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pharmacogenomics

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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 2019/04/04

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.

4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion.

Breast Cancer Res Treat. 2019 Apr 01;:

Authors: Wang G, Qin S, Zayas J, Ingle JN, Liu M, Weinshilboum RM, Shen K, Wang L

Abstract
PURPOSE: In early stage, ERα-positive breast cancer, concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous studies revealed that ZNF423 is a transcription factor for BRCA1 and an intronic single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Here, we identified mitosis-related genes that are regulated by ZNF423 which led us to investigate taxane response in a rs9940645 SNP- and tamoxifen-dependent fashion.
METHODS: The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes correlated with ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene regulation. We used CRISPR/Cas9 to engineer paired ZR-75-1 cells which differ only in ZNF423 rs9940645 SNP genotype to test SNP-dependent phenotypes including cell cycle and cell viability. We validated our findings in an additional two breast cancer cell lines, Hs578T-ERα and HCC1500.
RESULTS: Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. ZNF423 knockdown decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown enhanced docetaxel-induced G2/M arrest and cytotoxicity through VRK1 or PBK regulation. Lastly, cells carrying the rs9940645 variant genotype had increased G2/M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM.
CONCLUSIONS: We identified ZNF423 regulated genes involved in the G2/M phase of the cell cycle. 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen and docetaxel. This would impact a substantial proportion of patients because this SNP has a minor allele frequency of 0.47.

PMID: 30937657 [PubMed - as supplied by publisher]

Metformin Pharmacogenetics: Effects of SLC22A1, SLC22A2, and SLC22A3 Polymorphisms on Glycemic Control and HbA1c Levels.

J Pers Med. 2019 Mar 25;9(1):

Authors: Al-Eitan LN, Almomani BA, Nassar AM, Elsaqa BZ, Saadeh NA

Abstract
Type 2 diabetes mellitus (T2DM) constitutes a major portion of Jordan's disease burden, and incidence rates are rising at a rapid rate. Due to variability in the drug's response between ethnic groups, it is imperative that the pharmacogenetics of metformin be investigated in the Jordanian population. The objective of this study was to investigate the relationship between twenty-one single nucleotide polymorphisms (SNPs) in the SLC22A1, SLC22A2, and SLC22A3 genes and their effects on metformin pharmacogenetics in Jordanian patients diagnosed with type 2 diabetes mellitus. Blood samples were collected from 212 Jordanian diabetics who fulfilled the inclusion criteria, which were then used in SNP genotyping and determination of HbA1c levels. The rs12194182 SNP in the SLC22A3 gene was found to have a significant association (p < 0.05) with lower mean HbA1c levels, and this association more pronounced in patients with the CC genotype (i.e., p-value was significant before correcting for multiple testing). Moreover, the multinomial logistic regression analysis showed that SNP genotypes within the SLC22A1, SLC22A2, and SLC22A3 genes, body mass index (BMI) and age of diagnosis were significantly associated with glycemic control (p < 0.05). The results of this study can be used to predict response to metformin and other classes of T2DM drugs, making treatment more individualized and resulting in better clinical outcomes.

PMID: 30934600 [PubMed]

Warfarin dose requirement in patients having severe thrombosis or thrombophilia.

Br J Clin Pharmacol. 2019 Apr 01;:

Authors: Helin TA, Joutsi-Korhonen L, Asmundela H, Niemi M, Orpana A, Lassila R

Abstract
AIMS: Warfarin dose requirement varies significantly. We compared the clinically established international normalized ratio (INR) -based doses among patients with severe thrombosis and/or thrombophilia with estimates from genetic dosing algorithms.
METHODS: Fifty patients with severe thrombosis and/or thrombophilia requiring permanent anticoagulation, referred to the Helsinki University Hospital Coagulation Center, were screened for thrombophilias and genotyped for CYP2C9*2 (c.430C>T, rs1799853), CYP2C9*3 (c.1075A>C, rs1057910) and VKORC1 c.-1639G>A (rs9923231) variants. The warfarin maintenance doses (target INR 2.0-3.0 in 94%, 2.5-3.5 in 6%) were estimated by the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) algorithms. The individual warfarin maintenance dose was tailored, supplementing estimates with comprehensive clinical evaluation and INR data.
RESULTS: Mean patient age was 47 years (range, 20-76), and BMI 27 (SD 6), 68% being women. Forty-six (92%) had previous venous or arterial thrombosis, and 26 (52%) had a thrombophilia, with 22% having concurrent aspirin. A total of 40% carried the CYP2C9*2 or *3 allele and 54% carried the VKORC1-1639A allele. The daily mean maintenance dose of warfarin estimated by the Gage algorithm was 5.4 mg (95% CI 4.9-5.9 mg,), and by the IWPC algorithm was 5.2 mg (95% CI 4.7-5.7 mg,). The daily warfarin maintenance dose after clinical visits and follow-up was higher than the estimates, mean 6.9 mg (95% CI 5.6-8.2 mg, p<0.006), with highest dose in patients having multiple thrombophilic factors (p<0.03).
CONCLUSIONS: In severe thrombosis and/or thrombophilia, variation in thrombin generation and pharmacodynamics influences warfarin response. Pharmacogenetic dosing algorithms seem to underestimate dose requirement.

PMID: 30933373 [PubMed - as supplied by publisher]

The Low Molecular Weight Brain Derived Neurotrophic Factor Mimetics With Antidepressant-Like Activity.

Curr Pharm Des. 2019 Mar 29;:

Authors: Gudasheva TA, Povarnina P, Tarasiuk AV, Seredenin SB

Abstract
The search for new highly-effective, fast-acting antidepressant drugs is extremely relevant. Brain derived neurotrophic factor (BDNF) and signaling through its tropomyosin-related tyrosine kinase B (TrkB) receptor, represents one of the most promising therapeutic targets for treating depression. BDNF is a key regulator of neuroplasticity in the hippocampus and the prefrontal cortex, the dysfunction of which is considered to be the main pathophysiological hallmark of this disorder. BDNF itself has no favorable drug-like properties due to poor pharmacokinetics and possible adverse effects. The design of small, proteolytically stable BDNF mimetics might provide a useful approach for the development of therapeutic agents. There are two small molecule BDNF mimetics with antidepressant-like activity reported - 7, 8-dihydroxyflavone and the dimeric dipeptide mimetic of BDNF loop 4, GSB-106. The article reflects on current literature on the role of BDNF as a promising therapeutic target in the treatment of depression and on the current advances in development of small molecules on the base of this neurotrophin as potential antidepressants.

PMID: 30931847 [PubMed - as supplied by publisher]

NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis.

Nucleic Acids Res. 2019 Apr 01;:

Authors: Zhou G, Soufan O, Ewald J, Hancock REW, Basu N, Xia J

Abstract
The growing application of gene expression profiling demands powerful yet user-friendly bioinformatics tools to support systems-level data understanding. NetworkAnalyst was first released in 2014 to address the key need for interpreting gene expression data within the context of protein-protein interaction (PPI) networks. It was soon updated for gene expression meta-analysis with improved workflow and performance. Over the years, NetworkAnalyst has been continuously updated based on community feedback and technology progresses. Users can now perform gene expression profiling for 17 different species. In addition to generic PPI networks, users can now create cell-type or tissue specific PPI networks, gene regulatory networks, gene co-expression networks as well as networks for toxicogenomics and pharmacogenomics studies. The resulting networks can be customized and explored in 2D, 3D as well as Virtual Reality (VR) space. For meta-analysis, users can now visually compare multiple gene lists through interactive heatmaps, enrichment networks, Venn diagrams or chord diagrams. In addition, users have the option to create their own data analysis projects, which can be saved and resumed at a later time. These new features are released together as NetworkAnalyst 3.0, freely available at https://www.networkanalyst.ca.

PMID: 30931480 [PubMed - as supplied by publisher]

PLCE1 Polymorphisms and Risk of Esophageal and Gastric Cancer in a Northwestern Chinese Population.

