Identifying key transcription factors for pharmacogenetic studies of antipsychotics induced extrapyramidal symptoms.

Psychopharmacology (Berl). 2020 May 07;:

Authors: Boloc D, Rodríguez N, Torres T, García-Cerro S, Parellada M, Saiz-Ruiz J, Cuesta MJ, Bernardo M, Gassó P, Lafuente A, Mas S, Arnaiz JA

Abstract
INTRODUCTION: We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies.
METHODS: Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP.
RESULTS: Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1.
CONCLUSION: Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.

PMID: 32382784 [PubMed - as supplied by publisher]

Family medicine clinic finds success with pharmacogenomics.

Am J Health Syst Pharm. 2020 May 08;:

Authors: Traynor K

PMID: 32382730 [PubMed - as supplied by publisher]

African Pharmacogenomics Consortium: Consolidating pharmacogenomics knowledge, capacity development and translation in Africa: Consolidating pharmacogenomics knowledge, capacity development and translation in Africa.

AAS Open Res. 2019;2:19

Authors: Dandara C, Masimirembwa C, Haffani YZ, Ogutu B, Mabuka J, Aklillu E, Bolaji O, H3Africa

Abstract
The African Pharmacogenomics Consortium (APC) was formally launched on the 6th September 2018. This white paper outlines its vision, and objectives towards addressing challenges of conducting and applying pharmacogenomics in Africa and identifies opportunities for advancement of individualized drugs use on the continent.  Africa, especially south of the Sahara, is beset with a huge burden of infectious diseases with much co-morbidity whose multiplicity and intersection are major challenges in achieving the sustainable development goals (SDG), SDG3, on health and wellness. The profile of drugs commonly used in African populations lead to a different spectrum of adverse drug reactions (ADRs) when compared to other parts of the world. Coupled with the genetic diversity among Africans, the APC is established to promote pharmacogenomics research and its clinical implementation for safe and effective use of medicine in the continent.  Variation in the way patients respond to treatment is mainly due to differences in activity of enzymes and transporters involved in pathways associated with each drug's disposition.  Knowledge of pharmacogenomics, therefore, helps in identifying genetic variants in these proteins and their functional effects. Africa needs to consolidate its pharmacogenomics expertise and technological platforms to bring pharmacogenomics to use.

PMID: 32382701 [PubMed]

QKI deficiency leads to osteoporosis by promoting RANKL-induced osteoclastogenesis and disrupting bone metabolism.

Cell Death Dis. 2020 May 07;11(5):330

Authors: Du T, Yan Z, Zhu S, Chen G, Wang L, Ye Z, Wang W, Zhu Q, Lu Z, Cao X

Abstract
Quaking (QKI), an RNA-binding protein, has been reported to exhibit numerous biological functions, such as mRNA regulation, cancer suppression, and anti-inflammation. However, little known about the effects of QKI on bone metabolism. In this study, we used a monocyte/macrophage-specific QKI knockout transgenic mouse model to investigate the effects of QKI deficiency on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. The loss of QKI promoted the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) from bone marrow macrophages, and upregulated the expression of OC-specific markers, including TRAP (Acp5) and cathepsin K (Ctsk). The pro-osteoclastogenesis effect of QKI deficiency was achieved by amplifying the signaling cascades of the NF-κB and mitogen-activated protein kinase (MAPK) pathways; then, signaling upregulated the activation of nuclear factor of activated T cells c1 (NFATc1), which is considered to be the core transcription factor that regulates OC differentiation. In addition, QKI deficiency could inhibit osteoblast (OB) formation through the inflammatory microenvironment. Taken together, our data suggest that QKI deficiency promoted OC differentiation and disrupted bone metabolic balance, and eventually led to osteopenia under physiological conditions and aggravated the degree of osteoporosis under pathological conditions.

PMID: 32382069 [PubMed - in process]

Rat brain CYP2D activity alters in vivo central oxycodone metabolism, levels and resulting analgesia.

