Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a case-control study.

BJOG. 2017 Jan 31;:

Authors: Manuck TA, Watkins WS, Esplin MS, Biggio J, Bukowski R, Parry S, Zhan H, Huang H, Andrews W, Saade G, Sadovsky Y, Reddy UM, Ilekis J, Yandell M, Varner MW, Jorde LB, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR)

Abstract
OBJECTIVE: To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB).
DESIGN: Case-control.
SETTING: Three tertiary-care centres across the USA.
POPULATION: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P.
METHODS: Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P).
MAIN OUTCOME MEASURES: To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID).
RESULTS: Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction).
CONCLUSION: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P.
TWEETABLE ABSTRACT: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.

PMID: 28139890 [PubMed - as supplied by publisher]

Novel genetic variants in carboxylesterase 1 predict severe early-onset capecitabine-related toxicity.

Clin Pharmacol Ther. 2017 Jan 31;:

Authors: Hamzic S, Kummer D, Milesi S, Mueller D, Joerger M, Aebi S, Amstutz U, Largiadèr CR

Abstract
An important concern with the anticancer drug capecitabine (Cp), an oral prodrug of 5-fluorouracil, are dose-limiting adverse effects, in particular hand-foot syndrome (HFS) and diarrhea. Here, we evaluated the association of genetic variability in all enzymes of the Cp-activation pathway to 5-fluorouracil with Cp-related early-onset toxicity in 144 patients receiving Cp. We identified a haplotype encompassing five variants in the carboxylesterase 1 (CES1) gene region including an expression quantitative trait locus (Haplotype A3: ORadditive =2.2, 95%CI 1.2-4.0, Padjusted =0.012; ORrecessive =10.3, 95%CI 2.1-49.4, Padjusted = 0.0038) associated with early-onset Cp-toxicity. Furthermore, the association of two linked cytidine deaminase (CDA) promoter variants (c.1-451C>T: ORdominant =4.3, 95%CI 1.3-14.2, Padjusted =0.017; and c.1-92A>G: ORdominant =4.4, 95%CI 1.3-14.5, Padjusted =0.015) with Cp-related diarrhea was replicated. This first study identifying an association of genetic variation in CES1 with Cp-related toxicity provides further evidence for the existence of a functional noncoding CES1-variant with a possible regulatory impact. This article is protected by copyright. All rights reserved.

PMID: 28139840 [PubMed - as supplied by publisher]

Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy.

Pharmacogenomics J. 2017 Jan 31;:

Authors: Bank S, Andersen PS, Burisch J, Pedersen N, Roug S, Galsgaard J, Turino SY, Brodersen JB, Rashid S, Rasmussen BK, Avlund S, Olesen TB, Hoffmann HJ, Nexø BA, Sode J, Vogel U, Andersen V

Abstract
Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-γ), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.The Pharmacogenomics Journal advance online publication, 31 January 2017; doi:10.1038/tpj.2016.84.

PMID: 28139755 [PubMed - as supplied by publisher]

The CYP2C19*2 and CYP2C19*17 Polymorphisms play a Vital Role in Clopidogrel Responsiveness after Percutaneous Coronary Intervention: A Pharmacogenomics Study.

Basic Clin Pharmacol Toxicol. 2017 Jan 30;:

Authors: Saydam F, Değirmenci İ, Birdane A, Özdemir M, Ulus T, Özbayer C, Çolak E, Ata N, Güneş HV

