Activation of the pro-migratory bone morphogenetic protein receptor 1B gene in human MDA-MB-468 triple-negative breast cancer cells that over-express CYP2J2.

Int J Biochem Cell Biol. 2016 Nov;80:173-178

Authors: Allison SE, Chen Y, Petrovic N, Zimmermann S, Moosmann B, Jansch M, Cui PH, Dunstan CR, Mackenzie PI, Murray M

Abstract
Secondary metastases are the leading cause of mortality in patients with breast cancer. Cytochrome P450 (CYP) 2J2 (CYP2J2) is upregulated in many human tumors and generates epoxyeicosanoids from arachidonic acid that promote tumorigenesis and metastasis, but at present there is little information on the genes that mediate these actions. In this study MDA-MB-468 breast cancer cells were stably transfected with CYP2J2 (MDA-2J2 cells) and Affymetrix microarray profiling was undertaken. We identified 182 genes that were differentially expressed in MDA-2J2 cells relative to control (MDA-CTL) cells (log[fold of control] ≥2). From gene ontology pathway analysis bone morphogenetic protein (BMP) receptor 1B (BMPR1B) emerged as an important upregulated gene in MDA-2J2 cells. Addition of the BMPR1B ligand BMP2 stimulated the migration of MDA-2J2 cells, but not MDA-CTL cells, from 3D-matrigel droplets. Migration of MDA-2J2 cells was prevented by the BMPR antagonist dorsomorphin. These findings indicate that over-expression of CYP2J2 in MDA-MB-468-derived breast cancer cells activates BMPR1B expression that may contribute to increased migration. Targeting BMPR1B may be a novel approach to inhibit the metastatic activity of breast cancers that contain high levels of CYP2J2.

PMID: 27720933 [PubMed - indexed for MEDLINE]

Loss-of-function polymorphisms in the organic cation transporter OCT1 are associated with reduced postoperative tramadol consumption.

Pain. 2016 Nov;157(11):2467-2475

Authors: Stamer UM, Musshoff F, Stüber F, Brockmöller J, Steffens M, Tzvetkov MV

Abstract
The organic cation transporter OCT1 (SLC22A1) mediates uptake and metabolism of the active tramadol metabolite (+)O-desmethyltramadol in the liver. In this study, the influence of OCT1 genetic polymorphisms on pharmacokinetics and analgesic efficacy of tramadol in patients recovering from surgery was analyzed in addition to the CYP2D6 genotype. Postoperative patients who received tramadol through patient-controlled analgesia were enrolled. Genotypes resulting in 0, 1, or 2 active OCT1 alleles were determined as well as CYP2D6 genotypes. The primary endpoint was the 24-hour postoperative tramadol consumption in patients with 0 vs at least 1 active OCT1 allele. Secondary endpoint was the OCT1-dependent plasma concentration (areas under the concentration-time curves) of the active tramadol metabolite (+)O-desmethyltramadol. Of 205 patients, 19, 82, and 104 carried 0, 1, and 2 active OCT1 alleles, respectively. Cumulative tramadol consumption through patient-controlled analgesia was lowest in patients with 0 active OCT1 allele compared with the group of patients with 1 or 2 active alleles (343 ± 235 vs 484 ± 276 mg; P = 0.03). Multiple regression revealed that the number of active OCT1 alleles (P = 0.014), CYP2D6 (P = 0.001), pain scores (P < 0.001), and the extent of surgery (0.034) had a significant influence on tramadol consumption. Plasma areas under the concentration-time curves of (+)O-desmethyltramadol were 111.8 (95% confidence interval: 63.4-160.1), 80.2 (65.1-95.3), and 64.5 (51.9-77.2) h·ng·mL in carriers of 0, 1, or 2 active OCT1 alleles (P = 0.03). Loss of OCT1 function resulted in reduced tramadol consumption and increased plasma concentrations of (+)O-desmethyltramadol in patients recovering from surgery. Therefore, analyzing OCT1 next to CYP2D6 genotype might further improve future genotype-dependent dose recommendations for tramadol.