Addict Biol. 2019 03;24(2):228-238

Authors: McMillan DM, Miksys S, Tyndale RF

Abstract
Oxycodone is metabolized by CYP2D to oxymorphone. Despite oxymorphone being a more potent opioid-receptor agonist, its contribution to oxycodone analgesia may be minor because of low peripheral production, low blood-brain barrier permeability and central nervous system efflux. CYP2D metabolism within the brain may contribute to variation in central oxycodone and oxymorphone levels, thereby affecting analgesia. Brain CYP2D expression and activity are subject to exogenous regulation; nicotine induces rat brain, but not liver, CYP2D consistent with higher brain CYP2D in smokers. We assessed the role of rat brain CYP2D in orally administered oxycodone metabolism (in vivo brain microdialysis) and analgesia (tail-flick test) by inhibiting brain CYP2D selectively with intracerebroventricular propranolol (mechanism-based inhibitor) and inducing brain CYP2D with nicotine. Inhibiting brain CYP2D increased brain oxycodone levels (1.8-fold; P < 0.03) and analgesia (1.5-fold AUC0-60 ; P < 0.001) after oxycodone, while inducing brain CYP2D increased brain oxymorphone levels (4.6-fold; P < 0.001) and decreased analgesia (0.8-fold; P < 0.02). Inhibiting the induced brain CYP2D reversed the change in oxycodone levels (1.2-fold; P > 0.1) and analgesia (1.1-fold; P > 0.3). Brain, but not plasma, metabolic ratios were affected by pre-treatments. Peak analgesia was inversely correlated with ex vivo brain (P < 0.003), but not hepatic (P > 0.9), CYP2D activity. Altering brain CYP2D did not affect analgesia from oral oxymorphone (P > 0.9 for AUC0-60 across all groups), which is not a CYP2D substrate. Thus, brain CYP2D metabolism alters local oxycodone levels and response, suggesting that people with increased brain CYP2D activity may have reduced oxycodone response. Factors that alter individual oxycodone response may be useful for optimizing treatment and minimizing abuse liability.

PMID: 29266563 [PubMed - indexed for MEDLINE]

The COVID-19 pandemic: consideration for brain infection.

Neuroscience. 2020 May 04;:

Authors: Mao XY, Jin WL

PMID: 32380269 [PubMed - as supplied by publisher]

Recommendations for Clinical Warfarin Sensitivity Genotyping Allele Selection: A Report of the Association for Molecular Pathology and College of American Pathologists.

J Mol Diagn. 2020 May 04;:

Authors: Pratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, Whirl-Carrillo M, Weck KE

Abstract
The goals of the Association for Molecular Pathology (AMP) Clinical Practice Committee's AMP Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic (PGx) alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provide recommendations for a minimum panel of variant alleles ("Tier 1") and an extended panel of variant alleles ("Tier 2") that will aid clinical laboratories when designing assays for PGx testing. The AMP PGx Working Group considered functional impact of the variants, allele frequencies in multiethnic populations, the availability of reference materials (RMs), as well as other technical considerations for PGx testing when developing these recommendations. Our ultimate goal is to promote standardization of PGx gene/allele testing across clinical laboratories. These recommendations are not to be interpreted as prescriptive but to provide a reference guide. Of note, a separate article with recommendations for CYP2C9 allele selection was previously developed by the PGx Working Group that can be applied broadly to CYP2C9-related medications. The warfarin sensitivity allele recommendations in this report incorporate the previous CYP2C9 allele recommendations and additional genes and alleles that are specific to warfarin sensitivity testing.

PMID: 32380173 [PubMed - as supplied by publisher]

Implementation of a pharmacogenomic program in a Brazilian Public Institution.

