Protocol for the development of the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline: checklist of items for reporting pharmacogenetic studies.

BMJ Open. 2019 Jul 11;9(7):e030212

Authors: Richardson M, Kirkham JJ, Dwan KM, Sloan DJ, Davies G, Jorgensen A

Abstract
INTRODUCTION: Large sample sizes are often required to detect statistically significant associations between pharmacogenetic markers and treatment response. Meta-analysis may be performed to synthesise data from several studies, increasing sample size and consequently power to detect significant genetic effects. However, performing robust synthesis of data from pharmacogenetic studies is often challenging due to poor reporting of key data in study reports. There is currently no guideline for the reporting of pharmacogenetic studies. The aim of this project is to develop the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline. The STROPS guideline will facilitate the conduct of high-quality meta-analyses and thus improve the power to detect genetic associations.
METHODS AND ANALYSIS: We will establish a preliminary checklist of reporting items to be considered for inclusion in the guideline. We will then conduct a Delphi survey of key stakeholder groups to gain consensus opinion on which reporting items to include in the final guideline. The Delphi survey will consist of two rounds: the first round will invite participants to score items from the preliminary checklist and to suggest additional relevant items; the second round will provide feedback from the previous round and invite participants to re-score the items. Following the second round, we will summarise the distribution of scores for each item, stratified by stakeholder group. The Steering Committee for the project and representatives from the key stakeholder groups will meet to consider the results of the Delphi survey and to finalise the list of reporting items. We will then draft, pilot-test and publish the STROPS reporting guideline and accompanying explanatory document.
ETHICS AND DISSEMINATION: The University of Liverpool Ethics Committee has confirmed ethical approval for this study (reference: 3586). Dissemination activities will include presenting the reporting guideline at conferences relevant to pharmacogenetic research.

PMID: 31300508 [PubMed - in process]

Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART.

J Antimicrob Chemother. 2019 Jul 12;:

Authors: Neary M, Chappell CA, Scarsi KK, Nakalema S, Matovu J, Achilles SL, Chen BA, Siccardi M, Owen A, Lamorde M

Abstract
BACKGROUND: We previously demonstrated that etonogestrel concentrations were 82% lower in women using etonogestrel contraceptive implants plus efavirenz-based ART compared with women not receiving ART.
OBJECTIVES: To investigate the genetic contribution to this previously observed drug-drug interaction through studying SNPs in genes known to be involved in efavirenz, nevirapine or etonogestrel metabolism in the same group of women.
PATIENTS AND METHODS: Here, we present a secondary analysis evaluating SNPs involved in efavirenz, nevirapine and etonogestrel metabolism and associated etonogestrel pharmacokinetics among 57 women, 19 not receiving ART (control group), 19 receiving efavirenz- (600 mg daily) based ART and 19 receiving nevirapine- (200 mg twice daily) based ART. Associations between patient genotype and etonogestrel pharmacokinetic parameters were determined through univariate and multivariate linear regression. This study was registered at clinicaltrials.gov (NCT02082652).
RESULTS: Within the control group, CYP2B6 983 T>C was associated with 27% higher etonogestrel Cmax and 28% higher AUC0-24weeks. In the efavirenz group CYP2B6 516 G>T was associated with 43% lower etonogestrel Cmin and 34% lower AUC0-24weeks. For participants receiving nevirapine, NR1I2 63396 C>T was associated with 39% lower etonogestrel Cmin and 37% lower AUC0-24weeks.
CONCLUSIONS: This study demonstrates the influence of pharmacogenetics on the extent of drug-drug interactions between etonogestrel and efavirenz- or nevirapine-based ART. Efavirenz plus the etonogestrel contraceptive implant results in a detrimental drug-drug interaction irrespective of patient genetics, which is worsened in women possessing variant alleles for these CYP2B6 SNPs.

PMID: 31299074 [PubMed - as supplied by publisher]

Enhancing the Visibility and Prestige of Clinical Pharmacology as a Medical Subspecialty.

