Short- and Long-term Risks of Highly Active Antiretroviral Treatment with Incident Opportunistic Infections among People Living with HIV/AIDS.

Sci Rep. 2019 Mar 05;9(1):3476

Authors: Yen YF, Chen M, Jen IA, Chuang PH, Lee CY, Lin SI, Chen YA

Abstract
Highly active antiretroviral therapy (HAART) causes a rapid increase of CD4 + T cells counts during the first 3-6 months of treatment and may enhance the development of opportunistic infections (OIs). However, the short- and long-term effects of HAART exposure on the development of incident OIs has not been extensively studied. This nationwide longitudinal study followed up a total of 26,258 people living with HIV/AIDS (PLWHA) to ascertain the short- and long-term effects of HAART on incident OIs. During 150,196 person-years of follow-up, 6,413 (24.4%) PLWHA had new onset of OIs. After adjusting for demographics, comorbidities, and AIDS status, PLWHA who received HAART were more likely to develop OIs than those who did not receive HAART. Considering the short- and long-term effects of HAART on the development of OIs, HAART was found to be a risk factor for developing OIs during the first 90 days of treatment, but a protective factor against OIs after 180 days of HAART use. The risk for the development of active OIs significantly decreased as the duration of HAART increased (P < 0.001). Our study suggests that HAART is a risk factor for developing OIs in the short term, but is a protective factor in the long term.

PMID: 30837537 [PubMed - in process]

Predicting lithium treatment response in bipolar patients using gender-specific gene expression biomarkers and machine learning.

F1000Res. 2018;7:474

Authors: Eugene AR, Masiak J, Eugene B

Abstract
Background: We sought to test the hypothesis that transcriptome-level gene signatures are differentially expressed between male and female bipolar patients, prior to lithium treatment, in a patient cohort who later were clinically classified as lithium treatment responders. Methods: Gene expression study data was obtained from the Lithium Treatment-Moderate dose Use Study data accessed from the National Center for Biotechnology Information's Gene Expression Omnibus via accession number GSE4548. Differential gene expression analysis was conducted using the Linear Models for Microarray and RNA-Seq (limma) package and the Decision Tree and Random Forest machine learning algorithms in R. Results: Using quantitative gene expression values reported from patient blood samples, the RBPMS2 and LILRA5 genes classify male lithium responders with an area under the receiver operator characteristic curve (AUROC) of 0.92 and the ABRACL, FHL3, and NBPF14  genes classify female lithium responders AUROC of 1. A Decision Tree rule for establishing male versus female samples, using gene expression values were found to be: if RPS4Y1 ≥ 9.643, patient is a male and if RPS4Y1 < 9.643, patient is female with a probability=100%. Conclusions: We developed a pre-treatment gender- and gene-expression-based predictive model selective for classifying male lithium responders with a sensitivity of 96% using 2-genes and female lithium responders with sensitivity=92% using 3-genes.

PMID: 30828420 [PubMed - in process]

Warfarin Dose and CYP2C Gene Cluster: An African Ancestral-Specific Variant Is a Strong Predictor of Dose in Black South African Patients.

OMICS. 2019 01;23(1):36-44

Authors: Ndadza A, Cindi Z, Makambwa E, Chimusa E, Wonkam A, Kengne AP, Ntsekhe M, Dandara C

Abstract
Warfarin is a widely prescribed anticoagulant with a narrow therapeutic index. The rs12777823G>A single-nucleotide polymorphism (SNP) in the CYP2C gene cluster has been shown to influence optimal warfarin doses in African Americans. We report here effects of rs12777823G>A SNP on warfarin dose requirements in two South African population groups, black Africans (BA) and mixed ancestry (MA). A total of 425 participants on warfarin treatment were enrolled in the study. The age group of the studied population ranged between 44 and 66 years, with 69% females enrolled. Genetic characterization of the rs12777823G>A was done using the TaqMan SNP genotyping assay. To further compare effects of rs12777823G>A to those of other SNPs, VKORC1 g.-1639G>A and 4 SNPs in CYP2C9 gene (i.e., CYP2C9 c.430C>T, c.1075A>C, c.449G>A, and c.1003C>T) were analyzed. The rs12777823A variant allele frequencies were 0.28 and 0.25 in the BA and MA, respectively. The rs12777823A/A genotype was associated with significantly (p = 0.002) reduced mean warfarin dosage (27 ± 5.3 mg/week) compared with the G/G genotype (45 ± 16.1 mg/week) among BA, but not among the MA. The rs12777823G>A is located in a nongenomic region, suggesting that this SNP might be in linkage disequilibrium with another, likely causal SNP that is present in BA only. Given ongoing worldwide efforts to identify clinically relevant human genetic variation impacting on optimal warfarin dose selection, the African ancestry-specific genetic variant in the CYP2C cluster and others warrant further research and consideration in development of future warfarin dosing algorithms for precision medicine guidelines.

