Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury.

Curr Pharmacol Rep. 2018 Jun;4(3):171-181

Authors: Bao Y, Ma X, Rasmussen TP, Zhong XB

Abstract
Purpose of this Review: In order to combat the development of drug resistance, the clinical treatment of tuberculosis requires the combined use of several anti-tuberculosis (anti-TB) drugs, including isoniazid and rifampicin. Combinational treatment approaches are suggested by the World Health Organization (WHO) and are widely accepted throughout the world. Unfortunately, a major side effect of the treatment is the development of anti-tuberculosis drug-induced liver injury (AT-DILI). Many factors contribute to isoniazid- and rifampicin-mediated AT-DILI and genetic variations are among the most common factors. The purpose of this review is to provide information on genetic variations associated with isoniazid- and rifampicin-mediated AT-DILI.
Recent Findings: The genetic variations associated with AT-DILI have been identified in the genomic regions within or near genes encoding proteins in the following pathways: drug metabolizing enzymes (NAT2, CYP2E1, and GSTs), accumulation of bile acids, lipids, and heme metabolites (CYP7A1, BSEP, UGTs, and PXR), immune adaptation (HLAs and TNF-α), and oxidant challenge (TXNRD1, SOD1, BACH1, and MAFK).
Summary: The information summarized in this review considers the genetic bases of risk factors contributing to AT-DILI and provides information that may help for future studies. Some of the implicated genetic variations can be used in the design of genetic tests and serve as biomarkers for the prediction of isoniazid- and rifampicin-mediated AT-DILI risk in personalized medicine.

PMID: 30464886 [PubMed]

Association study between COMT, DRD2, and DRD3 gene variants and antipsychotic treatment response in Mexican patients with schizophrenia.

Neuropsychiatr Dis Treat. 2018;14:2981-2987

Authors: Escamilla R, Camarena B, Saracco-Alvarez R, Fresán A, Hernández S, Aguilar-García A

Abstract
Purpose: The efficacy of schizophrenia treatments using antipsychotics (APs) has long been established, but the benefit obtained by several patients using conventional APs (typical or atypical) has not been enough. Currently, the genetic study of the primary mechanisms of action of the APs has been focused on the dopaminergic pathways. The objective of this study was to determine if the response phenotypes (responder, resistance to treatment, and ultra-resistance to treatment groups) are associated with six single-nucleotide polymorphisms: COMT (Val158Met), DRD2 (A-241G, C376G, C939T, Taq1A), and DRD3 (Ser9Gly).
Patients and methods: We classified the patients through a retrospective/prospective methodology to define response phenotypes.
Results: COMT/Val158Met and DRD3/Ser9Gly were associated with the responder group (P<0.05). The single-nucleotide polymorphism A-241G of DRD2 gene was related with the resistant-to-treatment group (P<0.001). Finally, Met/Met of COMT and Ser/Gly of DRD3 genes showed a predictive effect associated with the resistant-to-treatment phenotype.
Conclusion: Further analyses should be performed to validate these genetic markers as mediators for the response to APs.

PMID: 30464483 [PubMed]

Cost-effectiveness of panel tests for multiple pharmacogenes associated with adverse drug reactions: An evaluation framework.

Clin Pharmacol Ther. 2018 Nov 22;:

Authors: Plumpton CO, Pirmohamed M, Hughes DA

Abstract
The cost-effectiveness of testing for multiple genes implicated in adverse drug reactions requires the simultaneous assessment of all actionable information, including future prescribing decisions based on incidental findings. We developed methodology for determining the value of pharmacogenetic panel tests, illustrated with a multi-gene panel including HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, HLA-B*58:01, HLA-B (158T) and HLA-DQB1 (126Q). If the findings for all alleles are acted upon, regardless of their individual cost-effectiveness, the HLA panel resulted in cost savings of £378 (US$491), and a QALY gain of 0.0069. Based on a stratified analysis and compared with no testing, initial use of the panel was cost-effective in patients eligible for abacavir (HLA-B*57:01), carbamazepine (HLA-A*31:01) and clozapine (HLA-B (158T) and HLA-DQB1 (126Q)) but not for carbamazepine (HLA-B*15:02) or allopurinol (HLA-B*58:01). The methods presented allow for the assessment of the cost-effectiveness of multiple-gene panels. This article is protected by copyright. All rights reserved.