PMID: 27541716 [PubMed - indexed for MEDLINE]

Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers.

J Cardiovasc Electrophysiol. 2016 Oct;27(10):1206-1213

Authors: Abdelhady AM, Shugg T, Thong N, Lu JB, Kreutz Y, Jaynes HA, Robarge JD, Tisdale JE, Desta Z, Overholser BR

Abstract
BACKGROUND: Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele.
OBJECTIVE: The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening.
METHODS: EFV was administered to healthy volunteers (n = 57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression.
RESULTS: EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ∆∆QTcF were observed at 6 hours (14 milliseconds; 95% CI [1; 27]), 12 hours (18 milliseconds; 95% CI [-4; 40]), and 18 hours (6 milliseconds; 95% CI [-1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 μg/mL significantly inhibited outward hERG tail currents (P < 0.05).
CONCLUSIONS: This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG.

PMID: 27333947 [PubMed - indexed for MEDLINE]

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

pharmacogenomics

These pubmed results were generated on 2017/11/07

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.

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

JACC Cardiovasc Interv. 2017 Oct 25;:

Authors: Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD, Voora D, Kimmel SE, McDonough CW, Gong Y, Dave CV, Pratt VM, Alestock TD, Anderson RD, Alsip J, Ardati AK, Brott BC, Brown L, Chumnumwat S, Clare-Salzler MJ, Coons JC, Denny JC, Dillon C, Elsey AR, Hamadeh IS, Harada S, Hillegass WB, Hines L, Horenstein RB, Howell LA, Jeng LJB, Kelemen MD, Lee YM, Magvanjav O, Montasser M, Nelson DR, Nutescu EA, Nwaba DC, Pakyz RE, Palmer K, Peterson JF, Pollin TI, Quinn AH, Robinson SW, Schub J, Skaar TC, Smith DM, Sriramoju VB, Starostik P, Stys TP, Stevenson JM, Varunok N, Vesely MR, Wake DT, Weck KE, Weitzel KW, Wilke RA, Willig J, Zhao RY, Kreutz RP, Stouffer GA, Empey PE, Limdi NA, Shuldiner AR, Winterstein AG, Johnson JA, IGNITE Network

Abstract
OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI).
BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI.
METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights.
RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60).
CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.

PMID: 29102571 [PubMed - as supplied by publisher]

Gut microbiota and hypertension: From pathogenesis to new therapeutic strategies.

Clin Res Hepatol Gastroenterol. 2017 Nov 01;:

Authors: Kang Y, Cai Y

Abstract
Hypertension (HTN) has become a global public health concern and a major risk factor for cardiovascular, cerebrovascular, and kidney diseases. The complex interplay of genetic and environmental influences is important for the development of the disease. Accumulating evidence has illustrated the association of dysbiosis of gut microbiota with hypertension. Certain gut microbial strains may play either a pathogenic or a protective role in the development of hypertension. Oral probiotics can therefore represent a therapeutic approach for hypertension treatment. However, the relevant scientific work has only just begun, and the available data in this field remain limited. Fortunately, recent technological developments that permit identification of microbes and their products using culture-independent molecular detection techniques. In this review, we summarize the role of gut microbiota in hypertension progression, and probiotics in the treatment of hypertension.

PMID: 29102544 [PubMed - as supplied by publisher]

Synthesis of piperazine sulfonamide analogs as diabetic-II inhibitors and their molecular docking study.

Eur J Med Chem. 2017 Oct 12;:

Authors: Taha M, Irshad M, Imran S, Chigurupati S, Selvaraj M, Rahim F, Ismail NH, Nawaz F, Khan KM

Abstract
Piperazine Sulfonamide analogs (1-19) have been synthesized, characterized by different spectroscopic techniques and evaluated for α-amylase Inhibition. Analogs 1-19 exhibited a varying degree of α-amylase inhibitory activity with IC50 values ranging in between 1.571 ± 0.05 to 3.98 ± 0.397 μM when compared with the standard acarbose (IC50 = 1.353 ± 0.232 μM). Compound 1, 2, 3 and 7 showed significant inhibitory effects with IC50 value 2.348 ± 0.444, 2.064 ± 0.04, 1.571 ± 0.05 and 2.118 ± 0.204 μM, respectively better than the rest of the series. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction of the compounds.