Pharmacogenomics. 2020 May 07;:

Authors: Suarez-Kurtz G, Kovaleski G, Elias AB, Motta V, Wolch K, Emerenciano M, Mansur MB, Palladino AM, Accioly MT, Ferreira M, Gonçalves AA, de Melo AC

Abstract
This narrative review describes implementation, current status and perspectives of a pharmacogenomic (PGx) program at the Brazilian National Cancer Institute (INCA), targeting the cancer chemotherapeutic drugs - fluoropyrimidines, irinotecan and thiopurines. This initiative, designed as a research project, was supported by a grant from the Brazilian Ministry of Health. A dedicated task force developed standard operational procedures from recruitment of patients to creating PGx reports with dosing recommendations, which were successfully applied to test 100 gastrointestinal cancer INCA outpatients and 162 acute lymphoblastic leukemia pediatric patients from INCA and seven other hospitals. The program has been subsequently expanded to include gastrointestinal cancer patients from three additional cancer treatment centers. We anticipate implementation of routine pre-emptive PGx testing at INCA but acknowledge challenges associated with this transition, such as continuous financing support, availability of trained personnel, adoption of the PGx-informed prescription by the clinical staff and, ultimately, evidence of cost-effectiveness.

PMID: 32378980 [PubMed - as supplied by publisher]

Unique Genotyping Protocol of CYP2D6 Allele Frequency Using Real Time Quantitative PCR from Japanese Healthy Women.

Biol Pharm Bull. 2020;43(5):904-907

Authors: Kisoi M, Imai M, Yamamura M, Sakaguchi Y, Murata S, Ichikawa A, Kinoshita K

Abstract
CYP2D6 is an important drug-metabolizing enzyme involved in the metabolism of 20-25% of commonly prescribed drugs. Genetic polymorphism of CYP has clinically significant modifications in patients' drug-metabolizing capacities. Since gene copy number variation (CNV) and single nucleotide polymorphism (SNP) frequently occur in the CYP2D6 gene, which the activity of CYP2D6 particularly depend on the genetic factors. This study aimed to investigate the frequencies of CYP2D6 genotypes in a Japanese female subject of 216 healthy volunteers. The volunteers were genotyped for CNV Exon 9 and four CYP2D6 genetic variants (*2, *5, *10, *14, *41) performed by TaqMan® genotyping assays. The CNV allele frequencies were 82.9% for two copies, 11.6% for one copy, 4.6% for three copies and 0.9% for zero copy, respectively. The frequencies of CYP2D6*1, *2, *5, *10, *14, and *41 were 38.7, 16.7, 6.3, 34.7, 0.2, and 1.2%, respectively. CYP2D6*5 and *14 were the major defective alleles. However, this genotyping is labor intensive, time consuming, and costly. We report an optimized novel protocol for the determination of CNV and SNP in CYP2D6 gene by real-time quantitative PCR. This can lower the cost and accurately determine CNV and SNP in the CYP2D6 gene with a higher output and enabling reliable estimates of disease prediction in large epidemiological samples.

PMID: 32378566 [PubMed - in process]

Use of pharmacogenomics in elderly patients treated for cardiovascular diseases.

Croat Med J. 2020 Apr 30;61(2):147-158

Authors: Božina N, Vrkić Kirhmajer M, Šimičević L, Ganoci L, Mirošević Skvrce N, Klarica Domjanović I, Merćep I

Abstract
Older people are increasingly susceptible to adverse drug reactions (ADRs) or therapeutic failure. This could be mediated by considerable polypharmacy, which increases the possibility of drug-drug and drug-gene interactions. Precision medicine, based on individual genetic variations, enables the screening of patients at risk for ADRs and the implementation of personalized treatment regimens. It combines genetic and genomic data with environmental and clinical factors in order to tailor prevention and disease-management strategies, including pharmacotherapy. The identification of genetic factors that influence drug absorption, distribution, metabolism, excretion, and action at the drug target level allows individualized therapy. Positive pharmacogenomic findings have been reported for the majority of cardiovascular drugs (CVD), suggesting that pre-emptive testing can improve efficacy and minimize the toxicity risk. Gene variants related to drug metabolism and transport variability or pharmacodynamics of major CVD have been translated into dosing recommendations. Pharmacogenetics consortia have issued guidelines for oral anticoagulants, antiplatelet agents, statins, and some beta-blockers. Since the majority of pharmacogenetics recommendations are based on the assessment of single drug-gene interactions, it is imperative to develop tools for the prediction of multiple drug-drug-gene interactions, which are common in the elderly with comorbidity. The availability of genomic testing has grown, but its clinical application is still insufficient.