Abstract
Clopidogrel inhibits platelet activation and aggregation by blocking the P2Y12 receptor. Dual antiplatelet therapy with clopidogrel and aspirin is recommended treatment by current guidelines for patients undergoing percutaneous interventions. Recurrent ischaemic cardiac events after this treatment showed lack of clopidogrel responsiveness. We aimed to investigate the most noticeable variants in the genes involved in clopidogrel pharmacokinetics and pharmacodynamics. 347 Turkish patients who underwent percutaneous coronary interventions with stent implantation were included in our study. Platelet reactivity (PRU) and % inhibition were measured with VerifyNow P2Y12 assay in blood samples collected from patients who took a standard dose of clopidogrel (75 mg/day) for at least 7 days. The variants in the CYP2C19, CYP3A4, CYP2B6, ABCB1, ITGB3 and PON1 genes were genotyped using the Sequenom MassARRAY system. When grouped, the patients with PRU values >208 as non-responsiveness to clopidogrel therapy; 104 (30%) patients were non-responders and 243 (70%) patients were responders. A significant association was found between the CYP2C19*2 (G636A) polymorphism and non-responsiveness to clopidogrel therapy (P<0.001). An allele frequency of this single nucleotide polymorphism was high in non-responders; its odds ratio was 2.92 compared to G allele (P<0.001). PRU values of CT genotypes were lower (P=0.029) and % inhibition values of CT genotypes were higher (P=0.008) compared to CC genotypes for the CYP2C19*17 (C806T) polymorphism. None of the other genetic variants were found to be statistically associated with non-responsiveness to clopidogrel and antiplatelet activity. Our findings suggest that the CYP2C19*2 polymorphism is associated with non-responsiveness to clopidogrel therapy and the CYP2C19*17 polymorphism enhances antiplatelet activity of clopidogrel. Depending on haplotypes of these two polymorphisms, clopidogrel-treated patients can be protected or not from stent thrombosis and ischaemic events. This article is protected by copyright. All rights reserved.

PMID: 28135763 [PubMed - as supplied by publisher]

Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans.

J Thromb Haemost. 2017 Jan 30;:

Authors: Hernandez W, Gamazon ER, Aquino-Michaels K, Smithberger E, O'Brien TJ, Harralson AF, Tuck M, Barbour A, Cavallari LH, Perera MA

Abstract
BACKGROUND: Warfarin is commonly used to control and prevent thromboembolic disorders. However, due to warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs).
OBJECTIVES: We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs.
PATIENTS/METHODS: We identified a total of 56 eQTLs for CYP2C9, VKORC1, and CALU derived from human livers and evaluated their association to warfarin dose response in two independent AA warfarin patient cohorts.
RESULTS: We found rs4889606, a strong cis-eQTL for VKORC1 (log10 Bayes Factor = 12.02), is significantly associated with increased warfarin dose requirement (p = 8.18x10(-6) ) in the Discovery Cohort (N=305) and in the Replication Cohort (p = 0.01; N = 141) even after conditioning on VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes, and clinical variables explained 31% of the interpatient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and Europe Americans which may explain the increased dose requirement found in AAs.
CONCLUSION: Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research. This article is protected by copyright. All rights reserved.

PMID: 28135054 [PubMed - as supplied by publisher]

Modeling diseases in multiple mouse strains for precision medicine studies.

Physiol Genomics. 2017 Jan 27;:physiolgenomics.00123.2016

Authors: Klein AD

Abstract
The genetic basis of the phenotypic variability observed in patients can be studied in mice by generating disease models through genetic or chemical interventions in many genetic backgrounds where the clinical phenotypes can be assessed and used for Genome-Wide Association Studies (GWAS). This is particularly relevant for rare disorders, where patients sharing identical mutations can present with a wide variety of symptoms, but there are not enough number of patients to ensure statistical power of GWAS. Inbred strains are homozygous for each loci and their Single Nucleotide Polymorphisms (SNPs) catalogues are known and freely available, facilitating the bioinformatics and reducing the costs of the study since it is not required to genotype every mouse. This kind of approach can be applied for pharmacogenomics studies as well.

PMID: 28130429 [PubMed - as supplied by publisher]

Improving medicines use for children: A global imperative.

Clin Pharmacol Ther. 2017 Jan 27;:

Authors: MacLeod SM

PMID: 28127760 [PubMed - as supplied by publisher]

Machine learning and systems genomics approaches for multi-omics data.

Biomark Res. 2017;5:2

Authors: Lin E, Lane HY

Abstract
In light of recent advances in biomedical computing, big data science, and precision medicine, there is a mammoth demand for establishing algorithms in machine learning and systems genomics (MLSG), together with multi-omics data, to weigh probable phenotype-genotype relationships. Software frameworks in MLSG are extensively employed to analyze hundreds of thousands of multi-omics data by high-throughput technologies. In this study, we reviewed the MLSG software frameworks and future directions with respect to multi-omics data analysis and integration. Our review was targeted at researching recent approaches and technical solutions for the MLSG software frameworks using multi-omics platforms.

PMID: 28127429 [PubMed]

CETP: Pharmacogenomics-Based Response to the CETP Inhibitor Dalcetrapib.