Clin Pharmacol Ther. 2019 Jul 12;:

Authors: Ratain MJ

PMID: 31298730 [PubMed - as supplied by publisher]

Quadrupole-Time-of-Flight Mass Spectrometric Identification of Hemoglobin Subunits α, β, γ and δ in Unknown Peaks of High Performance Liquid Chromatography of Hemoglobin in β-Thalassemias.

Hemoglobin. 2019 Jul 12;:1-6

Authors: Abdullah UYH, Ibrahim HM, Mahmud NB, Salleh MZ, Kek TL, Noorizhab MNFB, Jassim HM, Othman I, Zainal Abidin SA, Zilfalil BA, Wilairat P, Fucharoen S

Abstract
This is the first report of quadrupole time-of-flight (Q-TOF) mass spectrometric identification of the hemoglobin (Hb) subunits, α, β, δ and γ peptides, derived from enzymatic-digestion of proteins in the early unknown peaks of the cation exchange chromatography of Hb. The objectives were to identify the unknown high performance liquid chromatography (HPLC) peaks in healthy subjects and in patients with β-thalassemia (β-thal). The results demonstrate the existence of pools of free globin chains in red blood cells (RBCs). The α-, β-, δ- and γ-globin peptides were identified in the unknown HPLC peaks. The quantification and role of the free globin pool in patients with β-thal requires further investigation. Identification of all types of Hb subunits in the retention time (RT) before 1 min. suggests that altered Hbs is the nature of these fast-eluting peaks. Relevancy of thalassemias to the protein-aggregation disorders will require review of the role of free globin in the pathology of the disease.

PMID: 31298599 [PubMed - as supplied by publisher]

Neurexophilin and PC-esterase domain family member 4 (NXPE4) and prostate androgen-regulated mucin-like protein 1 (PARM1) as prognostic biomarkers for colorectal cancer.

J Cell Biochem. 2019 Jul 11;:

Authors: Liu YR, Hu Y, Zeng Y, Li ZX, Zhang HB, Deng JL, Wang G

Abstract
Owing to the high morbidity and mortality, novel biomarkers in the occurrence and development of colorectal cancer (CRC) are needed nowadays. In this study, the CRC-related datasets were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database. After screening the differentially expressed genes (DEGs) in R software, a total of 238 upregulated and 199 downregulated DEGs were revealed simultaneously. Then the Kaplan-Meier survival analysis and Cox regression analysis were used to reveal the prognostic function of these DEGs. Neurexophilin and PC-esterase domain family member 4 (NXPE4) and prostate androgen-regulated mucin-like protein 1 (PARM1) were two outstanding independent overall survival (OS) and relapse-free survival (RFS) prognostic genes of CRC in TCGA database. We next verified the expression of NXPE4 and PARM1 messenger RNA (mRNA) levels were significantly lower in CRC tumor tissue than in the adjacent noncancerous tissue in our clinical samples, and NXPE4 mRNA expression level was related to the tumor location and tumor size, while PARM1 was related to tumor location, lymph nodes metastasis, and tumor size. This study demonstrated that NXPE4 and PARM1 might be two potential novel prognostic biomarkers for CRC.

PMID: 31297877 [PubMed - as supplied by publisher]

ANKRD44 Gene Silencing: A Putative Role in Trastuzumab Resistance in Her2-Like Breast Cancer.