Biomed Res Int. 2019;2019:9765191

Authors: Liang P, Zhang W, Wang W, Dai P, Wang Q, Yan W, Wang W, Lei X, Cui D, Yan Z

Abstract
The reported risk susceptibility between phospholipase C epsilon 1 (PLCE1) polymorphisms and esophageal cancer (EC) and gastric cancer (GC) remained inconsistent and controversial, especially on variants other than rs2274223. The relationship between PLCE1 polymorphisms and gene expression is also unclear. Here we conducted a case-control study from northwest China, genotyped seven tag single nucleotide polymorphisms (SNPs) in PLCE1 with multiplexed SNP MassARRAY assay. Stratified analysis was carried out and PLCE1 expression was evaluated in specified groups with the method of qRT-PCR and immunohistochemistry. Results showed that the minor alleles of rs3765524, rs2274223, and rs10509670 were associated with increased risk of EC and GC. Linkage disequilibrium analysis revealed protective haplotypes of CCAAGTC and CCAA. By stratification, a more significant association was found in subgroups of male, age ≥ 54, tumor stages of I-II and tumor size ≤ 5 cm, EC and cardia cancer (CC) of stomach, and moderate to well differentiated squamous carcinoma. In addition, a significant association for rs3765524 with noncardia cancer (NCC) and adenocarcinoma which is predominant in China was also observed. Further expression analysis identified that PLCE1 was downregulated in NCC tissues comparing to their adjacent noncancerous tissues, and its protein expression was higher in genotype rs3765524 CT/TT than in rs3765524 CC. In summary, our study suggests that PLCE1 polymorphisms may affect its gene expression and are associated with not only EC and CC, but also, to some extent, NCC risk in this study population.

PMID: 30931333 [PubMed - in process]

Actionable Pharmacogenetic Variation in the Slovenian Genomic Database.

Front Pharmacol. 2019;10:240

Authors: Hočevar K, Maver A, Peterlin B

Abstract
Background: Genetic variability in some of the genes that affect absorption, distribution, metabolism, and elimination ("pharmacogenes") can significantly influence an individual's response to the drug and consequently the effectiveness of treatment and possible adverse drug events. The rapid development of sequencing methods in recent years and consequently the increased integration of next-generation sequencing technologies into the clinical settings has enabled extensive genotyping of pharmacogenes for personalized treatment. The aim of the present study was to investigate the frequency and variety of potentially actionable pharmacogenetic findings in the Slovenian population. Methods: De-identified data from diagnostic exome sequencing in 1904 cases submitted to our institution were analyzed for variants within 293 genes associated with drug response. Filtered variants were classified according to population frequency, variant type, the functional impact of the variant, pathogenicity predictions and characterization in the Pharmacogenomics Knowledgebase (PharmGKB) and ClinVar. Results: We observed a total of 24 known actionable pharmacogenetic variants (PharmGKB 1A or 1B level of evidence), comprising approximately 26 drugs, of which, 12 were rare, with the population frequency below 1%. Furthermore, we identified an additional 61 variants with PharmGKB 2A or 2B clinical annotations. We detected 308 novel/rare potentially actionable variants: 177 protein-truncating variants and 131 missense variants predicted to be pathogenic based on several pathogenicity predictions. Conclusion: In the present study, we estimated the burden of pharmacogenetic variants in nationally based exome sequencing data and investigated the potential clinical usefulness of detected findings for personalized treatment. We provide the first comprehensive overview of known pharmacogenetic variants in the Slovenian population, as well as reveal a great proportion of novel/rare variants with a potential to influence drug response.

PMID: 30930780 [PubMed]

Dual Functional Immunostimulatory Polymeric Prodrug Carrier with Pendent Indoximod for Enhanced Cancer Immunochemotherapy.