Arterioscler Thromb Vasc Biol. 2017 Jan 26;:

Authors: Tardif JC, Rhainds D, Rhéaume E, Dubé MP

Abstract
High-density lipoproteins are involved in reverse cholesterol transport and possess anti-inflammatory and antioxidative properties. Paradoxically, CETP inhibitors have been shown to increase inflammation as revealed by a raised plasma level of high-sensitivity C-reactive protein. CETP inhibitors did not improve clinical outcomes in large-scale clinical trials of unselected patients with coronary disease. Dalcetrapib is a CETP modulator in which effects on cardiovascular outcomes were demonstrated in the dal-OUTCOMES trial to be influenced by correlated polymorphisms in the ADCY9 (adenylate cyclase 9) gene (P=2.4×10(-)(8) for rs1967309). Patients with the AA genotype at rs1967309 had a relative reduction of 39% in the risk of presenting a cardiovascular event when treated with dalcetrapib compared with placebo (confidence interval, 0.41-0.92). In contrast, patients with the GG genotype had a 27% increase in risk, whereas heterozygotes (AG) presented a neutral result. Supporting evidence from the dal-PLAQUE-2 study using carotid ultrasonography revealed that the polymorphisms tested in the ADCY9 linkage disequilibrium block were associated with disease regression for patients with the protective genotype, progression for the harmful genotype, and no effect in heterozygotes (P≤0.05 and ≤0.01 for 10 and 3 polymorphisms, respectively) when comparing dalcetrapib to placebo. Strikingly concordant and significant genotype-dependent effects of dalcetrapib were also obtained for changes in high-sensitivity C-reactive protein and cholesterol efflux. The Dal-GenE randomized trial is currently being conducted in patients with a recent acute coronary syndrome bearing the AA genotype at rs1967309 in the ADCY9 gene to confirm the effects of dalcetrapib on hard cardiovascular outcomes.

PMID: 28126828 [PubMed - as supplied by publisher]

Genetic polymorphisms as predictive biomarker of survival in patients with gastrointestinal stromal tumors treated with sunitinib.

Pharmacogenomics J. 2017 Jan 24;:

Authors: Kloth JS, Verboom MC, Swen JJ, van der Straaten T, Sleijfer S, Reyners AK, Steeghs N, Gelderblom H, Guchelaar HJ, Mathijssen RH

Abstract
This study aimed to identify single-nucleotide polymorphisms (SNPs) that are associated with outcome to treatment with sunitinib in patients with advanced gastrointestinal stromal tumors (GIST). Forty-nine SNPS involved in the pharmacokinetic and pharmacodynamic pathway of sunitinib were associated with progression-free survival (PFS) and overall survival (OS) in 127 patients with advanced GIST who have been treated with sunitinib. PFS was significantly longer in carriers of the TT genotype in POR rs1056878 (hazards ratio (HR) 4.310, 95% confidence interval (CI):1.457-12.746, P=0.008). The presence of the T-allele in SLCO1B3 rs4149117 (HR 2.024, 95% CI:1.013-4.044, P=0.046), the CCC-CCC alleles in SLC22A5 haplotype (HR 2.603, 95% CI: 1.216-5.573, P=0.014), and the GC-GC alleles in the IL4 R haplotype (HR 7.131, 95% CI:1.518-33.496, P=0.013) were predictive for OS. This shows that polymorphisms in the pharmacokinetic and pharmacodynamic pathways of sunitinib are associated with survival in GIST. This may help to identify patients that benefit more from treatment with sunitinib.The Pharmacogenomics Journal advance online publication, 24 January 2017; doi:10.1038/tpj.2016.83.

PMID: 28117434 [PubMed - as supplied by publisher]

Cost-effectiveness of cytochrome P450 2C19 *2 genotype-guided selection of clopidogrel or ticagrelor in Chinese patients with acute coronary syndrome.