PMID: 29102178 [PubMed - as supplied by publisher]

Pharmacogenomics: Precision Medicine and Drug Response.

Mayo Clin Proc. 2017 Nov;92(11):1711-1722

Authors: Weinshilboum RM, Wang L

Abstract
Pharmacogenomics is the use of genomic and other "omic" information to individualize drug selection and drug use to avoid adverse drug reactions and to maximize drug efficacy. The science underlying pharmacogenomics has evolved rapidly over the 50 years since it was first suggested that genetics might influence drug response phenotypes. That process has occurred in parallel with advances in DNA sequencing and other molecular technologies, with striking increases in our understanding of the human genome. There are now many validated examples of the clinical utility of pharmacogenomics, and this type of clinical genomic information is increasingly being generated in clinical laboratories, incorporated into electronic health records, and used to "tailor" or individualize drug therapy. This review will survey the origins and development of pharmacogenomics; it will address some of the challenges associated with the clinical implementation of pharmacogenomics; and it will attempt to foresee future advances in this important genomic discipline, one that almost certainly will be among the earliest and most widely adopted aspects of clinical genomics.

PMID: 29101939 [PubMed - in process]

Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD.

Thorax. 2017 Nov 03;:

Authors: Dicker AJ, Crichton ML, Cassidy AJ, Brady G, Hapca A, Tavendale R, Einarsson GG, Furrie E, Elborn JS, Schembri S, Marshall SE, Palmer CNA, Chalmers JD

Abstract
BACKGROUND: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggest MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD.
METHODS: Patients with COPD (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested subcohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA PCR and sequencing, or airway inflammation during stable and exacerbated COPD.
FINDINGS: Patients with MBL deficiency with COPD were significantly less likely to have severe exacerbations (incidence rate ratio (IRR) 0.66, 95% CI 0.48 to 0.90, p=0.009), or to have moderate or severe exacerbations (IRR 0.77, 95% CI 0.60 to 0.99, p=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the subcohort, patients with MBL deficiency had a more diverse lung microbiota (p=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency.
INTERPRETATION: Patients with MBL deficient genotype with COPD have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.

PMID: 29101284 [PubMed - as supplied by publisher]

Considerations for the use of virally delivered genetic tools for in-vivo circuit analysis and behavior in mutant mice: a practical guide to optogenetics.

Behav Pharmacol. 2017 Nov 02;:

Authors: Zelena D, Demeter K, Haller J, Balázsfi D

Abstract
Optogenetics was the method of the year in 2010 according to Nature Neuroscience. Since then, this method has become widespread, the use of virally delivered genetic tools has extended to other fields such as pharmacogenetics, and optogenetic techniques have become frequently applied in genetically manipulated animals for in-vivo circuit analysis and behavioral studies. However, several issues should be taken into consideration when planning such experiments. We aimed to summarize the critical points concerning optogenetic manipulation of a specific brain area in mutant mice. First, the appropriate vector should be chosen to allow optimal optogenetic manipulation. Adeno-associated viral vectors are the most common carriers with different available serotypes. Light-sensitive channels are available in many forms, and the expression of the delivered genetic material can be influenced in many ways. Second, selecting the adequate stimulation protocol is also essential. The pattern, intensity, and timing could be determinative parameters. Third, the mutant strain might have a phenotype that influences the observed behavior. In conclusion, detailed preliminary experiments and numerous control groups are required to choose the best vector and stimulation protocol and to ensure that the mutant animals do not have a specific phenotype that can influence the examined behavior.