Acta Biomater. 2019 Mar 28;:

Authors: Wan Z, Sun J, Xu J, Moharil P, Chen J, Xu J, Zhu J, Li J, Huang Y, Xu P, Ma X, Xie W, Lu B, Li S

Abstract
Immunotherapy based on checkpoint blockade has been regarded as one of the most promising approaches towards many types of cancers. However, low response rate hinders its application due to insufficient tumor immunogenicity and immunosuppressive tumor microenvironment. To achieve an overall enhanced therapeutic outcome, we developed a dual-functional immuno-stimulatory polymeric prodrug carrier modified with pendent indoximod, an indoleamine 2,3-dioxygenase (IDO) inhibitor that can be used to reverse immune suppression, for co-delivery of Doxorubicin (Dox), a hydrophobic anticancer agent that can promote immunogenic cell death (ICD) and elicit antitumor immunity. The resulted carrier denoted as POEG-b-PVBIND, consisting of poly (oligo (ethylene glycol) methacrylate) (POEG) hydrophilic blocks and indoximod conjugated hydrophobic blocks, is rationally designed to improve immunotherapy by synergistically modulating the tumor microenvironment (TME). Our data showed that Dox-triggered ICD promoted intra-tumoral infiltration of CD8+ T cells and IFN-γ-production by CD8+ T cells. Meanwhile, cleaved indoximod significantly increased CD8+ T cell infiltration while reducing the immunosuppressive T regulatory cells (Tregs). More importantly, Dox/POEG-b-PVBIND micelles led to significantly improved tumor regression in an orthotopic murine breast cancer model compared to both Dox-loaded POEG-b-PVB micelles (a control inert carrier) and POEG-b-PVBIND micelles alone, confirming combination effect of indoximod and Dox in improving the overall antitumor activity. STATEMENT OF SIGNIFICANCE: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that can induce immune suppressive microenvironment in tumors. As a well-studied IDO inhibitor, indoximod (IND) represents a promising agent for cancer immunotherapy and could be particularly useful in combination with other chemotherapeutic agents. However, three major problems hinder its application: (1) IND is barely soluble in water; (2) IND delivery efficiency is limited (3) simultaneous delivery of two agents into tumor site is still challenging. Currently, most reports largely focus on improving the pharmacokinetic profile of IND alone via different formulations such as IND prodrug and IND nanocrystal. However, there is limited information about IND based co-delivery systems, especially for delivering hydrophobic chemotherapeutic agents. Here, we developed a new dual-functional polymeric prodrug carrier modified with a number of pendent IND units (denoted as POEG-b-PVBIND). POEG-b-PVBIND shows immunostimulatory and antitumor activities by itself. More importantly, POEG-b-PVBIND polymer is able to self-assemble into nano-sized micelles that are highly effective in formulating and codelivering other hydrophobic agents including doxorubicin (Dox), sunitinib (Sun), and daunorubicin (Dau), which can elicit antitumor immunity via promoting immunogenic cell death (ICD). We have shown that our new combination therapy led to a significantly improved antitumor activity in an aggressive murine breast cancer model (4T1.2).

PMID: 30930305 [PubMed - as supplied by publisher]

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure.

Br J Clin Pharmacol. 2018 02;84(2):358-368

Authors: Brussee JM, Vet NJ, Krekels EHJ, Valkenburg AJ, Jacqz-Aigrain E, van Gerven JMA, Swart EL, van den Anker JN, Tibboel D, de Hoog M, de Wildt SN, Knibbe CAJ

Abstract
AIMS: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice.
METHODS: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics.
RESULTS: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%).
CONCLUSION: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates.

PMID: 29072785 [PubMed - indexed for MEDLINE]

Testing the role of genetic variation of the MC4R gene in Chinese population in antipsychotic-induced metabolic disturbance.

Sci China Life Sci. 2019 Mar 26;:

Authors: Zhang Y, Ren H, Wang Q, Deng W, Yue W, Yan H, Tan L, Chen Q, Yang G, Lu T, Wang L, Zhang F, Yang J, Li K, Lv L, Tan Q, Zhang H, Ma X, Yang F, Li L, Wang C, Zhang D, Zhao L, Wang H, Li X, Guo W, Hu X, Tian Y, Ma X, Li T, Chinese Antipsychotics Pharmacogenomics Consortium

Abstract
Antipsychotic-induced metabolic disturbance (AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor (MC4R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4R in Chinese population by genotyping two SNPs (rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index (BMI), waist circumference (WC), glucose, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status (drug-naïve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-naïve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.