Pharmacogenomics J. 2017 Jan 24;:

Authors: Wang Y, Yan BP, Liew D, Lee VW

Abstract
The choice of antiplatelet therapy among Asian populations for the treatment of acute coronary syndrome (ACS) is complicated owing to the high prevalence of cytochrome P450 2C19 (CYP2C19) genetic polymorphism that has been associated with reduced efficacy of clopidogrel. Ticagrelor is a potent but more expensive alternative antiplatelet agent that is not affected by CYP2C19 polymorphism. This study aimed to evaluate the cost-effectiveness, from the Hong Kong health-care provider's perspective, of CYP2C19*2 genotype-guided selection of antiplatelet therapy compared with the universal use of clopidogrel or ticagrelor among ACS patients who undergo percutaneous coronary intervention (PCI). In the present study, a two-part model consisting of a 1-year decision tree and a lifetime Markov model was built to simulate the progress of a typical cohort of 60-year-old Chinese patients until age 85 years and compare three treatment strategies: (i) generic clopidogrel or ticagrelor based on CYP2C19*2 genotype, (ii) universal use of generic clopidogrel or (iii) universal use of ticagrelor for all patients. Incremental cost-effectiveness ratios (ICERs) of <1 gross domestic product per capita locally (US dollar (USD)42 423/quality-adjusted life year (QALY)) were considered cost-effective. Base-case results showed universal ticagrelor use was cost-effective compared with universal clopidogrel, but was dominated by genotype-guided treatment. Genotype-guided treatment was cost-effective compared with universal clopidogrel use (ICER of USD2560/QALY). Sensitivity analysis demonstrated that with the cost of genotype testing up to USD400, CYP2C19*2 genotype-guided antiplatelet treatment remained a cost-effective strategy compared with either universal use of generic clopidogrel or ticagrelor in post-PCI ACS patients in Hong Kong.The Pharmacogenomics Journal advance online publication, 24 January 2017; doi:10.1038/tpj.2016.94.

PMID: 28117433 [PubMed - as supplied by publisher]

Pharmacogenomic challenges in cardiovascular diseases: examples of drugs and considerations for future integration in clinical practice.

Curr Pharm Biotechnol. 2017 Jan 23;

Authors: Chatelin J, Stathopoulou MG, Arguinano AA, Xie T, Visvikis-Siest S

Abstract
Introduction Even if cardiovascular disease (CVD) drugs are supported by high level proofs, the results of CVD treatment present great disparities: there are still patients dying with supposed optimal treatment, patients facing adverse events and CVD remain the primary cause of death in the world. Pharmacogenomics is the basis of personalisation of the treatment able to allow higher medication success rates. In this review, we will present detailed examples of CVD drugs to highlight the complexity of this challenging field and we will discuss novel concepts that should be considered for a fastest integration of pharmacogenomics in clinical practice of CVD. Areas covered The complexity of pharmacogenetics and pharmacogenomics of CVD drugs are presented though examples of medications such as statins, with a focus on their effectiveness and adverse effects. Expert opinion The application of personalised medicine in the CVD medical practice requires the study of human genome in regards to drugs pharmacokinetics, pharmacodynamics, interactions and tolerance profile. The existing state -of-the-art of CVD drugs gives hopes for a future revolution in the drug development that will maximise cardiovascular patients benefit while decreasing their risks for adverse effects. Article Highlights box Coronary heart disease (CHD) remains the first cause of death worldwide • Cardiovascular treatment has a significant percentage of insufficient efficacy, poor tolerance and compliance • Predicting the response to therapy while diminishing the side effects is the basis of personalised medicine; pharmacogenomics is leading towards this direction • The response to CVD therapy and side effects are in the heart of CVD pharmacogenomics and significant progress has been noted. • The application of pharmacogenomics in the CVD medical practice is facing many methodological, technical, ethical, behavioral and financial issues, while cost-effectiveness is the main prerequisite. • The consideration of gene × gene × environment interactions and the inclusion of "omics" data in pharmacogenomic studies of CVD drugs will facilitate the generation of reliable results and will promote tailored treatments and new strategies of drug research and development.

PMID: 28117005 [PubMed - as supplied by publisher]

Genetic HLA Study of Kurds in Iraq, Iran and Tbilisi (Caucasus, Georgia): Relatedness and Medical Implications.