PMID: 29099403 [PubMed - as supplied by publisher]

Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children.

J Pers Med. 2017 Nov 02;7(4):

Authors: Aka I, Bernal CJ, Carroll R, Maxwell-Horn A, Oshikoya KA, Van Driest SL

Abstract
Cytochrome P450 (CYP) enzymes are commonly involved in drug metabolism, and genetic variation in the genes encoding CYPs are associated with variable drug response. While genotype-guided therapy has been clinically implemented in adults, these associations are less well established for pediatric patients. In order to understand the frequency of pediatric exposures to drugs with known CYP interactions, we compiled all actionable drug-CYP interactions with a high level of evidence using Clinical Pharmacogenomic Implementation Consortium (CPIC) data and surveyed 10 years of electronic health records (EHR) data for the number of children exposed to CYP-associated drugs. Subsequently, we performed a focused literature review for drugs commonly used in pediatrics, defined as more than 5000 pediatric patients exposed in the decade-long EHR cohort. There were 48 drug-CYP interactions with a high level of evidence in the CPIC database. Of those, only 10 drugs were commonly used in children (ondansetron, oxycodone, codeine, omeprazole, lansoprazole, sertraline, amitriptyline, citalopram, escitalopram, and risperidone). For these drugs, reports of the drug-CYP interaction in cohorts including children were sparse. There are adequate data for implementation of genotype-guided therapy for children for three of the 10 commonly used drugs (codeine, omeprazole and lansoprazole). For the majority of commonly used drugs with known CYP interactions, more data are required to support pharmacogenomic implementation in children.

PMID: 29099060 [PubMed]

Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model.

Sci Rep. 2017 Nov 06;7(1):14620

Authors: Bauer S, Wennberg Huldt C, Kanebratt KP, Durieux I, Gunne D, Andersson S, Ewart L, Haynes WG, Maschmeyer I, Winter A, Ämmälä C, Marx U, Andersson TB

Abstract
Human in vitro physiological models studying disease and drug treatment effects are urgently needed as more relevant tools to identify new drug targets and therapies. We have developed a human microfluidic two-organ-chip model to study pancreatic islet-liver cross-talk based on insulin and glucose regulation. We have established a robust co-culture of human pancreatic islet microtissues and liver spheroids maintaining functional responses up to 15 days in an insulin-free medium. Functional coupling, demonstrated by insulin released from the islet microtissues in response to a glucose load applied in glucose tolerance tests on different days, promoted glucose uptake by the liver spheroids. Co-cultures maintained postprandial glucose concentrations in the circulation whereas glucose levels remained elevated in both single cultures. Thus, insulin secreted into the circulation stimulated glucose uptake by the liver spheroids, while the latter, in the absence of insulin, did not consume glucose as efficiently. As the glucose concentration fell, insulin secretion subsided, demonstrating a functional feedback loop between the liver and the insulin-secreting islet microtissues. Finally, inter-laboratory validation verified robustness and reproducibility. Further development of this model using tools inducing impaired glucose regulation should provide a unique in vitro system emulating human type 2 diabetes mellitus.

PMID: 29097671 [PubMed - in process]

Genetic Variants Associated With Uncontrolled Blood Pressure on Thiazide Diuretic/β-Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) Trials.

J Am Heart Assoc. 2017 Nov 02;6(11):

Authors: Magvanjav O, Gong Y, McDonough CW, Chapman AB, Turner ST, Gums JG, Bailey KR, Boerwinkle E, Beitelshees AL, Tanaka T, Kubo M, Pepine CJ, Cooper-DeHoff RM, Johnson JA

Abstract
BACKGROUND: The majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure (BP) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β-blocker.
METHODS AND RESULTS: A genome-wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance (P<1.0E-05) were tested for replication in an external cohort, INVEST (International Verapamil-SR Trandolapril study). We also examined genome-wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95% confidence interval, 1.69-3.88, P=8.64E-06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95% confidence interval, 1.35-2.57, P=0.001) and approached genome-wide significance in the meta-analysis between discovery and replication cohorts (odds ratio: 2.16, 95% confidence interval, 1.63-2.86, P=8.60E-08). Other genes in the region surrounding rs261316 (ALDH1A2) include AQP9 and LIPC.
CONCLUSIONS: A single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/β-blocker combination.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.