PMID: 30929193 [PubMed - as supplied by publisher]

Germline Genetic Variants in GATA3 and Breast Cancer Treatment Outcomes in SWOG S8897 Trial and the Pathways Study.

Clin Breast Cancer. 2019 Mar 06;:

Authors: Larsen V, Barlow WE, Yang JJ, Zhu Q, Liu S, Kwan ML, Ergas IJ, Roh JM, Hutchins LF, Kadlubar SA, Albain KS, Rae JM, Yeh IT, Ravdin PM, Martino S, Lyss AP, Osborne CK, Hortobagyi GN, Kushi LH, Hayes DF, Ambrosone CB, Yao S

Abstract
INTRODUCTION: GATA3 is a critical transcription factor in maintaining the differentiated state of luminal mammary epithelial cells. We sought to determine the prognostic and predictive roles of GATA3 genotypes for breast cancer.
PATIENTS AND METHODS: Twelve single nucleotide polymorphisms (SNPs) were genotyped in 2 breast cancer cohorts, including the SWOG S8897 trial where patients were treated with adjuvant chemotherapy (CAF [cyclophosphamide, doxorubicin, 5-fluorouracil] vs. CMF [cyclophosphamide, methotrexate, 5-fluorouracil]) or untreated, and the observational Pathways Study.
RESULTS: In the S8897 trial, rs3802604 and rs568727 were associated with disease-free survival and overall survival in the treated group, regardless of chemotherapy regimen. The GG genotype of rs3802604 conferred poorer overall survival (adjusted hazard ratio, 2.45; 95% confidence interval, 1.48-4.05) and disease-free survival (adjusted hazard ratio, 1.95; 95% confidence interval, 1.27-2.99) compared with the AA genotype. Similar associations were found for rs568727. In contrast, no association with either SNP was found in the untreated group. Subgroup analyses indicated that these 2 SNPs more strongly influenced outcomes in the patients who also received tamoxifen. However, the associations in the subgroup with tamoxifen treatment were not replicated in the Pathways Study, possibly owing to substantial differences between the 2 patient cohorts, such as chemotherapy regimen and length of follow-up. Results from joint analyses across these 2 cohorts were marginally significant, driven by the results in S8897. Bioinformatic analyses support potential functional disruption of the GATA3 SNPs in breast tissue.
CONCLUSIONS: The present study provides some evidence for the predictive value of GATA3 genotypes for breast cancer adjuvant therapies. Future replication studies in appropriate patient populations are warranted.

PMID: 30928413 [PubMed - as supplied by publisher]

Biotechnology, Big Data and Artificial Intelligence.

Biotechnol J. 2019 Mar 30;:e1800613

Authors: Oliveira AL

Abstract
Developments in biotechnology are increasingly dependent on the extensive use of big data, generated by modern high-throughput instrumentation technologies and stored in thousands of databases, public and private. Future developments in this area depend, critically, on the ability of biotechnology researchers to master the skills required to effectively integrate their own contributions with the large amounts of information available in these databases. This article offers a perspective of the relations that exist between the fields of big data and biotechnology, including the related technologies of artificial intelligence and machine learning, and describes how data integration, data exploitation and process optimization correspond to three essential steps in any future biotechnology project. The article also lists a number of application areas where the ability to use big data will become a key factor, including drug discovery, drug recycling, drug safety, functional and structural genomics, proteomics, pharmacogenetics and pharmacogenomics, among others. This article is protected by copyright. All rights reserved.

PMID: 30927505 [PubMed - as supplied by publisher]

Challenges and lessons learned from clinical pharmacogenetic implementation of multiple gene-drug pairs across ambulatory care settings.