PMID: 32378381 [PubMed - in process]

Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015.

Breast Cancer Res Treat. 2020 May 06;:

Authors: O'Donnell PH, Trubetskoy V, Nurhussein-Patterson A, Hall JP, Nath A, Huo D, Fleming GF, Ingle JN, Abramson VG, Morrow PK, Storniolo AM, Forero A, Van Poznak C, Liu MC, Chang JC, Merkel DE, Peppercorn JM, Rugo HS, Dees EC, Hahn OM, Hoffman PC, Rosner GL, Huang RS, Ratain MJ, Cox N, Olopade OI, Wolff AC, Dolan ME, Nanda R, Translational Breast Cancer Research Consortium (TBCRC)

Abstract
PURPOSE: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool.
METHODS: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint.
RESULTS: Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea-DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = - 0.74; P = 1.46 × 10-23), representing a previously unidentified mechanism for HFS.
CONCLUSIONS: This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

PMID: 32378051 [PubMed - as supplied by publisher]

Pharmacogenomics: an Update for Child and Adolescent Psychiatry.

Curr Psychiatry Rep. 2020 May 06;22(5):26

Authors: Namerow LB, Walker SA, Loftus M, Bishop JR, Ruaño G, Malik S

Abstract
PURPOSE OF REVIEW: This paper aims to acquaint child and adolescent psychiatrists with the field of pharmacogenomics (PGX) and review the most up-to-date evidence-based practices to guide the application of this field in clinical care.
RECENT FINDINGS: Despite much research being done in this area, the field of PGX continues to yield controversial findings. In the adult world, studies have focused on the impact of combinatorial gene panels that guide medication selection by providing reports that estimate the impact of multiple pharmacodynamic and pharmacokinetic genes, but to date, these have not been directly examined in younger patient populations. Pharmacokinetic genes, CYP2D6 and CYP2C19, and hypersensitivity genes, HLA-A and HLA-B, have the strongest evidence base for application to pharmacotherapy in children. Although the field is evolving, and the evidence is mixed, there may be a role for PGX testing in children to help guide dosing and monitoring strategies. However, evidence-based medicine, rather than PGX testing, continues to play the lead role in guiding medication selection in pediatric psychopharmacology.

PMID: 32377970 [PubMed - in process]

Altered Expression of Three EGFR Posttranslational Regulators MDGI, MIG6, and EIG121 in Invasive Breast Carcinomas.

Anal Cell Pathol (Amst). 2020;2020:9268236

Authors: Meseure D, Drak Alsibai K, Vacher S, Hatem R, Nicolas A, Callens C, Lerebours F, Bieche I

Abstract
Epidermal growth factor receptor (EGFR) signalling is a highly regulated process with a tight balance between receptor activation and inactivation in invasive breast carcinomas (IBCs) particularly in triple-negative carcinomas (TNC). Clinical trials using anti-EGFR therapies are actually performed although no activating alterations (mutations, amplifications, or rearrangements) of EGFR have been clearly recognized in order to identify new targeted modalities for IBCs. We explored mammary-derived growth inhibitor (MDGI), estrogen-induced gene-121 (EIG121), and mitogen-induced gene-6 (MIG6), three posttranslational EGFR trafficking molecules implicated in EGFR spatiotemporal regulatory pathway. We quantified MDGI, EIG121, and MIG6 at mRNA levels by using real-time quantitative RT-PCR in a series of 440 IBCs and at protein levels by using immunohistochemistry in a series of 88 IBCs. Results obtained by RT-PCR showed that in IBCs, MDGI, MIG6, and EIG121 mRNA were mainly underexpressed (25.7%, 45.0%, and 16.1%, respectively) particularly in the TNC subtype for EIG121 (60.3%). We also observed mRNA overexpression of MDGI and EIG121, respectively, in 12.7% and 22.3% of IBCs. These altered mRNA expressions were confirmed at the protein level. Some links were found between expression patterns of these three genes and several classical pathological and clinical parameters. Only EIG121 was found to have a prognostic significance (p = 0.0038). Altered expression of these three major EGFR posttranslational negative regulators could create an aberrant EGFR-mediated oncogenic signalling pathway in IBCs. MDGI, MIG6, and EIG121 expression status also may be potential useful biomarkers (sensitivity or resistance) in targeted EGFR therapy.