PMID: 30466189 [PubMed - as supplied by publisher]

Pharmacogenetics of treatments for inflammatory bowel disease.

Expert Opin Drug Metab Toxicol. 2018 Nov 22;:

Authors: Lucafò M, Franca R, Selvestrel D, Curci D, Pugnetti L, Decorti G, Stocco G

Abstract
INTRODUCTION: Inflammatory bowel diseases is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.

PMID: 30465611 [PubMed - as supplied by publisher]

Paediatric anthracycline-induced cardiotoxicity: mechanisms, pharmacogenomics and pluripotent stem cell modelling.

Clin Pharmacol Ther. 2018 Nov 21;:

Authors: Tripaydonis A, Conyers R, Elliott DA

Abstract
Anthracycline-induced cardiotoxicity (ACT) is a severe adverse drug reaction for a subset of children treated with anthracyclines as part of chemotherapy protocols. The identification of genetic markers associated with increased ACT susceptibility has clinical significance towards improving patient care and our understanding of the molecular mechanisms involved in ACT. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) represent a novel approach to determine the pharmacogenomics of ACT and guide the development of genetic screening tests. This article is protected by copyright. All rights reserved.

PMID: 30460992 [PubMed - as supplied by publisher]

The c-MYC/NAMPT/SIRT1 feedback loop is activated in early classical and serrated route colorectal cancer and represents a therapeutic target.

Med Oncol. 2018 Nov 20;36(1):5

Authors: Brandl L, Kirstein N, Neumann J, Sendelhofert A, Vieth M, Kirchner T, Menssen A

Abstract
We have recently identified a positive feedback loop in which c-MYC increases silent information regulator 1 (SIRT1) protein level and activity through transcriptional activation of nicotinamide phosphoribosyltransferase (NAMPT) and NAD+ increase. Here, we determined the relevance of the c-MYC-NAMPT-SIRT1 feedback loop, including the SIRT1 inhibitor deleted in breast cancer 1 (DBC1), for the development of conventional and serrated colorectal adenomas. Immunohistochemical analyses of 104 conventional adenomas with low- and high-grade dysplasia and of 157 serrated lesions revealed that elevated expression of c-MYC, NAMPT, and SIRT1 characterized all conventional and serrated adenomas, whereas DBC1 was not differentially regulated. Analyzing publicly available pharmacogenomic databases from 43 colorectal cancer cell lines demonstrated that responsiveness towards a NAMPT inhibitor was significantly associated with alterations in PTEN and TGFBR2, while features such as BRAF or RNF43 alterations, or microsatellite instability typical for serrated route colorectal cancer, showed increased sensitivities for inhibition of NAMPT and SIRT1. Our findings suggest an activation of the c-MYC-NAMPT-SIRT1 feedback loop that may crucially contribute to initiation and development of both routes to colorectal cancer. Targeting of NAMPT or SIRT1 may represent novel therapeutic strategies with putative higher sensitivity of the serrated route colorectal cancer subtype.

PMID: 30460421 [PubMed - in process]

CYP genetic variants and toxicity related to anti-tubercular agents: a systematic review and meta-analysis.