Front Oncol. 2019;9:547

Authors: La Ferla M, Lessi F, Aretini P, Pellegrini D, Franceschi S, Tantillo E, Menicagli M, Marchetti I, Scopelliti C, Civita P, De Angelis C, Diodati L, Bertolini I, Roncella M, McDonnell LA, Hochman J, Del Re M, Scatena C, Naccarato AG, Fontana A, Mazzanti CM

Abstract
Trastuzumab is an effective therapeutic treatment for Her2-like breast cancer; despite this most of these tumors develop resistance to therapy due to specific gene mutations or alterations in gene expression. Understanding the mechanisms of resistance to Trastuzumab could be a useful tool in order to identify combinations of drugs that elude resistance and allow a better response for the treated patients. Twelve primary biopsies of Her2+/hormone receptor negative (ER-/PgR-) breast cancer patients were selected based on the specific response to neoadjuvant therapy with Trastuzumab and their whole exome was sequenced leading to the identification of 18 informative gene mutations that discriminate patients selectively based on response to treatment. Among these genes, we focused on the study of the ANKRD44 gene to understand its role in the mechanism of resistance to Trastuzumab. The ANKRD44 gene was silenced in Her2-like breast cancer cell line (BT474), obtaining a partially Trastuzumab-resistant breast cancer cell line that constitutively activates the NF-kb protein via the TAK1/AKT pathway. Following this activation an increase in the level of glycolysis in resistant cells is promoted, also confirmed by the up-regulation of the LDHB protein and by an increased TROP2 protein expression, found generally associated with aggressive tumors. These results allow us to consider the ANKRD44 gene as a potential gene involved in Trastuzumab resistance.

PMID: 31297336 [PubMed]

Effects of GRM4, SCN2A and SCN3B polymorphisms on antiepileptic drugs responsiveness and epilepsy susceptibility.

Saudi Pharm J. 2019 Jul;27(5):731-737

Authors: Al-Eitan LN, Al-Dalalah IM, Aljamal HA

Abstract
Background: Pharmacotherapy of epilepsy including antiepileptic drugs (AEDs) is one of the main treatment approaches. As a biological target, sodium channels (Nav channels) and glutamate receptor genes are playing a major role in the etiology and treatment of epilepsy.
Objective: This study aims to investigate the genetic associations of certain genetic polymorphisms with increased risk of epilepsy susceptibility and variability in response to AEDs treatment in a Jordanian Arab population.
Method: A pharmacogenetics and case-control study on 296 unrelated epileptic Jordanian patients recruited from the pediatric neurology clinic at the Queen Rania Al-Abdullah Hospital (QRAH) in Amman, Jordan and 299 healthy individuals was conducted. Children up to 15 years old which receiving AEDs for at least three months were scanned for genetic association of 7 single nucleotide polymorphisms (SNPs) within three candidate genes (SCN2A, SCN3B and GRM4) with epilepsy susceptibility.
Results: SCN2A rs2304016 (P = 0.04) and GRM4 rs2499697 (P = 0.031) were statistically significant with generalized epilepsy. Haplotype of CAACG GRM4 was genetically associated with epilepsy and partial epilepsy (P = 0.036; P = 0.024, respectively). This study also found that TGTAA genetic haplotype formed within GRM4 gene was associated with generalized epilepsy susceptibility (P = 0.006). While, no significant linkage of SCN3B rs3851100 to either disease susceptibility or drug responsiveness was found.
Conclusion: This study identified no significant associations of allelic or genotypic SNPs with the susceptibility of epilepsy and medication response with an exception of rs2304016 and rs2499697 SNPs that were associated with the generalized type of epilepsy among Jordanian population. Further studies are required in different populations to confirm our results and identify genetic factors that involved in susceptibility and treatment response.

PMID: 31297029 [PubMed]

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.

Clin Cancer Res. 2019 Jul 11;:

Authors: Trendowski MR, El Charif O, Ratain MJ, Monahan P, Mu Z, Wheeler HE, Dinh PC, Feldman DR, ArdeshirRouhaniFard S, Hamilton R, Vaughn DJ, Fung C, Kollmannsberger C, Mushiroda T, Kubo M, Hannigan R, Strathmann FG, Einhorn LH, Fossa SD, Travis LB, Dolan ME

Abstract
PURPOSE: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels.
EXPERIMENTAL DESIGN: Eligible TCS given 300 or 400 (±15) mg/m2cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a bi-exponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model.
RESULTS: Serum platinumlevels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted p = 2.13x10-3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted p=6.58x10-3). Patients with high residual platinum levels experienced greater Raynaud's phenomenon than those with medium or low levels (age-adjusted ORhigh/low =1.46; p = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low= 1.68, p = 0.07). GWAS identified one single nucleotide polymorphism (SNP) meeting genome-wide significance rs1377817 (p=4.6x10-8, a SNP intronic to MYH14) Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.