Genet Med. 2019 Mar 30;:

Authors: Cicali EJ, Weitzel KW, Elsey AR, Orlando FA, Vinson M, Mosley S, Smith DM, Davis R, Drum L, Estores D, Franciosi JP, Hagen MG, Jerkins GJ, Mercado ES, Nainaparampil J, Padron A, Rosenberg EI, Wright A, Schmidt SO, Mathews CA, Cavallari LH, Johnson JA

Abstract
PURPOSE: Incorporating a patient's genotype into the clinical decision-making process is one approach to precision medicine. The University of Florida (UF) Health Precision Medicine Program is a pharmacist-led multidisciplinary effort that has led the clinical implementation of six gene-drug(s) pairs to date. This study focuses on the challenges encountered and lessons learned with implementing pharmacogenetic testing for three of these: CYP2D6-opioids, CYP2D6/CYP2C19-selective serotonin reuptake inhibitors, and CYP2C19-proton pump inhibitors within six pragmatic clinical trials at UF Health and partners.
METHODS: We compared common measures collected within each of the pharmacogenetic implementations as well as solicited feedback from stakeholders to identify challenges, successes, and lessons learned.
RESULTS: We identified several challenges related to trial design and implementation, and learned valuable lessons. Most notably, case discussions are effective for prescriber education, prescribers need clear concise guidance on genotype-based actions, having genotype results available at the time of the patient-prescriber encounter helps optimize the ability to act on them, children prefer noninvasive sample collection, and study participants are willing to answer patient-reported outcomes questionnaires if they are not overly burdensome, among others.
CONCLUSION: The lessons learned from implementing three gene-drug pairs in ambulatory care settings will help shape future pharmacogenetic clinical trials and clinical implementations.

PMID: 30926959 [PubMed - as supplied by publisher]

Pharmacogenomics of chronic obstructive pulmonary disease.

Expert Rev Respir Med. 2019 Mar 29;:

Authors: Hersh CP

Abstract
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, which presents the opportunity for precision therapy based on genetics or other biomarkers. Areas covered: Alpha-1 antitrypsin deficiency, a genetic form of emphysema, provides an example of this precision approach to diagnosis and therapy. To date, research in COPD pharmacogenomics has been limited by small sample sizes, lack of accessible target tissue, failure to consider COPD subtypes, and different outcomes relevant for various medications. There have been several published genome-wide association studies and other omics studies in COPD pharmacogenomics; however, clinical implementation remains far away. There is a growing evidence base for precision prescription of inhaled corticosteroids in COPD, based on clinical phenotypes and blood biomarkers, but not yet based on pharmacogenomics. Expert opinion: At this time, there is insufficient evidence for clinical implementation of COPD pharmacogenomics. Additional genome-wide studies will be required to discover predictors of drug response and to identify genomic biomarkers of COPD subtypes, which could be targeted with subtype-directed therapies.

PMID: 30925849 [PubMed - as supplied by publisher]

Genome-wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol.

Clin Pharmacol Ther. 2019 Mar 28;:

Authors: Brackman DJ, Yee SW, Enogieru OJ, Shaffer C, Ranatunga D, Denny JC, Wei WQ, Kamatani Y, Kubo M, Roden DM, Jorgenson E, Giacomini KM

Abstract
Allopurinol, which lowers uric acid (UA) concentration, is increasingly being recognized for its benefits in cardiovascular and renal disease. However, response to allopurinol is variable. We gathered samples from 4,446 multiethnic subjects for a genome-wide association study of allopurinol response. Consistent with previous studies, we observed that the Q141K variant in ABCG2 (rs2231142), which encodes the efflux pump BCRP, associated with worse response to allopurinol. However, for the first time this association reached genome-wide level significance (p=8.06 x 10-11 ). Additionally, we identified a novel association with a variant in GREM2 (rs1934341, p=3.2 x 10-6 ). In vitro studies identified oxypurinol, the active metabolite of allopurinol, as an inhibitor of the UA transporter GLUT9, suggesting that oxypurinol may modulate UA reabsorption. These results provide strong evidence for a role of BCRP Q141K in allopurinol response, and suggest that allopurinol may have additional hypouricemic effects beyond xanthine oxidase inhibition. This article is protected by copyright. All rights reserved.