PMID: 30566377 [PubMed - indexed for MEDLINE]

Appreciating the need for greater understanding of the pharmacokinetics of drugs in children and adolescents.

Pediatr Transplant. 2018 12;22(8):e13312

Authors: Filler G, Bravo M

PMID: 30499623 [PubMed - indexed for MEDLINE]

The MTNR1B rs10830963 Variant in Interaction with Pre-Pregnancy BMI is a Pharmacogenetic Marker for the Initiation of Antenatal Insulin Therapy in Gestational Diabetes Mellitus.

Int J Mol Sci. 2018 Nov 23;19(12):

Authors: Firneisz G, Rosta K, Al-Aissa Z, Hadarits O, Harreiter J, Nádasdi Á, Bancher-Todesca D, Németh L, Igaz P, Rigó J, Sziller I, Kautzky-Willer A, Somogyi A

Abstract
The rs10830963 variant of the Melatonin Receptor 1B (MTNR1B) gene is associated with the development of gestational diabetes mellitus (GDM). We hypothesized that carrying the rs10830963/G risk allele had effect on antenatal insulin therapy (AIT) initiation in GDM in a body mass index (BMI)-dependent manner. Design: In this post hoc analysis the MTNR1B rs10830963 genotype and the clinical data of 211 Caucasian GDM patients were assessed. As a first step, a pre-pregnancy BMI threshold was determined where the effect of MTNR1B rs10830963/G allele carrying on AIT initiation was the most significant using logistic regression. Maternal age adjusted real-life odds ratios (OR) values were calculated. The chi-square test was also used to calculate the p value and 10.000 bootstrap simulations were performed in each case to re-assess the statistical power and the OR. Carrying the MTNR1B rs10830963/G allele increased the odds of AIT initiation (OR = 5.2, p = 0.02 [χ² test], statistical power = 0.53) in GDM patients with pre-pregnancy BMI ≥ 29 kg/m². The statistical power reached 0.77, when the pre-pregnancy BMI cutoff of 27 kg/m² was used and the genetic effect on AIT initiation was still significant, but only using the logistic regression model. Carrying the MTNR1B rs10830963/G risk allele-in interaction with pre-pregnancy BMI-is likely be considered as a candidate pharmacogenetic marker of antenatal insulin therapy initiation and should be further assessed in precision medicine trials in GDM.

PMID: 30477160 [PubMed - indexed for MEDLINE]

Candida species biotypes in the oral cavity of infants and children with orofacial clefts under surgical rehabilitation.

Microb Pathog. 2018 Nov;124:203-215

Authors: Silva JJD, Silva TAD, Almeida H, Rodrigues Netto MF, Cerdeira CD, Höfling JF, Boriollo MFG