Syst Rev. 2018 Nov 20;7(1):204

Authors: Richardson M, Kirkham J, Dwan K, Sloan DJ, Davies G, Jorgensen AL

Abstract
BACKGROUND: Treatment with anti-tuberculosis drugs may cause patients to experience serious adverse effects. Genetic factors, such as polymorphisms of CYP genes, may increase the likelihood of a patient experiencing such adverse drug reactions. In this systematic review and meta-analysis, we synthesised evidence for associations between CYP genetic variants and anti-tuberculosis drug-related toxicity outcomes.
METHODS: We searched MEDLINE, PubMed, EMBASE, BIOSIS and Web of Science to identify relevant studies. We performed meta-analyses to obtain an effect estimate for each genetic variant on each outcome, and stratified all analyses by country. We qualitatively assessed the methodological quality of the included studies.
RESULTS: We included data from 28 distinct cohorts of patients in the review. We identified many areas of concern with regard to the quality of included studies. Patients with homozygous mutant-type or heterozygous genotype at the CYP2E1 RsaI polymorphism were significantly less likely to experience hepatotoxicity than patients with homozygous wild-type genotype (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.56-1.00; p = 0.047, I2 = 58.2%). No significant differences were observed for the CYP2E1 DraI and PstI polymorphisms. For the 96-bp deletion-insertion single-nucleotide polymorphism (SNP) of the CYP2E1 gene, homozygous mutant-type significantly increased hepatotoxicity risk compared with homozygous wild-type (OR = 8.20, 95% CI 1.38-48.68, I2 = 0%); no significant difference was observed for heterozygous genotype compared with homozygous wild-type (OR = 0.77, 95% CI 0.19-3.21, I2 = 0%).
CONCLUSIONS: Generally, we identified that coverage of the association between SNPs of CYP genes and anti-tuberculosis drug-related toxicity outcomes is incomplete. We observed significant associations between the RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 gene and anti-tuberculosis drug-related hepatotoxicity. We were unable to comment on the impact of ethnicity on the investigated associations, as information on participants' ethnicity was sparsely reported in the included studies.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42017068448.

PMID: 30458875 [PubMed - in process]

Pipeline design to identify key features and classify the chemotherapy response on lung cancer patients using large-scale genetic data.

BMC Syst Biol. 2018 Nov 20;12(Suppl 5):97

Authors: Valdés MG, Galván-Femenía I, Ripoll VR, Duran X, Yokota J, Gavaldà R, Rafael-Palou X, de Cid R

Abstract
BACKGROUND: During the last decade, the interest to apply machine learning algorithms to genomic data has increased in many bioinformatics applications. Analyzing this type of data entails difficulties for managing high-dimensional data, class imbalance for knowledge extraction, identifying important features and classifying individuals. In this study, we propose a general framework to tackle these challenges with different machine learning algorithms and techniques. We apply the configuration of this framework on lung cancer patients, identifying genetic signatures for classifying response to drug treatment response. We intersect these relevant SNPs with the GWAS Catalog of the National Human Genome Research Institute and explore the Regulomedb, GTEx databases for functional analysis purposes.
RESULTS: The machine learning based solution proposed in this study is a scalable and flexible alternative to the classical uni-variate regression approach to analyze large-scale data. From 36 experiments executed using the machine learning framework design, we obtain good classification performance from the top 5 models with the highest cross-validation score and the smallest standard deviation. One thousand two hundred twenty four SNPs corresponding to the key features from the top 20 models (cross validation F1 mean >= 0.65) were compared with the GWAS Catalog finding no intersection with genome-wide significant reported hits. From these, new genetic signatures in MAE, CEP104, PRKCZ and ADRB2 show relevant biological regulatory functionality related to lung physiology.
CONCLUSIONS: We have defined a machine learning framework using data with an unbalanced large data-set of SNP-arrays and imputed genotyping data from a pharmacogenomics study in lung cancer patients subjected to first-line platinum-based treatment. This approach found genome signals with no genome-wide significance in the uni-variate regression approach (GWAS Catalog) that are valuable for classifying patients, only few of them with related biological function. The effect results of these variants can be explained by the recently proposed omnigenic model hypothesis, which states that complex traits can be influenced mostly by genes outside not only by the "core genes", mainly found by the genome-wide significant SNPs, but also by the rest of genes outside of the "core pathways" with apparent unrelated biological functionality.

PMID: 30458782 [PubMed - in process]

Fecal metabolomic dataset of American ginseng-treated DSS mice: Correlation between ginseng enteric inflammation inhibition and its biological signatures.

