the innate immunity pathway were found to be associated with carotid artery intima-medial thickness (CIMT) and coronary arterial calcification (CAC) in women (n = 606) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Whether MHT might affect these associations is unknown. The association of treatment outcomes with variation in the same 764 candidate genes was evaluated in the same KEEPS participants 4 yr after randomization to either oral conjugated equine estrogens (0.45 mg/day), transdermal 17β-estradiol (50 μg/day), each with progesterone (200 mg/day) for 12 days each month, or placebo pills and patch. Twenty SNPs within the innate immunity pathway most related with CIMT after 4 yr were not among those associated with CIMT prior to MHT. In 403 women who completed the study in their assigned treatment group, single nucleotide polymorphisms (SNPs) within the innate immunity pathway were found to alter the treatment effect on 4 yr change in CIMT (i.e., significant interaction between treatment and genetic variation in the innate immunity pathway; P < 0.001). No SNPs by treatment effects were observed with changes of CAC >5 Agatston units after 4 yr. Results of this study suggest that hormonal status may interact with genetic variants to influence cardiovascular phenotypes, specifically, the pharmacogenomic effects within the innate immunity pathway for CIMT.

PMID: 26508701 [PubMed - indexed for MEDLINE]