PLoS One. 2017;12(1):e0169929

Authors: Arnaiz-Villena A, Palacio-Grüber J, Muñiz E, Campos C, Alonso-Rubio J, Gomez-Casado E, Salih SF, Martin-Villa M, Al-Qadi R

Abstract
Kurds from Iraq (Dohuk and Erbil Area, North Iraq) have been analyzed for HLA genes. Their HLA genetic profile has been compared with that of other Kurd groups from Iran and Tbilisi (Georgia, Caucasus) and also Worldwide populations. A total of 7,746 HLA chromosomes have been used. Genetic distances, NJ dendrograms and correspondence analyses have been carried out. Haplotype HLA-B*52-DRB1*15 is present in all three analyzed Kurd populations. HLA-A*02-B*51-DRB1*11 is present in Iraq and Georgia Kurds. Haplotypes common to Iran and Iraq Kurds are HLA DRB1*11-DQB1*03, HLA DRB1*03-DQB1*02 and others in a lower frequency. Our HLA study conclusions are that Kurds most probably belong to an ancient Mediterranean / Middle East / Caucasian genetic substratum and that present results and those previously obtained by us in Kurds may be useful for Medicine in future Kurd transplantation programs, HLA Epidemiology (HLA linked diseases) and Pharmacogenomics (HLA-associated drug side effects) and also for Anthropology. It is discussed that one of the most ancient Kurd ancestor groups is in Hurrians (2,000 years BC).

PMID: 28114347 [PubMed - in process]

Pharmacogenomics testing in a community pharmacy: patient perceptions and willingness-to-pay.

Pharmacogenomics. 2017 Jan 23;:

Authors: Gibson ML, Hohmeier KC, Smith CT

Abstract
AIM: To determine patient knowledge, interest and willingness-to-pay for pharmacogenomics testing in a community pharmacy.
PATIENTS & METHODS: The link to a cross-sectional, anonymous online survey was distributed to a convenience sample of patients. The contingent valuation method was used to assess willingness-to-pay.
RESULTS: Twenty seven surveys were completed. Eighty one percent of patients were interested in the service, but patients felt that they would be more likely to use the service if insurance covered the cost.
CONCLUSION: Patients indicated interest in a pharmacogenomics test, but varying levels of willingness-to-pay. Patients may not be able to connect the benefits of testing to their health, justifying further patient education in order to increase the viability of pharmacogenomics testing as a pharmacy service.

PMID: 28112585 [PubMed - as supplied by publisher]

Implementing Genomic Clinical Decision Support for Drug-Based Precision Medicine.

CPT Pharmacometrics Syst Pharmacol. 2017 Jan 20;:

Authors: Freimuth RR, Formea CM, Hoffman JM, Matey E, Peterson JF, Boyce RD

PMID: 28109071 [PubMed - as supplied by publisher]

Apply Resources to Practice: Use Current Genetics and Genomics Content in Oncology.

Clin J Oncol Nurs. 2017 Feb 01;21(1):34-38

Authors: Mahon SM

Abstract
Genetic and genomic science directly affects oncology nursing care. Many resources are available to enable oncology nurses to better understand and deliver competent genomic care to patients and families. This article relays resources for germline genetic testing, tumor profiling, pharmacogenomics, and nursing education.

PMID: 28107338 [PubMed - in process]

Tissue is the issue and tissue competition. Re-biopsy for mutation T790: where and why?

Clin Transl Med. 2017 Dec;6(1):6

Authors: Zarogoulidis P, Gaga M, Huang H, Darwiche K, Rapti A, Hohenforst-Schmidt W

Abstract
Lung cancer is still the leading cause of death among all cancers. During the last 15 years, pharmacogenomics of lung cancer have established targeted therapy with tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR) positive patients in adenocarcinoma or mixed adenosquamus lung cancer patients. However; while novel drugs are released in the market, at the same time novel mutations are observed after tyrosine kinase inhibitor administration. Recently the novel mutation T790 was observed and is highly prevalent in patients already treated with a TKI. A new drug targeting this mutation is already on the market, however; the most important factor for successful treatment in these patients, is adequate tissue re-sampling so that novel mutations can be detected.

PMID: 28101783 [PubMed - in process]

Addressing the Crisis in the Treatment of Osteoporosis: A Path Forward.