Data Brief. 2018 Dec;21:1403-1408

Authors: Wang CZ, Zhang CF, Zhang QH, Hesse-Fong J, Lager M, Du W, Xu M, Yuan CS

Abstract
Although anti-inflammatory effects of American ginseng metabolites have been investigated at systemic and cellular levels, the biological signatures of ginseng microbial metabolite-induced bioactivities are still unknown. To fill this knowledge gap and to support the findings published in the companion research article entitled "American ginseng microbial metabolites attenuated DSS-induced colitis and abdominal pain" (Wang et al., 2018), we are here to provide datasets of enteric microbiome biotransformation and fecal metabolomics. For the microbiome biotransformation study, data were obtained from C57BL6 mice treated with a broad-spectrum antibiotic metronidazole. After oral administration of ginseng extract, we observed that compound K (CK) was undetectable in metronidazole-treated mouse stools but was detected in stools from vehicle-treated mice, suggesting biotransformation of CK is gut microbial dependent. In the fecal metabolomic study, three small molecules which were associated with gut inflammation were identified. In the DSS mice, the levels of lactate, linoleic acid, and malic acid increased significantly in the model group. After ginseng treatment, the expressions of these metabolites reduced significantly. Thus, the selective fecal endogenous metabolites could be used as biological signatures reflecting severity of enteric inflammation and ginseng treatment outcomes. Our results showed the enteric microbiome plays a key role for CK conversion, and the effects of CK on enteric inflammation can be demonstrated by the metabolomics data.

PMID: 30456264 [PubMed]

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study.

Thromb J. 2018;16:28

Authors: Sennesael AL, Larock AS, Douxfils J, Elens L, Stillemans G, Wiesen M, Taubert M, Dogné JM, Spinewine A, Mullier F

Abstract
Background: Serious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.
Methods: This analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected.
Results: Rivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP).
Conclusions: Rivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.

PMID: 30455596 [PubMed]

Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence.

BMC Genomics. 2018 Nov 20;19(1):826

Authors: Lee SH, Ahn WY, Seweryn M, Sadee W

Abstract
BACKGROUND: The CHRNA5/A3/B4 gene locus is associated with nicotine dependence and other smoking related disorders. While the non-synonymous CHRNA5 variant rs16969968 appears to be the main risk factor, linkage disequilibrium (LD) bins in the gene cluster carry frequent variants that regulate expression. Pairwise LD and haplotype analyses had identified at least three haplotype tagging SNPs including rs16969968 as main genetic risk factors. Searching for variants with evidence of regulatory functions, we have reported interactions between CHRNA5 and CHRNA3 enhancer variants (tagged by rs880395 and rs1948, respectively) and rs16969968, forming 3-SNP haplotypes and diplotypes that may more accurately reflect the cluster's combined effects on nicotine dependence (Barrie et al., Hum Mutat 38:112-9, 2017). Here we address further contributions by variants affecting CHRNB4, a possibly limiting component of nicotinic receptors.
RESULTS: We identify an LD bin (tagged by rs4887074) associated with expression of CHRNB4. Additive logistic regression models indicate that rs4887074 is associated with nicotine dependence and modulates the effect of rs16969968 in GWAS datasets (COGEND, UW-TTURC, SAGE). 4-SNP haplotype and diplotype analyses (rs880395-rs16969968-rs1948 -rs4887074) yield nicotine dependence risk values that further differentiate those obtained with the 3-SNP model. Moreover, both the main G allele of rs16969968 and the minor G allele of rs4887074 (associated with reduced expression of CHRNB4), residing predominantly on common haplotypes that are protective, represent significant allele-specific variance QTLs, indicating that they interact with each other.
CONCLUSIONS: These results indicate rs4887074 is associated with CHRNB4 expression, and along with two regulatory variants of CHRNA3 and CHRNA5, modulates the effect of rs16969968 on nicotine dependence risk. Assignable to individuals because of strong LD structures, 4-SNP haplotypes and diplotypes serve to assess the combined genetic influence of this multi-gene cluster on complex traits, accounting for complex LD relationships and tissue-specific genetic effects (CHRNA5/3) relevant to the traits analyzed. The 4-SNP haplotypes account at least in part for previous tagging SNPs, including the highly GWAS-significant rs6495308, located in a distinct pair-wise LD bin but included in protective 4-SNP haplotypes. Our approach refines and integrates the cluster's overall genetic influence, an important variable when integrating the genetics of multiple genomic loci.

PMID: 30453884 [PubMed - in process]

Pooled genome-wide CRISPR screening for basal and context-specific fitness gene essentiality in Drosophila cells.