Abstract
Patients with orofacial clefts present various risk factors for oral infectious diseases, resulting from anatomical and physiological changes and those resulting from rehabilitating therapeutic interventions. The incidence of Candida species in groups of babies and children with orofacial clefts, during pre- and post-operative periods and until return to first consultation, and the profiles for antifungal sensitivity and virulence in vitro were investigated. Oral samples were collected at different times over the surgical procedures and post-surgical clinical consultation and seeded in chromogenic culture media CHROMagar Candida®. Candida biotypes were identified by accessing species-specific genomic DNA sequences by PCR techniques and electrophoretic procedures. Antifungal susceptibility testing was performed by the method of microdilution in broth using the antifungals amphotericin B (AP), nystatin (NYS) and fluconazole (FLC). SAP and PL exoenzyme activities were determined by classical microbiological methods. Some orofacial clefts occurred preferentially in male or female. Low incidence (39.1%) of oral colonization by Candida species (C. albicans, C. krusei, C. tropicalis and Candida spp.) was reported in patient admission to surgical ward, with no correlation to orofacial cleft types or surgical history. Significant reduction in frequencies of Candida and changes of species, over sampling periods, showed dynamic patterns of oral colonization: elimination, maintenance or neocolonization of the biotypes. These biotypes showed sensitivity to AP (100%), partial resistance to FLC (<10%) and variable MICs for NYS (0.125-4 μg/mL), in addition to strong exoenzyme activities, especially for SAP. Clinical and therapeutic conducts for surgical rehabilitation, anatomical and physiological characteristics of patients with orofacial clefts, and cultural behavior and regionalism of the patient population served could influence the frequencies and dynamics of oral colonization by Candida species. The data showed Candida biotypes resistant to FLC and sensitive (AP) or clinically compatible (NYS) to polyenes, especially C. albicans, in the oral cavity of patients predisposed to oral colonization and candidiases, contributing to clinical conducts in possible antifungal therapies. These biotypes were considered potentially virulent and able to partially modulate their virulence factors, especially SAP, under the conditions favored by host.

PMID: 30138757 [PubMed - indexed for MEDLINE]

Pharmacogenetics of drug dependence: Polymorphisms of genes involved in glutamate neurotransmission.

Neurosci Lett. 2019 Mar 02;:

Authors: Nudmamud-Thanoi S, Iamjan SA, Kerdsan-Phusan W, Thanoi S

Abstract
Multiple studies provide evidence to support dysfunction of glutamate neurotransmission in the pathogenesis of drug dependence. Pharmacogenetic investigation of glutamate-related genes has provided further support for the involvement of this neurotransmitter in the risk of, and consequences of, drug abuse and dependence. This paper aims to provide a brief review of these association studies. Findings involving single nucleotide polymorphisms (SNPs) in glutamate receptor genes (GRIN, GRIA) and glutamate transporter genes (SLC1A, SLC17 A) are reviewed as potential risk factors. As yet a clear perspective of the functional consequences and interactions of the various reported findings is lacking.

PMID: 30836121 [PubMed - as supplied by publisher]

Pharmacogenomic and Pharmacotranscriptomic Profiling of Childhood Acute Lymphoblastic Leukemia: Paving the Way to Personalized Treatment.

Genes (Basel). 2019 Mar 01;10(3):

Authors: Pavlovic S, Kotur N, Stankovic B, Zukic B, Gasic V, Dokmanovic L

Abstract
Personalized medicine is focused on research disciplines which contribute to the individualization of therapy, like pharmacogenomics and pharmacotranscriptomics. Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. It is one of the pediatric malignancies with the highest cure rate, but still a lethal outcome due to therapy accounts for 1%⁻3% of deaths. Further improvement of treatment protocols is needed through the implementation of pharmacogenomics and pharmacotranscriptomics. Emerging high-throughput technologies, including microarrays and next-generation sequencing, have provided an enormous amount of molecular data with the potential to be implemented in childhood ALL treatment protocols. In the current review, we summarized the contribution of these novel technologies to the pharmacogenomics and pharmacotranscriptomics of childhood ALL. We have presented data on molecular markers responsible for the efficacy, side effects, and toxicity of the drugs commonly used for childhood ALL treatment, i.e., glucocorticoids, vincristine, asparaginase, anthracyclines, thiopurines, and methotrexate. Big data was generated using high-throughput technologies, but their implementation in clinical practice is poor. Research efforts should be focused on data analysis and designing prediction models using machine learning algorithms. Bioinformatics tools and the implementation of artificial i Lack of association of the CEP72 rs924607 TT genotype with intelligence are expected to open the door wide for personalized medicine in the clinical practice of childhood ALL.

PMID: 30832275 [PubMed]

Candidate gene and pathway analyses identifying genetic variations associated with prasugrel pharmacokinetics and pharmacodynamics.