PMID: 31296530 [PubMed - as supplied by publisher]

Anti-VEGF treatment and response in Age-related Macular Degeneration: Disease´s susceptibility, pharmacogenetics and pharmacokinetics.

Curr Med Chem. 2019 Jul 10;:

Authors: Álvarez ÁC, Amigo OM, Quintanilla LG, Rodríguez AL, Ferreiro AF, Pellicer AL, Abraldes MJ, Lamas MJ

Abstract
The current review is focussing on different factors that contribute and directly correlate to the onset and progression of Age-related Macular Degeneration (AMD). In particular, the susceptibility to AMD due to genetic and non-genetic factors and the establishment of risk scores, based on the analysis of different genes to measure the risk of developing the disease. A correlation with the actual therapeutic landscape to treat AMD patients from the point of view of pharmacokinetics and pharmacogenetics is also exposed. Treatments commonly used, as well as different regimes of administration will be especially important in trying to classify individuals as "responders" and "non-responders". Analysis of different genes correlated with drug response and also the emerging field of microRNAs (miRNAs) as possible biomarkers for early AMD detection and response will be also reviewed. This article aims to provide the reader a review of different publications correlated with AMD from the molecular and kinetic point of view as well as its commonly used treatments, major pitfalls and future directions that, to our knowledge, could be interesting to assess and follow in order to develop a personalized medicine model for AMD.

PMID: 31296152 [PubMed - as supplied by publisher]

No genetic associations with mepolizumab efficacy in COPD with peripheral blood eosinophilia.

Respir Med. 2019 Jul 05;155:26-28

Authors: Condreay LD, Gao C, Bradford E, Yancey SW, Ghosh S

Abstract
INTRODUCTION: Improved understanding of genetic effects on response to treatments with novel approaches for COPD with peripheral blood eosinophilia, such as mepolizumab (a humanized monoclonal antibody to IL-5), may improve treatment outcomes. We conducted a study to identify genetic variants associated with efficacy of mepolizumab COPD.
MATERIALS AND METHODS: Using generalized linear and logistic regression models, genome-wide association analyses were performed to investigate genetic associations with frequency of moderate and/or severe COPD exacerbations in COPD subjects receiving mepolizumab (weeks 0-52). Additional analyses included: (i) frequency of COPD exacerbations requiring hospitalization or emergency department visit (weeks 0-52), (ii) change from baseline mean total St. George's Respiratory Questionnaire (SGRQ) score (week 24), and (iii) SGRQ response defined as achieving a 4 unit or greater decrease of SGRQ score from baseline (week 24). This study included 610 patients with COPD, a subset of the Intent-to-treat (ITT) populations in two phase III double-blind trials assessing the efficacy and safety of mepolizumab, METREX (NCT02105948) and METREO (NCT02105961). All subjects had elevated eosinophil levels (≥150 cells/μL at screening or ≥300 cell/μL in the 12 months prior to study), were treated with mepolizumab, and provided consent for genetic analysis.
RESULTS: From this post-hoc analysis, no genetic variant was significantly associated with moderate and/or severe COPD exacerbations or any of the other endpoints tested (threshold for statistical significance at the genome-wide level, p = 5 × 10-8).
CONCLUSIONS: In this exploratory study in patients with COPD, with peripheral blood eosinophilia, no genetic effects on mepolizumab-treatment response were identified.