PMID: 30924126 [PubMed - as supplied by publisher]

Genetic polymorphisms of histone methyltransferase SETD2 predicts prognosis and chemotherapy response in Chinese acute myeloid leukemia patients.

J Transl Med. 2019 Mar 28;17(1):101

Authors: Wang S, Yuan X, Liu Y, Zhu K, Chen P, Yan H, Zhang D, Li X, Zeng H, Zhao X, Chen X, Zhou G, Cao S

Abstract
BACKGROUND: SETD2, the single mediator of trimethylation of histone 3 at position lysine 36, has been reported associated with initiation progression and chemotherapy resistance in acute myeloid leukemia (AML). Whether polymorphisms of SETD2 affect prognosis and chemotherapy response of AML remains elusive.
METHODS: Three tag single-nucleotide polymorphisms (tagSNPs) of SETD2 were genotyped in 579 AML patients by using Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, overall survival (OS) and relapse-free survival (RFS) were analyzed.
RESULT: Survival analysis indicated that SETD2 rs76208147 TT genotype was significantly associated with poor prognosis of AML (TT vs. CC + CT hazard ratio: HR = 1.838, 95% confidence interval (CI) 1.005-3.360, p = 0.048). After adjusting for the known prognostic factors including risk stratification, age, allo-SCT, WBC count and LDH count, rs76208147 TT genotype was still associated with OS in the multivariate analysis (TT vs. CC + CT HR = 1.923, 95% CI 1.007-3.675, p = 0.048). In addition, after adjusting by other clinical features, patients with rs4082155  allele G carries showed higher rate of complete remission which indicated by CR rate (AG + GG vs. AA odd ratio (OR) = 0.544, 95% CI 0.338-0.876, p = 0.012).
CONCLUSIONS: SETD2 genetic polymorphism is associated with AML prognosis and chemotherapy outcome, suggesting the possibility for development in AML diagnostics and therapeutics towards SETD2.

PMID: 30922329 [PubMed - in process]

Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism.

Am J Psychiatry. 2019 Mar 29;:appiajp201918050589

Authors: Pardiñas AF, Nalmpanti M, Pocklington AJ, Legge SE, Medway C, King A, Jansen J, Helthuis M, Zammit S, MacCabe J, Owen MJ, O'Donovan MC, Walters JTR

Abstract
OBJECTIVE:: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia.
METHODS:: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics.
RESULTS:: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data.
CONCLUSIONS:: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.

PMID: 30922102 [PubMed - as supplied by publisher]

The Role of Tumor Necrosis Factor α in the Biology of Uterine Fibroids and the Related Symptoms.

Int J Mol Sci. 2018 Dec 04;19(12):

Authors: Ciebiera M, Włodarczyk M, Zgliczyńska M, Łukaszuk K, Męczekalski B, Kobierzycki C, Łoziński T, Jakiel G

Abstract
Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. The incidence of UFs has been estimated at 25⁻80% depending on selected population. The pathophysiology of UFs remains poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is the main component of all pathways leading to UF tumor formation and tumor necrosis factor α (TNF-α) is believed to be one of the key factors in this field. TNF-α is a cell signaling protein involved in systemic inflammation and is one of the cytokines responsible for the acute phase reaction. This publication presents current data about the role of tumor necrosis factor α in the biology of UFs and the related symptoms. TNF-α is an extremely important cytokine associated with the biology of UFs, UF-related symptoms and complaints. Its concentration has been proven to be elevated in women with clinically symptomatic UFs. The presented data suggest the presence of an "inflammation-like" state in women with UFs where TNF-α is a potent inflammation inducer. The origin of numerous symptoms reported by women with UFs can be traced back to the TNF-α influence. Nevertheless, our knowledge on this subject remains limited and TNF-α dependent pathways in UF pathophysiology should be investigated further.

PMID: 30518097 [PubMed - indexed for MEDLINE]