Thromb Res. 2019 01;173:27-34

Authors: Liu Z, Xiang Q, Zhao X, Wang Z, Mu G, Xie Q, Zhou S, Chen S, Hu K, Xu J, Ma L, Cui Y

Abstract
AIM: We aimed to investigate the genetic polymorphisms and pharmacogenetic variability associated with the pharmacodynamics (PD) and pharmacokinetics (PK) of prasugrel, in healthy Han Chinese subjects.
PATIENTS & METHODS: Healthy, native, Han Chinese subjects (n = 36) aged 18 to 45 years with unknown genotypes were included. All subjects received a loading dose (LD) on day 1 and a maintenance dose (MD) from day 2 until day 11. Candidate gene association and gene-set analysis of biological pathways related to prasugrel and platelet activity were analyzed.
RESULTS: 28 SNPs of 17 candidate genes previously associated with prasugrel or platelet activity were selected after a literature search. In the 30 mg LD groups (n = 24), ITGA2-rs28095 was found to be significantly associated with the P2Y12 reaction unit (PRU) value at 24 h after the LD (p = 0.015). 165 study genes related to platelet activation-related processes and prasugrel activity were selected from the MSigDB database, including curated gene sets from KEGG, Bio Carta, and Gene Cards. 14 SNPs of 9 genes were found to be significantly correlated both at 24 h and 12 days after LD: ADAMTSL1, PRKCA, ITPR2, P2RY12, P2RY14, PLCB4, PRKG1, ADCY1, and LYN. Seven SNPs of 6 protein-coding genes associated with area under the concentration-time curve (AUC0-tlast) were significantly identified among the 47 selected genes, including ADAMTSL1, CD36, P2RY1, PCSK9, PON1, and SCD.
CONCLUSION: These results show that genetic variation affects the PK and PD of prasugrel in normal individuals. Further studies with larger sample sizes are required to explore whether the SNPs are associated only with prasugrel activity or also with cardiovascular events and all-cause mortality.

PMID: 30458339 [PubMed - indexed for MEDLINE]

The trimeric coiled-coil HSBP1 protein promotes WASH complex assembly at centrosomes.

EMBO J. 2018 07 02;37(13):

Authors: Visweshwaran SP, Thomason PA, Guerois R, Vacher S, Denisov EV, Tashireva LA, Lomakina ME, Lazennec-Schurdevin C, Lakisic G, Lilla S, Molinie N, Henriot V, Mechulam Y, Alexandrova AY, Cherdyntseva NV, Bièche I, Schmitt E, Insall RH, Gautreau A

Abstract
The Arp2/3 complex generates branched actin networks that exert pushing forces onto different cellular membranes. WASH complexes activate Arp2/3 complexes at the surface of endosomes and thereby fission transport intermediates containing endocytosed receptors, such as α5β1 integrins. How WASH complexes are assembled in the cell is unknown. Here, we identify the small coiled-coil protein HSBP1 as a factor that specifically promotes the assembly of a ternary complex composed of CCDC53, WASH, and FAM21 by dissociating the CCDC53 homotrimeric precursor. HSBP1 operates at the centrosome, which concentrates the building blocks. HSBP1 depletion in human cancer cell lines and in Dictyostelium amoebae phenocopies WASH depletion, suggesting a critical role of the ternary WASH complex for WASH functions. HSBP1 is required for the development of focal adhesions and of cell polarity. These defects impair the migration and invasion of tumor cells. Overexpression of HSBP1 in breast tumors is associated with increased levels of WASH complexes and with poor prognosis for patients.

PMID: 29844016 [PubMed - indexed for MEDLINE]

Understanding the influence of antipsychotic drugs on global methylation events and its relevance in treatment response.

Epigenomics. 2018 03;10(3):233-247

Authors: Swathy B, Saradalekshmi KR, Nair IV, Nair C, Banerjee M

Abstract
AIM: The present study intends to evaluate whether antipsychotic drugs can modulate the host epigenome and if so whether drug-induced epigenetic modulation can explain the heterogeneity in drug response.
METHODS: Present study was conducted in in vitro cells and significance of these in vitro observations was further evaluated in a clinical setting, between drug responsive and nonresponsive schizophrenia patients. A number of DNA modifications were assessed at global level using 5-methylcytosine, 5-hydroxymethylcytosine and 5-formylcytosine followed by evaluating the expression of epigenetic modifier genes and their crosstalk with miRNAs.
RESULTS: In vitro data demonstrated that antipsychotic drugs induce epigenetic response by downregulating miRNA that target DNA methyltransferases, resulting in global hypermethylation. Similar trend was observed in clinical setting too and alterations were markedly associated with drug response rather than disease pathogenesis.
CONCLUSION: Study demonstrates that antipsychotic drugs can influence host methylome and thereby indicating its role in mediating a strong pharmacoepigenomic response.