PMID: 31295674 [PubMed - as supplied by publisher]

Polymorphisms in the BDNF and BDNFOS genes are associated with hypothalamus-pituitary axis regulation in major depression.

Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jul 08;:109686

Authors: Hennings JM, Kohli MA, Uhr M, Holsboer F, Ising M, Lucae S

Abstract
Major depression is a stress-related disorder with robust clinical and preclinical data implicating that both, dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) axis and of the neurotrophin system of the brain are involved in the pathophysiology. Genetic variations within the brain-derived neurotrophic factor (BDNF) gene region, a major representative of the brain neurotrophins, are suggested to influence response to antidepressant treatment. Specifically, we recently identified two BDNF single nucleotide polymorphisms (SNP), rs2049046 and rs11030094, as associated with antidepressant treatment response in a large pharmacogenetic study of hospitalized patients. We now analyzed these two SNPs in a sub-sample for their association with HPA axis dysregulation using the combined dexamethasone suppression/corticotropin releasing hormone challenge (dex/CRH) test at hospital admission (N = 266) and at discharge (N = 190). Rs11030094, located 3' outside the coding region of BDNF, is also located in an intron of BDNFOS coding for a functional antagonist of BDNF. We further included the non-synonymous Val66Met (rs6265) polymorphism in our analysis, for which - albeit being extensively studied - conflicting results in respect to its role in antidepressant treatment response have been reported. Similar to the previous analysis, rs2049046 and rs11030094 showed a significant effect on antidepressant response. In a gene-dose dependent manner, we found significant lower cortisol responses to the dex/CRH test at discharge in carriers of the respective SNP alleles ('T' of rs2049046 and 'G' of rs11030094) that were associated with antidepressant response (beneficial alleles). These genetic effects on HPA axis regulation were independent of age, sex, medication and depressive symptomatology. Although not reaching statistical significance, the same direction of effect was observed for cortisol at admission, as well as the ACTH response at admission and discharge. An interaction analysis of both SNPs revealed highest cortisol levels in subjects that were non-carriers of both beneficial alleles. The Val66Met (rs6265) was neither associated with antidepressant response nor with HPA axis regulation. Our findings provide further evidence for an interaction of the HPA axis and the neurotrophin system in major depression. This study stresses the importance investigating BDNF variants beyond the extensively studied Val66Met polymorphism. In-depth analyses of both pathophysiologically relevant systems may point to possible new targets for pharmaceutical intervention and precision medicine of major depression in the future.

PMID: 31295515 [PubMed - as supplied by publisher]

Pharmacogenetics of FSH Action in the Female.

Front Endocrinol (Lausanne). 2019;10:398

Authors: Conforti A, Vaiarelli A, Cimadomo D, Bagnulo F, Peluso S, Carbone L, Di Rella F, De Placido G, Ubaldi FM, Huhtaniemi I, Alviggi C

Abstract
The purpose of a pharmacogenomic approach is to tailor treatment on the basis of an individual human genotype. This strategy is becoming increasingly common in medicine, and important results have been obtained in oncologic and antimicrobial therapies. The rapid technological developments and availability of innovative methodologies have revealed the existence of numerous genotypes that can influence the action of medications and give rise to the idea that a true "individualized" approach could become in the future a reality in clinical practice. Moreover, compared to the past, genotype analyses are now more easily available at accessible cost. Concerning human reproduction, there is ample evidence that several variants of gonadotropins and their receptors influence female reproductive health and ovarian response to exogenous gonadotropins. In more detail, variants in genes of follicle-stimulating hormone β-chain (FSH-B) and its receptor (FSH-R) seem to be the most promising candidates for a pharmacogenomic approach to controlled ovarian stimulation in assisted reproductive technologies. In the present review, we summarize the evidence regarding FSH-B and FSH-R variants, with special reference to their impact on reproductive health and assisted reproductive technology treatments.

PMID: 31293516 [PubMed]

Development of Standard Operating Protocols for the Optimization of Cannabis-Based Formulations for Medical Purposes.