Elife. 2018 07 27;7:

Authors: Viswanatha R, Li Z, Hu Y, Perrimon N

Abstract
Genome-wide screens in Drosophila cells have offered numerous insights into gene function, yet a major limitation has been the inability to stably deliver large multiplexed DNA libraries to cultured cells allowing barcoded pooled screens. Here, we developed a site-specific integration strategy for library delivery and performed a genome-wide CRISPR knockout screen in Drosophila S2R+ cells. Under basal growth conditions, 1235 genes were essential for cell fitness at a false-discovery rate of 5%, representing the highest-resolution fitness gene set yet assembled for Drosophila, including 407 genes which likely duplicated along the vertebrate lineage and whose orthologs were underrepresented in human CRISPR screens. We additionally performed context-specific fitness screens for resistance to or synergy with trametinib, a Ras/ERK/ETS inhibitor, or rapamycin, an mTOR inhibitor, and identified key regulators of each pathway. The results present a novel, scalable, and versatile platform for functional genomic screens in invertebrate cells.

PMID: 30051818 [PubMed - indexed for MEDLINE]

Pharmacogenetics: The Solution for All Future Challenges?

Drug Res (Stuttg). 2018 Nov;68(S 01):S24

Authors: van Gelder T

Abstract

PMID: 30453372 [PubMed - in process]

Analyses of Adverse Drug Reactions-Nationwide Active Surveillance Network: Canadian Pharmacogenomics Network for Drug Safety Database.

J Clin Pharmacol. 2018 Nov 19;:

Authors: Tanoshima R, Khan A, Biala AK, Trueman JN, Drögemöller BI, Wright GEB, Hasbullah JS, Groeneweg GSS, Ross CJD, Carleton BC, Canadian Pharmacogenomics Network for Drug Safety Consortium

Abstract
Adverse drug reactions (ADRs) are a major problem in modern medicine, representing up to the fourth-highest cause of mortality. Pharmacogenomic tests are 1 of the most promising methods to tackle the challenge of ADRs. The objective of this study was to analyze the clinical and demographic information of the pan-Canadian active surveillance network, Canadian Pharmacogenomics Network for Drug Safety (CPNDS). Information entered into the database by trained active surveillors between May 15, 2005 and May 9, 2017 was collected and analyzed. Specific data included for analysis were number of ADR reports, reports of drug use without ADRs, date of onset of ADR, suspected drugs, concomitant drugs, and fatal ADR cases. The CPNDS database consisted of 93,974 reports of medication use, including 10,475 reports of ADRs, of which 72.6% occurred in pediatric patients (≤21 years old). Self-reported ancestries were predominantly Europe (38.2%), Canada (9.6%), and East Asia (4.9%). The 5 most frequent ADRs were cutaneous ADRs, peripheral neuropathy, cardiotoxicity, central nervous system toxicity, and ototoxicity. The 5 drugs most commonly suspected to cause ADRs were methotrexate, vincristine, doxorubicin, cisplatin, and L-asparaginase. The CPNDS database is a valuable resource to identify clinical and genomic predictors of ADRs. The database also highlights our candidate ADRs for pharmacogenomic discovery research to identify additional ADR biomarkers. Additionally, the database provides information that can be used for developing strategies to prevent ADRs and raises awareness of ADRs among Canadian healthcare professionals.

PMID: 30452777 [PubMed - as supplied by publisher]

Characterization of ADME genes variation in Roma and 20 populations worldwide.

PLoS One. 2018;13(11):e0207671

Authors: Škarić-Jurić T, Tomas Ž, Zajc Petranović M, Božina N, Smolej Narančić N, Janićijević B, Salihović MP