PMID: 29097388 [PubMed - in process]

Association between ABCG2 and SLCO1B1 polymorphisms and adverse drug reactions to regorafenib: a preliminary study
.

Int J Clin Pharmacol Ther. 2017 May;55(5):409-415

Authors: Maeda A, Ando H, Ura T, Komori A, Hasegawa A, Taniguchi H, Kadowaki S, Muro K, Tajika M, Kobara M, Matsuzaki M, Hashimoto N, Maeda M, Kojima Y, Aoki M, Kondo E, Mizutani A, Fujimura A

Abstract
OBJECTIVE: Due to the occurrence of severe adverse drug reactions to regorafenib, a drug used in cancer therapy, the identification of a predictive marker(s) is needed to increase the therapeutic applicability of this compound. We therefore investigated whether polymorphisms in the <i>ABCG2</i> and <i>SLCO1B</i> genes are associated with adverse drug reactions to regorafenib.
METHODS: For these analyses, 37 Japanese cancer patients were treated with regorafenib, genotyped for polymorphisms in <i>ABCG2</i> and <i>SLCO1B</i>, and evaluated for drug-related adverse drug reactions.
RESULTS: There was no association between the <i>ABCG2</i> 421C>A variant and adverse drug reactions to regorafenib. After treatment, the incidences of increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as increased total bilirubin (grade ≥ 2) were 8%, 4%, and 12%, and 42%, 25%, and 25% among <i>SLCO1B1*1b</i> carriers and non-carriers, respectively. There were no significant associations between elevated ALT and bilirubin and the <i>SLCO1B1*1b</i> allele. However, there were significantly lower incidences of increased AST (8% vs. 42%) and anemia (16% vs. 50%) in <i>SLCO1B1*1b</i> carriers than in non-carriers.
CONCLUSIONS: The absence of <i>SLCO1B1*1b</i> allele appears to be associated with the development of adverse drug reactions to regorafenib; however, further studies involving larger test groups and other populations are needed to confirm these findings.
.

PMID: 28157071 [PubMed - indexed for MEDLINE]

Genetic and Clinical Predictive Factors of Sulfonylurea Failure in Patients with Type 2 Diabetes.

Diabetes Technol Ther. 2016 Sep;18(9):586-93

Authors: Ren Q, Xiao D, Han X, Edwards SL, Wang H, Tang Y, Zhang S, Li X, Zhang X, Cai X, Liu Z, Paul SK, Ji L

Abstract
BACKGROUND: Sulfonylureas are widely used to treat type 2 diabetes (T2DM). Although genetic variations are associated with sulfonylurea treatment responses in T2DM patients, whether these variations can be used to predict heterogeneous treatment responses is unclear. In this study, we assessed the potential utility of combining information from multiple variants and phenotypes to predict sulfonylurea response.
METHODS: Using data from the "Glibenclamide" arm (365 patients) of the Xiaoke Pill Trial that evaluated the safety and efficacy of sulfonylurea, we identified genetic variants associated with sulfonylurea treatment response, and we explored their ability to predict drug response when combined with phenotype information.
RESULTS: The association of 780 single-nucleotide polymorphisms (using Infinium HD iSelect chip) with drug efficacy was evaluated, and four genes identified with drug metabolism (FMO2, FMO3, UGT2B15, and CYP51A1, P < 0.05) were found to be associated with changes in HbA1c. In a clinical model, the baseline values of HbA1c and disposition index (DI) were significantly associated with HbA1c and fasting plasma glucose (FPG) target achievements. Compared with clinical models, the inclusion of genetic markers significantly increased the predictive ability for both HbA1c- and FPG-based outcomes.
CONCLUSIONS: Our findings suggest that altered protein function in multiple pathways may cooperatively contribute to the increased discrimination by area under receiver operating curve for T2DM patients, and it may explain, in part, the relationship between inter-individual variability and the sulfonylurea response.