PMID: 29343074 [PubMed - indexed for MEDLINE]

Genome-scale analysis identifies NEK2, DLGAP5 and ECT2 as promising diagnostic and prognostic biomarkers in human lung cancer.

Sci Rep. 2017 08 14;7(1):8072

Authors: Shi YX, Yin JY, Shen Y, Zhang W, Zhou HH, Liu ZQ

Abstract
This study aims to identify promising biomarkers for the early detection of lung cancer and evaluate the prognosis of lung cancer patients. Genome-wide mRNA expression data obtained from the Gene Expression Omnibus (GSE19188, GSE18842 and GSE40791), including 231 primary tumor samples and 210 normal samples, were used to discover differentially expressed genes (DEGs). NEK2, DLGAP5 and ECT2 were found to be highly expressed in tumor samples. These results were experimentally confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The elevated expression of the three candidate genes was also validated using the Cancer Genome Atlas (TCGA) datasets, which consist of 349 tumor and 58 normal tissues. Furthermore, we performed receiver operating characteristics (ROC) analysis to assess the diagnostic value of these lung cancer biomarkers, and the results suggested that NEK2, DLGAP5 and ECT2 expression levels could robustly distinguish lung cancer patients from normal subjects. Finally, Kaplan-Meier analysis revealed that elevated NEK2, DLGAP5 and ECT2 expression was negatively correlated with both overall survival (OS) and relapse-free survival (RFS). Taken together, these findings indicate that these three genes might be used as promising biomarkers for the early detection of lung cancer, as well as predicting the prognosis of lung cancer patients.

PMID: 28808310 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/03/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial.

BMJ Open. 2019 Mar 01;9(3):e024363

Authors: Padmapriyadarsini C, Bhavani PK, Natrajan M, Ponnuraja C, Kumar H, Gomathy SN, Guleria R, Jawahar SM, Singh M, Balganesh T, Swaminathan S

Abstract
INTRODUCTION: Shorter duration of treatment for the management of drug-susceptible pulmonary tuberculosis (TB) would be a significant improvement in the care of patients suffering from the disease. Besides newer drugs and regimens, other modalities like host-directed therapy are also being suggested to reach this goal. This study's objective is to assess the efficacy and safety of metformin-containing anti-TB treatment (ATT) regimen in comparison to the standard 6-month ATT regimen in the treatment of patients with newly diagnosed sputum smear-positive drug-sensitive pulmonary TB.
METHODS AND ANALYSIS: We are conducting a multicentric, randomised open-label controlled clinical trial to achieve the study objective. The intervention group will receive isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) along with 1000 mg of daily metformin (Met) for the first 2 months while the control group will receive only HRZE. After 2 months, both the groups will receive HRE daily for 4 months. The primary endpoint is time to sputum culture conversion. Secondary endpoints will include time to detection of Mycobacterium tuberculosis in sputum, pharmacokinetics and pharmacogenomics of study drugs, drug-drug interactions, safety and tolerability of the various combinations and measurement of autophagy and immune responses in the study participants.
ETHICS AND DISSEMINATION: The ethics committee of the participating institutes have approved the study. Results from this trial will contribute to evidence towards constructing a shorter, effective and safe regimen for patients with TB. The results will be shared widely with the National Programme managers, policymakers and stakeholders through open access publications, dissemination meetings, conference abstracts and policy briefs. This is expected to provide a new standard of care for drug-sensitive patients with pulmonary TB who will not only reduce the number of clinic visits and lost to follow-up of patients from treatment but also reduce the burden on the healthcare system.
TRIAL REGISTRATION NUMBER: CTRI/2018/01/011176; Pre-results.