Abstract
The products of the polymorphic ADME genes are involved in Absorption, Distribution, Metabolism, and Excretion of drugs. The pharmacogenetic data have been studied extensively due to their clinical importance in the appropriate drug prescription, but such data from the isolated populations are rather scarce. We analyzed the distribution of 95 polymorphisms in 31 core ADME genes in 20 populations worldwide and in newly genotyped samples from the Roma (Gypsy) population living in Croatia. Global distribution of ADME core gene loci differentiated three major clusters; (1) African, (2) East Asian, and (3) joint European, South Asian and South American cluster. The SLCO1B3 (rs4149117) and CYP3A4 (rs2242480) genes differentiated at the highest level the African group of populations, while NAT2 gene loci (rs1208, rs1801280, and rs1799929) and VKORC1 (rs9923231) differentiated East Asian populations. The VKORC1 rs9923231 was among the investigated loci the one with the largest global minor allele frequency (MAF) range; its MAF ranged from 0.027 in Nigeria to 0.924 in Han Chinese. The distribution of the investigated gene loci positions Roma population within the joined European and South Asian clusters, suggesting that their ADME gene pool is a combination of ancestral (Indian) and more recent (European) surrounding, as it was already implied by other genetic markers. However, when compared to the populations worldwide, the Croatian Roma have extreme MAF values in 10 out of the 95 investigated ADME core gene loci. Among loci which have extraordinary MAFs in Roma population two have strong proof of clinical importance: rs1799853 (CYP2C9) for warfarin dosage, and rs12248560 (CYP2C19) for clopidogrel dosage, efficacy and toxicity. This finding confirms the importance of taking the Roma as well as the other isolated populations`genetic profiles into account in pharmaco-therapeutic practice.

PMID: 30452466 [PubMed - in process]

Cancer-Related Pain: Understanding Genetic Influences and Determining Implications for Practice.

Clin J Oncol Nurs. 2018 Dec 01;22(6):607-609

Authors: Jakub K

Abstract
Pain can be highly variable and unpredictable. Genetics may be key to identifying pain mechanisms that control the intensity, duration, and physiologic response in individuals with chronic pain. Pharmaco-genomics and precision medicine are permitting advances in pain control with analgesic drugs that have increased effectiveness and lead to decreased side effects. Knowledge of genetic variations related to how and why patients experience pain will aid in identifying those at risk, provide a better understanding of the phenomenon of pain, and possibly lead to innovative therapies to control pain.

PMID: 30452003 [PubMed - in process]

Perineural Invasion is a Strong Prognostic Moderator in Ampulla of Vater Carcinoma: A Meta-analysis.

Pancreas. 2018 Nov 17;:

Authors: Luchini C, Veronese N, Nottegar A, Riva G, Pilati C, Mafficini A, Stubbs B, Simbolo M, Mombello A, Corbo V, Cheng L, Yachida S, Wood LD, Lawlor RT, Salvia R, Scarpa A

Abstract
OBJECTIVE: Ampulla of Vater carcinoma (AVC) has a broad spectrum of different prognoses. As such, new moderators of survival are urgently needed. We aimed at clarifying the prognostic role of perineural invasion in AVC.
METHODS: Using PubMed and SCOPUS databases, we conducted the first systematic review and meta-analysis on this topic.
RESULTS: Analyzing 29 articles for a total of 2379 patients, we found that the presence of perineural invasion increased the risk of all-cause mortality of more than 2 times (relative risk [RR], 2.07; 95% confidence interval [CI], 1.78-2.42 [P < 0.0001]; hazard ratio [HR], 2.72; 95% CI, 1.86-3.97 [P < 0.0001]), of cancer-specific mortality of more than 6 times (RR, 6.12; 95% CI, 3.25-11.54 [P < 0.0001]; HR, 6.59; 95% CI, 2.29-3.49 [P < 0.0001]), and of recurrence of more than 2 times (RR, 2.63; 95% CI, 1.89-3.67 [P < 0.0001]; HR, 2.54; 95% CI, 1.24-5.21 [P = 0.01]).
CONCLUSIONS: Perineural invasion is strongly associated with a poorer prognosis in AVC, influencing both survival and risk of recurrence. It should be reported in the final pathology report and should be taken into account by future oncologic staging systems, identifying a group of AVC with a more malignant biological behavior.

PMID: 30451797 [PubMed - as supplied by publisher]

Pharmacogenomics and Psychiatric Nursing.