PMID: 32377505 [PubMed - in process]

Obesity and STING1 genotype associate with 23-valent pneumococcal vaccination efficacy.

JCI Insight. 2020 May 07;5(9):

Authors: Sebastian M, Hsiao CJ, Futch HS, Eisinger RS, Dumeny L, Patel S, Gobena M, Katikaneni DS, Cohen J, Carpenter AM, Spiryda L, Heldermon CD, Jin L, Brantly ML

Abstract
BACKGROUNDObesity has been associated with attenuated vaccine responses and an increased risk of contracting pneumococcal pneumonia, but no study to our knowledge has assessed the impact of obesity and genetics on 23-valent pneumococcal vaccine (PPSV23) efficacy. We assessed the relationship of obesity (primary analysis) and stimulator of interferon genes (STING1) genotype (secondary analysis) on PPSV23 efficacy.METHODSNonobese (BMI 22-25 kg/m2) and obese participants (BMI ≥30 kg/m2) were given a single dose of PPSV23. Blood was drawn immediately prior to and 4-6 weeks after vaccination. Serum samples were used to assess PPSV23-specific antibodies. STING1 genotypes were identified using PCR on DNA extracted from peripheral blood samples.RESULTSForty-six participants were categorized as nonobese (n = 23; 56.5% women; mean BMI 23.3 kg/m2) or obese (n = 23; 65.2% women; mean BMI 36.3 kg/m2). Obese participants had an elevated fold change in vaccine-specific responses compared with nonobese participants (P < 0.0001). The WT STING1 group (R232/R232) had a significantly higher PPSV23 response than individuals with a single copy of HAQ-STING1 regardless of BMI (P = 0.0025). When WT was assessed alone, obese participants had a higher fold serotype-specific response compared with nonobese participants (P < 0.0001), but no difference was observed between obese and nonobese individuals with 1 HAQ allele (P = 0.693).CONCLUSIONSThese observations demonstrate a positive association between obesity and PPSV23 efficacy specifically in participants with the WT STING1 genotype.TRIAL REGISTRATIONClinicalTrials.gov NCT02471014.FUNDINGThis research was supported by the NIH and the University of Florida MD-PhD Training Program.

PMID: 32376795 [PubMed - in process]

[Artificial intelligence empowers laboratory medicine in Industry 4.0].

Nan Fang Yi Ke Da Xue Xue Bao. 2020 Feb 29;40(2):287-296

Authors: Zhou Q, Qi S, Xiao B, Li Q, Sun Z, Li L

Abstract
Since 2017, China, the United States, and the European Union have successively issued national-level artificial intelligence (AI) strategic development plans, and the human history is about to witness the 4th industrial revolution with the theme of "intelligence". In the field of medical testing, the explosive growth of AI theories and technologies also provide a new direction for the development of medical testing theory, methods and applications. We review the evolution of AI and the recent progress in three major elements of AI, namely algorithms, data and computing power, and elaborate on the combined innovation of "AI + testing" in light of the key application dimensions of medical testing. The major applications include specimen collection robots, sample dilution robots and sample transfer robots involved in the processing of test specimens; test item mining such as tumor markers and pharmacogenomics; cytomorphology, laboratory medicine data processing, auxiliary diagnostic models, and internet-based medical tests. With the advent of the era of Industry 4.0, AI technology will promote the development of medical testing from automation to a highly intelligent stage.

PMID: 32376538 [PubMed - in process]

The influence of genetic polymorphisms in drug metabolism enzymes and transporters on the pharmacokinetics of different fluvastatin formulations.