PMID: 27403931 [PubMed - indexed for MEDLINE]

MDR1 mediated chemoresistance: BMI1 and TIP60 in action.

Biochim Biophys Acta. 2016 08;1859(8):983-93

Authors: Banerjee Mustafi S, Chakraborty PK, Naz S, Dwivedi SK, Street M, Basak R, Yang D, Ding K, Mukherjee P, Bhattacharya R

Abstract
Chemotherapy-induced emergence of drug resistant cells is frequently observed and is exemplified by the expression of family of drug resistance proteins including, multidrug resistance protein 1 (MDR1). However, a concise mechanism for chemotherapy-induced MDR1 expression is unclear. Mechanistically, mutational selection, epigenetic alteration, activation of the Wnt pathway or impaired p53 function have been implicated. The present study describes that the surviving fraction of cisplatin resistant cells co- upregulate MDR1, BMI1 and acetyl transferase activity of TIP60. Using complementary gain and loss of function approaches, we demonstrate that the expression of MDR1 is positively regulated by BMI1, a stem-cell factor classically known as a transcriptional repressor. Our study establishes a functional interaction between TIP60 and BMI-1 resulting in upregulation of MDR1 expression. Chromatin immunoprecipitation (ChIP) assays further establish that the proximal MDR1 promoter responds to cisplatin in a BMI1 dependent manner. BMI1 interacts with a cluster of E-box elements on the MDR1 promoter and recruits TIP60 resulting in acetylation of histone H2A and H3. Collectively, our data establish a hitherto unknown liaison among MDR1, BMI1 and TIP60 and provide mechanistic insights into cisplatin-induced MDR1 expression resulting in acquired cross-resistance against paclitaxel, doxorubicin and likely other drugs. In conclusion, our results advocate utilizing anti-BMI1 strategies to alleviate acquired resistance to chemotherapy.

PMID: 27295567 [PubMed - indexed for MEDLINE]

15 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 2017/11/03

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.

COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression.

Hum Mol Genet. 2017 Oct 28;:

Authors: Nedeljkovic I, Lahousse L, Carnero Montoro E, Faiz A, Vonk JM, de Jong K, van der Plaat DA, van Diemen CC, van den Berge M, Obeidat M, Bossé Y, Nickle DC, Bios consortium, Uitterlinden AG, van Meurs JBJ, Stricker BHC, Brusselle GG, Postma DS, Boezen HM, van Duijn CM, Amin N

Abstract
Chronic obstructive pulmonary disease (COPD) is among the major health burdens in adults. While cigarette smoking is the leading risk factor, a growing number of genetic variations have been discovered to influence disease susceptibility. Epigenetic modifications may mediate the response of the genome to smoking and regulate gene expression. Chromosome 19q13.2 region is associated with both smoking and COPD, yet its functional role is unclear. Our study aimed to determine whether rs7937 (RAB4B, EGLN2), a top genetic variant in 19q13.2 region identified in genome-wide association studies of COPD, is associated with differential DNA methylation in blood (N = 1490) and gene expression in blood (N = 721) and lungs (N = 1087). We combined genetic and epigenetic data from the Rotterdam Study (RS) to perform the epigenome-wide association analysis of rs7937. Further, we used genetic and transcriptomic data from blood (RS) and from lung tissue (Lung expression quantitative trait loci mapping study), to perform the transcriptome-wide association study of rs7937. Rs7937 was significantly (FDR<0.05) and consistently associated with differential DNA methylation in blood at 4 CpG sites in cis, independent of smoking. One methylation site (cg11298343-EGLN2) was also associated with COPD (P=0.001). Additionally, rs7937 was associated with gene expression levels in blood in cis (EGLN2), 42% mediated through cg11298343, and in lung tissue, in cis and trans (NUMBL, EGLN2, DNMT3A, LOC101929709 and PAK2). Our results suggest that changes of DNA methylation and gene expression may be intermediate steps between genetic variants and COPD, but further causal studies in lung tissue should confirm this hypothesis.