Front Pharmacol. 2019;10:701

Authors: Baratta F, Simiele M, Pignata I, Ravetto Enri L, Torta R, De Luca A, Collino M, D'Avolio A, Brusa P

Abstract
Under current legislation in Italy, Cannabis for medical purposes may be administered orally in the form of decoction or Cannabis oil extract. The scientific literature reports a number of preparation methods, mainly for oils, but no study is available that compares thoroughly, from a technological viewpoint, the Cannabis-based formulations currently administered to patients. With this in mind, this research work aimed to carry out specific formulation studies to design standard operating procedures for the preparation and optimization of Cannabis-based galenic formulations. Both decoctions and oils were prepared under different operating conditions to identify the most efficient process for the production of formulations with a high concentration of decarboxylated delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Regarding Cannabis oil, a new procedure has been developed that allows significantly higher recovery rates for THC and CBD compared with those for water-based extraction methods (decoction) and those for oil-based methods currently in use. Moreover, based on the results, it is possible to affirm that the prescription of Cannabis-based decoctions should not be the recommended first-choice solution for therapy, considering the low concentration of THC and CBD and, consequently, the high volume of decoction that the patient would have to ingest.

PMID: 31293423 [PubMed]

Association of P2RX7 functional variants with localized aggressive periodontitis.

J Periodontal Res. 2019 Jul 10;:

Authors: Harris TH, Wallace MR, Huang H, Li H, Mohiuddeen A, Gong Y, Kompotiati T, Harrison P, Aukhil I, Shaddox LM

Abstract
OBJECTIVE: The purpose of this study was to investigate involvement of the P2X7 receptor in the rare condition, localized aggressive periodontitis.
MATERIAL AND METHODS: Peripheral blood from 220 African Americans (103 with localized aggressive periodontitis and 117 healthy unrelated controls) was stimulated with lipopolysaccharide from E coli and Porphyromonas gingivalis. P2RX7 single nucleotide polymorphisms rs208294 (H155Y), rs1718119 (T348A), rs2230911 (T357S) and rs3751143 (E496A) were genotyped in 103 localized aggressive periodontitis patients and 117 healthy unrelated subjects. We examined genetic association between four P2RX7 single nucleotide polymorphisms and localized aggressive periodontitis, and tested for correlations between the single nucleotide polymorphisms and inflammatory response to lipopolysaccharide in blood samples from these patients.
RESULTS: A significant association with localized aggressive periodontitis was observed with rs1718119 A (Thr) allele (P = 0.0063, odds ratio = 1.904) and with a haplotype containing this allele (P = 0.0075). Additionally, significant correlations with these data were found: the rs1718119 G allele correlated with greater production of IL-6, IL-2 and GM-CSF; the C (His) allele of rs208294 correlated with lower levels of IL-12p40; and the C (Thr) allele of rs2230911 correlated with greater levels of G-CSF.
CONCLUSIONS: The data from these analyses support a possible biological relationship between P2RX7 genetic variants and inflammatory response in localized aggressive periodontitis patients.

PMID: 31292966 [PubMed - as supplied by publisher]

Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor Binding Sites Influence AHR Ligand-Dependent Gene Expression.

Drug Metab Dispos. 2019 Jul 10;:

Authors: Neavin DR, Lee JH, Liu D, Ye Z, Li H, Wang L, Ordog T, Weinshilboum RM

Abstract
Greater than 90% of significant genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are in noncoding regions of the genome but only 25.6% are known expression quantitative trait loci (eQTLs). Therefore, the function of many significant GWAS SNPs remains unclear. We have identified a novel type of eQTL for which SNPs distant from ligand-activated transcription factor (TF) binding sites can alter target gene expression in a SNP genotype-by-ligand-dependent fashion that we refer to as "pharmacogenomic eQTLs" (PGx-eQTLs)--loci which may have important pharmacotherapeutic implications. In the present study, we integrated ChIP-seq with RNA-seq and SNP genotype data for a panel of lymphoblastoid cell lines (LCLs) to identify 10 novel cis PGx-eQTLs dependent on the ligand-activated TF aryl hydrocarbon receptor (AHR)--a critical environmental sensor for xenobiotic (drug) and immune response. Those 10 cis PGx-eQTLs were eQTLs only after AHR ligand treatment even though the SNPs did not create/destroy an AHR response element--the DNA sequence motif recognized and bound by AHR. Additional functional studies in multiple cell lines demonstrated that some cis PGx-eQTLs are functional in multiple cell types while others displayed SNP-by-ligand-dependent effects in just one cell type. Further, four of those cis PGx-eQTLs had previously been associated with clinical phenotypes, indicating that those loci might have the potential to inform clinical decisions. Therefore, SNPs across the genome that are distant from TF binding sites for ligand-activated TFs might function as PGx-eQTLs and, as a result, might have important clinical implications for interindividual variation in drug response. SIGNIFICANCE STATEMENT: More than 90% of single nucleotide polymorhpisms (SNPs) that are associated with clinical phenotypes are located in non-coding regions of the genome. However, the mechanisms of action of many of those SNPs have not been elucidated and drugs may ‘unmask’ functional expression quantitative trail loci (eQTLs). In the current study, we used drugs that bind to the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and identified SNPs that were associated with interindividual variation in gene expression following drug exposure – termed pharmacogenomics (PGx)-eQTLs. Possibly of greater significance, those PGx-eQTL SNPs were outside of AHR binding sites indicating that they do not interrupt AHR DNA recognition. PGx-eQTLs such as those described here may have crucial implications for interindividual variation in drug.

PMID: 31292129 [PubMed - as supplied by publisher]

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux.

J Exp Clin Cancer Res. 2019 Jul 10;38(1):298

Authors: Wen ZP, Zeng WJ, Chen YH, Li H, Wang JY, Cheng Q, Yu J, Zhou HH, Liu ZZ, Xiao J, Chen XP

Abstract
BACKGROUND: Gliomas are the most common primary tumors in central nervous system. Despite advances in diagnosis and therapy, the prognosis of glioma remains gloomy. Autophagy is a cellular catabolic process that degrades proteins and damaged organelles, which is implicated in tumorigenesis and tumor progression. Autophagy related 4C cysteine peptidase (ATG4C) is an autophagy regulator responsible for cleaving of pro-LC3 and delipidation of LC3 II. This study was designed to investigate the role of ATG4C in glioma progression and temozolomide (TMZ) chemosensitivity.
METHODS: The association between ATG4C mRNA expression and prognosis of gliomas patients was analyzed using the TCGA datasets. The role of ATG4C in proliferation, apoptosis, autophagy, and TMZ chemosensitivity were investigated by silencing ATG4C in vivo. Ectopic xenograft nude mice model was established to investigate the effects of ATG4C on glioma growth in vivo.
RESULTS: The median overall survival (OS) time of patients with higher ATG4C expression was significantly reduced (HR: 1.48, p = 9.91 × 10- 7). ATG4C mRNA expression was evidently increased with the rising of glioma grade (p = 2.97 × 10- 8). Knockdown ATG4C suppressed glioma cells proliferation by inducing cell cycle arrest at G1 phase. ATG4C depletion suppressed autophagy and triggered apoptosis through ROS accumulation. Depletion of ATG4C suppressed TMZ-activated autophagy and promoted sensitivity of glioma cells to TMZ. Additionally, ATG4C knockdown suppressed the growth of glioma remarkably in nude mice.
CONCLUSION: ATG4C is a potential prognostic predictor for glioma patient. Targeting ATG4C may provide promising therapy strategies for gliomas treatment.

PMID: 31291988 [PubMed - in process]

Influence of DNMT3A R882 mutations on AML prognosis determined by the allele ratio in Chinese patients.