PMID: 30826761 [PubMed - in process]

CYP2C19*2 polymorphism in Polish peptic ulcer patients.

Pharmacol Rep. 2018 Dec 22;71(2):272-275

Authors: Sałagacka-Kubiak A, Żebrowska-Nawrocka M, Jeleń A, Mirowski M, Balcerczak E

Abstract
BACKGROUND: CYP2C19 isoenzyme of cytochrome P450 in the liver catabolises proton pump inhibitors, one of the therapeutics utilized in Helicobacter pylori eradication therapy, and in this way could influence the eradication effectiveness. The isoensyme contributes also to metabolism of endogenous substances, which derivatives are involved in the pathogenesis of peptic ulceration. CYP2C19*2 polymorphism (rs4244285) changing the CYP2C19 function could be relevant in the predisposition to peptic ulcer disease.
METHODS: CYP2C19*2 polymorphism in 197 peptic ulcer patients and 107 healthy subjects of Polish origin by PCR-RFLP method was investigated.
RESULTS: There were no statistically significant differences in genotypes and alleles frequencies for investigated polymorphism between peptic ulcer patients and healthy individuals. No associations between frequencies of particular CYP2C19 genotypes and alleles and the presence of H. pylori infection in peptic ulcer patients were stated. However, significant association between CYP2C19*2 and gender in H. pylori-infected but not -uninfected peptic ulcer individuals was found.
CONCLUSIONS: Investigated polymorphism is not a risk factor for peptic ulcer in Polish population. Obtained results could suggested there is some interaction between gender, CYP2C19*2 polymorphism, and pathogenesis of H. pylori infection development. However, this hypothesis should be verified in the further studies.

PMID: 30826566 [PubMed - as supplied by publisher]

Contribution of cholinergic interneurons to striatal pathophysiology in Parkinson's disease.

Neurochem Int. 2019 Feb 27;:

Authors: Ztaou S, Amalric M

Abstract
Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of nigral dopaminergic neurons innervating the striatum, the main input structure of the basal ganglia. This creates an imbalance between dopaminergic inputs and cholinergic interneurons (ChIs) within the striatum. The efficacy of anticholinergic drugs, one of the earliest therapy for PD before the discovery of L-3,4-dihydroxyphenylalanine (L-DOPA) suggests an increased cholinergic tone in this disease. The dopamine (DA)-acetylcholine (ACh) balance hypothesis is now revisited with the use of novel cutting-edge techniques (optogenetics, pharmacogenetics, new electrophysiological recordings). This review will provide the background of the specific contribution of ChIs to striatal microcircuit organization in physiological and pathological conditions. The second goal of this review is to delve into the respective contributions of nicotinic and muscarinic receptor cholinergic subunits to the control of striatal afferent and efferent neuronal systems. Special attention will be given to the role played by muscarinic acetylcholine receptors (mAChRs) in the regulation of striatal network which may have important implications in the development of novel therapeutic strategies for motor and cognitive impairment in PD.

PMID: 30825602 [PubMed - as supplied by publisher]

A pathway-driven predictive model of tramadol pharmacogenetics.

Eur J Hum Genet. 2019 Mar 01;:

Authors: Wendt FR, Novroski NMM, Rahikainen AL, Sajantila A, Budowle B

Abstract
Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.

PMID: 30824817 [PubMed - as supplied by publisher]

Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study.

Lancet Gastroenterol Hepatol. 2019 Feb 26;:

Authors: Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, Thomas A, Nice R, Perry MH, Bouri S, Chanchlani N, Heerasing NM, Hendy P, Lin S, Gaya DR, Cummings JRF, Selinger CP, Lees CW, Hart AL, Parkes M, Sebastian S, Mansfield JC, Irving PM, Lindsay J, Russell RK, McDonald TJ, McGovern D, Goodhand JR, Ahmad T, UK Inflammatory Bowel Disease Pharmacogenetics Study Group