PMID: 29092026 [PubMed - as supplied by publisher]

Influence of ABCB11 and HNF4α genes on daclatasvir plasma concentration: preliminary pharmacogenetic data from the Kineti-C study.

J Antimicrob Chemother. 2017 Oct 01;72(10):2846-2849

Authors: Cusato J, De Nicolò A, Boglione L, Favata F, Ariaudo A, Mornese Pinna S, Guido F, Avataneo V, Carcieri C, Cariti G, Di Perri G, D'Avolio A

Abstract
Background: Daclatasvir is an inhibitor of HCV non-structural 5A protein and is a P-glycoprotein substrate. Pharmacogenetics has had a great impact on previous anti-HCV therapies, particularly considering the association of IL-28B polymorphisms with dual therapy outcome.
Objectives: We investigated the association between daclatasvir plasma concentrations at 2 weeks and 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCB11 and HNF4α).
Patients and methods: Allelic discrimination was achieved through real-time PCR, whereas plasma concentrations were evaluated through LC-MS/MS.
Results: Fifty-two patients were analysed, all enrolled in the Kineti-C study. HNF4α 975 C > G polymorphism was found to be associated with the daclatasvir plasma concentrations at 2 weeks (P = 0.009) and 1 month of therapy (P = 0.006). Linear regression analysis suggested that, at 2 weeks of therapy, age, baseline BMI and haematocrit were significant predictors of daclatasvir concentrations, whereas at 1 month of therapy ABCB111131 CC and HNF4α CG/GG genotypes were significant predictors of daclatasvir concentrations.
Conclusions: These are the first and preliminary results from our clinical study focusing on daclatasvir pharmacogenetics, showing that this approach could have a role in the era of new anti-HCV therapies.

PMID: 29091211 [PubMed - in process]

Pharmacogenetics of metabolic genes of anthracyclines in acute myeloid leukemia.

Curr Drug Metab. 2017 Nov 01;:

Authors: Megias-Vericat JE, Martinez-Cuadron D, Herrero MJ, Alino SF, Poveda JL, Sanz MA, Montesinos P

Abstract
BACKGROUND: Anthracyclines in combination with cytarabine have been the standard therapy for acute myeloid leukemia (AML) for decades with high efficacy. However, the majority of patients will show initial resistance or will relapse after initial complete remission. Genetic variability in genes involved in anthracyclines metabolic pathway could be one of the causes of the interindividual differences in clinical outcomes.
METHODS: A systematic review of published studies in AML cohorts was carried out in order to analyze the influence of polymorphisms in genes of anthracycline metabolism on efficacy and toxicity.
RESULTS: Polymorphisms in the main enzymes of anthracyclines metabolism (CBR, AKR, NQO1, NOS3) have been related to lower enzymatic activity and higher cardiotoxicity. Moreover, variant alleles in genes of carcinogens and chemotherapy neutralizing enzymes (GST, SULT, NADP(H) oxidase) have been associated with ROS generation and drug efficacy, influencing in survival rates and cardiac toxicities. In addition, genetic variability in transporters of anthracyclines could affect the intake in cells, including influx (SLC28A3, SLC22A12, SLCO1B1) and efflux transporters (ABCB1, ABCC1, ABCC3, ABCG2).
CONCLUSION: The knowledge of the role of pharmacogenetics in anthracyclines metabolism could explain the differences observed in their disposition in leukemic cells. These genetic variants are proposed biomarkers in clinical practice in order to individualize chemotherapy schemes, potentially increasing the effectiveness and reducing the toxicities.

PMID: 29090664 [PubMed - as supplied by publisher]