Asian J Pharm Sci. 2020 Mar;15(2):264-272

Authors: Xiang Q, Wu W, Zhao N, Li C, Xu J, Ma L, Zhang X, Xie Q, Zhang Z, Wang J, Xu W, Zhao X, Cui Y

Abstract
The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics. In addition, we compared the fluvastatin pharmacokinetics differences between extended-release (ER) 80 mg tablet and immediate-release (IR) 40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms. In this open-label, randomized, two-period, two-treatment, crossover study (n = 24), effects of ABCG2, SLCO1B1, ABCB1, CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed. The administration dosage for IR 40 mg and ER 80 mg were twice and once daily, respectively, for total 7 d. Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d. The lower exposure following ER was observed. For ER tablets, SLCO1B1 T521C genotype correlated with AUC0-24 of repeat doses (P = 0.010). SLCO1B1 T521C genotype had no statistically significant effect on AUC0-24 of IR capsule of fluvastatin after single or repeated doses. In vitro study demonstrated that when the concentration of fluvastatin was low (< 1 µmol/l), the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1 521TT (Km =0.18 µmol/l) was faster than that with SLCO1B1 521CC (Km =0.49 µmol/l), On the other hand, when concentration reached to higher level (> 1 µmol/l), transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1 521TT (Km  = 11.4 µmol/l) and with SLCO1B1 521TCC (Km =15.1 µmol/l) tend to be the same. It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations. We recommend that formulation should be incorporated into future pharmacogenomics studies.

PMID: 32373204 [PubMed]

HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

Pharmacogenomics. 2020 May 06;:

Authors: Gagné V, St-Onge P, Beaulieu P, Laverdière C, Leclerc JM, Tran TH, Sallan SE, Neuberg D, Silverman LB, Sinnett D, Krajinovic M

Abstract
Aim: To evaluate the association between human leukocyte antigen (HLA) alleles and native Escherichia coli asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Patients & methods: HLA-DQA1, HLA-DRB1 and HLA-DQB1 alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts. Results: Two alleles in linkage disequilibrium (HLA-DRB1*07:01 and DQA1*02:01) were associated with AH. Additional analyses, performed to distinguish between HLA-DRB1*07:01 haplotypes with and without DQB1*02:02 allele, showed that the association was dependent on the presence of DQB1*02:02. Conclusion: This study confirms the implication of HLA-DRB1*07:01, DQA1*02:01 and DQB1*02:02 alleles in developing AH in childhood ALL.

PMID: 32372697 [PubMed - as supplied by publisher]

Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment.

Pharmacogenomics. 2020 May 06;:

Authors: Pisanu C, Congiu D, Manchia M, Caria P, Cocco C, Dettori T, Frau DV, Manca E, Meloni A, Nieddu M, Noli B, Pinna F, Robledo R, Sogos V, Ferri GL, Carpiniello B, Vanni R, Bocchetta A, Severino G, Ardau R, Chillotti C, Zompo MD, Squassina A

Abstract
Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). Materials & methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Conclusion: Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.

PMID: 32372689 [PubMed - as supplied by publisher]

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PG-path: Modeling and personalizing pharmacogenomics-based pathways.

PLoS One. 2020;15(5):e0230950

Authors: Hong JY, Kim JH

Abstract
A pharmacogenomics-based pathway represents a series of reactions that occur between drugs and genes in the human body after drug administration. PG-path is a pharmacogenomics-based pathway that standardizes and visualizes the components (nodes) and actions (edges) involved in pharmacokinetic and pharmacodynamic processes. It provides an intuitive understanding of the drug response in the human body. A pharmacokinetic pathway visualizes the absorption, distribution, metabolism, and excretion (ADME) at the systemic level, and a pharmacodynamic pathway shows the action of the drug in the target cell at the cellular-molecular level. The genes in the pathway are displayed in locations similar to those inside the body. PG-path allows personalized pathways to be created by annotating each gene with the overall impact degree of deleterious variants in the gene. These personalized pathways play a role in assisting tailored individual prescriptions by predicting changes in the drug concentration in the plasma. PG-path also supports counseling for personalized drug therapy by providing visualization and documentation.

PMID: 32365122 [PubMed - as supplied by publisher]