Issues Ment Health Nurs. 2018 Nov 19;:1-5

Authors: White MM, Walker DK, Howington LL, Cheek DJ

Abstract
The treatment of mental illness is often done on a trial-and-error basis and achieving therapeutic benefits from a medication is not always guaranteed. Pharmacogenomics explores the role of gene-gene interactions and interindividual responses to a drug and may be promising in the guidance of pharmacotherapeutic options. In the present study, the impact of pharmacogenomic testing in management of mental health medication was investigated. Participants were identified at a local outpatient mental health facility through convenience sampling. Retrospective chart review included medication history, adverse drug reactions, pharmacogenomic history, and demographic data including insurance coverage. Chart review focused on six months pre- and post-pharmacogenomic for a comparison with the patient serving as their own control. Results indicate a high incidence of alterations in two specific cytochrome enzymes, CYP2D6 and CYP2C19. In total, 82% of the sample had variations with CYP2D6, while 64% of individuals had variations with CYP2C19. In total, 91% of patients tested received Medicaid or Medicare. Post-pharmacogenomic testing, all patient drug regimens were modified, and all reported less adverse side effects. Moreover, advanced practice nurse providers educated patients about the availability of genetic testing, initiated testing and provided care based on findings. These results demonstrate the utility of genetic testing in the realm of mental health. Future directions involve further exploring the benefits of pharmacogenomic testing in this vulnerable population.

PMID: 30451558 [PubMed - as supplied by publisher]

Impulsivity and vitamin D in bariatric surgery candidates.

Pharmacol Rep. 2018 Aug;70(4):688-693

Authors: Wrzosek M, Sawicka A, Tałałaj M, Wojnar M, Nowicka G

Abstract
BACKGROUND: Obesity is recognized as a major health problem. Vitamin D is involved in maintaining energy metabolism by regulation of glucose transporters, uncoupling proteins, and normal brain function. We aimed to explore a relationship between impulsivity, eating behaviors, and 25-hydroxyvitamin D concentration in a sample of 322 bariatric surgery candidates.
METHODS: Participants completed a questionnaire on their health, eating habits and The Eating Disorders Examination-Questionnaire (EDE-Q). Impulsivity was evaluated with the Barratt Impulsiveness Scale (BIS-11). Blood samples were obtained to measure levels of 25(OH)D, lipids (cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol), and glucose.
RESULTS: Overall scores on the BIS-11, along with scores on the Attentional Subscale of the BIS were significantly higher in participants with higher frequency of snack food consumption. Scores on the Attentional Subscale of the BIS were higher in participants who self-reported eating in response to emotions. Participants who reported eating at night or declared intense emotions associated with a desire-to-eat had the highest global, attentional, and non-planning impulsivity levels. Scores on the Non-planning Subscale of the BIS-11 were elevated in participants with 25-hydroxyvitamin D concentrations lower than 10ng/ml.
CONCLUSIONS: The results suggest that the higher level of impulsivity among the patients with obesity is associated with eating habits, and support the hypothesis that vitamin D deficiency may contribute to impulsiveness.

PMID: 29920421 [PubMed - indexed for MEDLINE]

Genetics of Lithium Response in Bipolar Disorder.

Pharmacopsychiatry. 2018 Sep;51(5):206-211

Authors: Papiol S, Schulze TG, Alda M

Abstract
INTRODUCTION: Lithium remains the best-established long-term treatment for bipolar disorder because of its efficacy in maintaining periods of remission and reducing the risk of suicide. Not all patients successfully respond to lithium treatment, and the individual response, including the occurrence of side effects, is highly variable and not easy to predict. The genetic basis of lithium response is supported by the fact that the response clusters in families. Likewise, recent high-throughput genomic analyses have shed light on its genetic architecture.
METHODS: This nonsystematic review summarizes the main results obtained in genetic association studies using lithium response as target trait.
RESULTS: These studies suggest that several genetic loci might modulate the way a patient responds to lithium maintenance treatment. Further studies to fully characterize the genetic architecture of lithium response are warranted.
DISCUSSION: The identification of genetic factors associated with lithium response will be important for (1) better understanding of lithium's mode of action and (2) development of a predictive model for optimization of long-term treatment of bipolar disorder.

PMID: 29579760 [PubMed - indexed for MEDLINE]