Abstract
BACKGROUND: Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal.
METHODS: The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure.
FINDINGS: We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23·8%, 95% CI 21·4-26·2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63·1%, 60·3-65·8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7·8%, 6·6-9·2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0·35 [95% CI 0·20-0·62], p=0·00038; adalimumab: 0·13 [0·06-0·28], p<0·0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12·4% [95% CI 6·9-19·9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0·29 [0·16-0·52] for infliximab; 0·03 [0·01-0·12] for adalimumab; p<0·0001 for both). The proportion of patients who developed anti-drug antibodies (immunogenicity) was 62·8% (95% CI 59·0-66·3) for infliximab and 28·5% (24·0-32·7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immunomodulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0·39 [95% CI 0·32-0·46] for infliximab; 0·44 [0·31-0·64] for adalimumab; p<0·0001 for both). For infliximab, multivariable analysis of immunododulator use, and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission (odds ratio 0·56 [95% CI 0·38-0·83], p=0·004).
INTERPRETATION: Anti-TNF treatment failure is common and is predicted by low drug concentrations, mediated in part by immunogenicity. Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes.
FUNDING: Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion.

PMID: 30824404 [PubMed - as supplied by publisher]

Description of an Innovative Pediatric Individualized Therapeutics Clinic: Working toward Precision Drug Therapy.

Children (Basel). 2019 Feb 25;6(2):

Authors: Sandritter TL, Dinh JC, Wagner JA, Lowry JA

Abstract
The GOLDILOKs® (Genomic and Ontogeny-Linked Dose Individualization and cLinical Optimization for KidS) Clinic aims to provide families and physicians with data to make more informed decisions with regard to pharmacological therapy by using innovative therapy and genomic technologies. The objectives are two-fold: (1) To describe the utility of the GOLDILOKs® Clinic to referring prescribers by evaluating the type of referrals made to the GOLDILOKs® Clinic and (2) to assess the most often utilized technologies (e.g., genotyping) completed to formulate therapy recommendations. Patient data from July 2010 to June 2016 was retrospectively reviewed following Institutional Review Board (IRB) approval. The GOLDILOKs® Clinic evaluated 306 patients and had increases in annual referrals from 14 in 2010⁻2011 to 84 in 2016⁻2017. The children that were referred were predominately Caucasian (82%) and male (59%) with an average age of 12.4 ± 5.9 years. Subspecialty versus primary care referrals accounted for 82% and 18% of referrals, respectively. Adverse drug reactions (n = 166) and poor medication response (n = 179) were the major reasons for referral. However, it must be noted that patients could have multiple reasons for referral. Pharmacogenetic results were extensively used to provide guidance for future therapy in patients with medication-related problems. Genotyping of drug metabolizing enzymes and drug target receptors was performed in 221 patients (72.2%). Recommendations were fully accepted by 63% and partially accepted by 22% of internal provider referrals.

PMID: 30823616 [PubMed]

Relationship between a Weighted Multi-Gene Algorithm and Blood Pressure Controlin Hypertension.

J Clin Med. 2019 Feb 28;8(3):

Authors: Phelps PK, Kelley EF, Walla DM, Ross JK, Simmons JJ, Bulock EK, Ayres A, Akre MK, Sprissler R, Olson TP, Snyder EM

Abstract
Hypertension (HTN) is a complex disease with interactions among multiple organ systems, including the heart, vasculature, and kidney with a strong heritable component. Despite the multifactorial nature of HTN, no clinical guidelines utilize a multi-gene approach to guide blood pressure (BP) therapy. Non-smokers with a family history of HTN were included in the analysis (n = 384; age = 61.0 ± 0.9, 11% non-white). A total of 17 functional genotypes were weighted according to the previous effect size in the literature and entered into an algorithm. Pharmacotherapy was ranked from 1⁻4 as most to least likely to respond based on the algorithmic assessment of individual patient's genotypes. Three-years of data were assessed at six-month intervals for BP and medication history. There was no difference in BP at diagnosis between groups matching the top drug recommendation using the multi-gene weighted algorithm (n = 92) vs. those who did not match (n = 292). However, from diagnosis to nadir, patients who matched the primary recommendation had a significantly greater drop in BP when compared to patients who did not. Further, the difference between diagnosis to current 1-year average BP was lower in the group that matched the top recommendation. These data suggest an association between a weighted multi-gene algorithm on the BP response to pharmacotherapy.

PMID: 30823438 [PubMed]