J Bone Miner Res. 2016 Dec 29;:

Authors: Khosla S, Cauley JA, Compston J, Kiel DP, Rosen C, Saag KG, Shane E

Abstract
Considerable data and media attention have highlighted a potential "crisis" in the treatment of osteoporosis. Specifically, despite the availability of several effective drugs to prevent fractures, many patients who need pharmacological therapy are either not being prescribed these medications or if prescribed a medication, are simply not taking it. Although there are many reasons for this "gap" in the treatment of osteoporosis, a major factor is physician and patient concerns over the risk of side effects, especially atypical femur fractures (AFFs) related to bisphosphonate (and perhaps other antiresorptive) drug therapy. In this perspective, we review the current state of undertreatment of patients at increased fracture risk and suggest possible short-, intermediate-, and long-term approaches to address patient concerns, specifically those related to AFF risk. We suggest improved patient and physician education on prodromal symptoms, extended femur scans using dual-energy X-ray absorptiometry (DXA) to monitor patients on antiresorptive treatment, better identification of high-risk patients perhaps using geometrical parameters from DXA and other risk factors, and more research on pharmacogenomics to identify risk markers. Although not the only impediment to appropriate treatment of osteoporosis, concern over AFFs remains a major issue and one that needs to be resolved for effective dissemination of existing treatments to reduce fracture risk. © 2017 American Society for Bone and Mineral Research.

PMID: 28099754 [PubMed - as supplied by publisher]

A landscape of synthetic viable interactions in cancer.

Brief Bioinform. 2017 Jan 17;:

Authors: Gu Y, Wang R, Han Y, Zhou W, Zhao Z, Chen T, Zhang Y, Peng F, Liang H, Qi L, Zhao W, Yang D, Guo Z

Abstract
Synthetic viability, which is defined as the combination of gene alterations that can rescue the lethal effects of a single gene alteration, may represent a mechanism by which cancer cells resist targeted drugs. Approaches to detect synthetic viable (SV) interactions in cancer genome to investigate drug resistance are still scarce. Here, we present a computational method to detect synthetic viability-induced drug resistance (SVDR) by integrating the multidimensional data sets, including copy number alteration, whole-exome mutation, expression profile and clinical data. SVDR comprehensively characterized the landscape of SV interactions across 8580 tumors in 32 cancer types by integrating The Cancer Genome Atlas data, small hairpin RNA-based functional experimental data and yeast genetic interaction data. We revealed that the SV interactions are favorable to cells and can predict clinical prognosis for cancer patients, which were robustly observed in an independent data set. By integrating the cancer pharmacogenomics data sets from Cancer Cell Line Encyclopedia (CCLE) and Broad Cancer Therapeutics Response Portal, we have demonstrated that SVDR enables drug resistance prediction and exhibits high reliability between two databases. To our knowledge, SVDR is the first genome-scale data-driven approach for the identification of SV interactions related to drug resistance in cancer cells. This data-driven approach lays the foundation for identifying the genomic markers to predict drug resistance and successfully infers the potential drug combination for anti-cancer therapy.

PMID: 28096076 [PubMed - as supplied by publisher]

Weight of ABCB1 and POR genes on oral tacrolimus exposure in CYP3A5 nonexpressor pediatric patients with stable kidney transplant.

Pharmacogenomics J. 2017 Jan 17;:

Authors: Almeida-Paulo GN, Dapía García I, Lubomirov R, Borobia AM, Alonso-Sánchez NL, Espinosa L, Carcas-Sansuán AJ

Abstract
Tacrolimus (TAC) is highly effective for the prevention of acute organ rejection. However, its clinical use may be challenging due to its large interindividual pharmacokinetic variability, which can be partially explained by genetic variations in TAC-metabolizing enzymes and transporters. The aim of this study was to evaluate the influence of genetic and clinical factors on TAC pharmacokinetic variability in 21 stable pediatric renal transplant patients. This study was nested in a previous Prograf to Advagraf conversion clinical trial. CYP3A5, ABCB1 and two POR genotypes were assessed by real-time PCR. The impact on TAC pharmacokinetics of individual genetic variants on CYP3A5 nonexpressors was evaluated by genetic score. Explicative models for TAC AUC0-24h, Cmax and Cmin after Advagraf were developed by linear regression. The built genetic scores explain 13.7 and 26.5% of the total AUC0-24h and Cmin total variability, respectively. Patients genetic information should be considered to monitorizate and predict TAC exposure.The Pharmacogenomics Journal advance online publication, 17 January 2017; doi:10.1038/tpj.2016.93.

PMID: 28094348 [PubMed - as supplied by publisher]