J Transl Med. 2019 Jul 10;17(1):220

Authors: Yuan XQ, Chen P, Du YX, Zhu KW, Zhang DY, Yan H, Liu H, Liu YL, Cao S, Zhou G, Zeng H, Chen SP, Zhao XL, Yang J, Zeng WJ, Chen XP

Abstract
BACKGROUND: The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. Besides, it is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations.
METHODS: DNMT3A R882 mutations in 870 adult AML patients receiving standard induction therapy were detected by pyrosequencing. Associations of the mutants with responses to induction therapy and disease prognosis were analyzed.
RESULTS: DNMT3A R882 mutations were detected in 74 (8.51%) patients and allele ratio of the mutations ranged from 6 to 50% in the cohort. After the first and second courses of induction therapy including aclarubicin, complete remission rates were significantly lower in carriers of the DNMT3A R882 mutants as compared with R882 wildtype patients (P = 0.022 and P = 0.038, respectively). Compared with R882 wild-type patients, those with the R882 mutations showed significantly shorter overall survival (OS) and disease-free survival (DFS) (P = 1.92 × 10-4 and P = 0.004, respectively). Patients with higher allele ratio of R882 mutations showed a significantly shorter OS as compared with the lower allele ratio group (P = 0.035).
CONCLUSION: Our results indicate that the impact of DNMT3A R882 mutations on AML prognosis was determined by the mutant-allele ratio and higher allele ratio could predict a worse prognosis, which might improve AML risk stratification. In addition, DNMT3A R882 mutations were associated with an inferior response to induction therapy with aclarubicin in Chinese AML patients.

PMID: 31291961 [PubMed - in process]

Potent chemogenetics.

Nat Methods. 2019 05;16(5):363

Authors: Vogt N

PMID: 31040421 [PubMed - indexed for MEDLINE]

Using pharmacogenetics in primary care.

JAAPA. 2019 Jul 08;:

Authors: Murfin M

Abstract
Pharmacogenetics offers a way to personalize medication prescribing for patients. Through the use of genetic tests that identify variations in enzymes important to drug metabolism, PAs can have patients' genetic information before prescribing a medication. This may reduce the risks of adverse reactions and lost treatment time when patients are given drugs to which they are unlikely to respond. Laboratory testing can identify common genetic variants that alter how the body metabolizes drugs. PAs with knowledge of these variants can choose medications that are more personalized and effective for each patient. Clinical pharmacogenetic guidelines are under development and will help providers identify which drugs are most likely to be affected by genetic variations so they can prescribe for patients based on their specific genetic phenotypes.

PMID: 31290773 [PubMed - as supplied by publisher]

Thiopurine Therapy in Patients With Inflammatory Bowel Disease: A Focus on Metabolism and Pharmacogenetics.

Dig Dis Sci. 2019 Jul 09;:

Authors: Chang JY, Cheon JH

Abstract
Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. To balance the efficacy, safety, and tolerability of thiopurines, regular monitoring of biomarkers (complete blood cell count, liver function test, and metabolic profiles), steady dose escalation, and pretreatment thiopurine S-methyltransferase (TPMT) genotype screening have been routinely recommended. However, the complex thiopurine metabolic pathway and individual differences attributed to pharmacogenetic diversity limit the effectiveness of these strategies in the optimization of thiopurine therapy. Recently, in an effort to facilitate more accurate and personalized prediction of thiopurine response or toxicity, novel genetic markers including NUDT15 and FTO genes were discovered. These discoveries are remarkable because TPMT screening has minimal efficacy for predicting myelosuppression especially in Asian populations, despite the fact that thee populations have a higher frequency of myelosuppression than Western populations. This review focuses on the current understanding of the metabolic pathway and the pharmacogenetics of thiopurines and suggests a personalized preventive strategy against potential adverse drug reactions to optimize their therapeutic application.

PMID: 31290039 [PubMed - as supplied by publisher]