Common polymorphisms of CYP2B6 influence stereoselective bupropion disposition.

Clin Pharmacol Ther. 2018 May 14;:

Authors: Kharasch ED, Crafford A

Abstract
Bupropion hydroxylation is a bioactivation and metabolic pathway, and the standard clinical CYP2B6 probe. This investigation determined the influence of CYP2B6 allelic variants on clinical concentrations and metabolism of bupropion enantiomers. Secondary objectives evaluated the influence of CYP2C19 and P450 oxidoreductase variants. Healthy volunteers in specific cohorts (CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6, and also CYP2B6*4 carriers) received single-dose oral bupropion. Plasma and urine bupropion and hydroxybupropion was quantified. Subjects were also genotyped for CYP2C19 and P450 oxidoreductase variants. Hydroxylation of both bupropion enantiomers, assessed by plasma hydroxybupropion/bupropion AUC ratios and urine hydroxybupropion formation clearances, was lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes, and numerically greater in CYP2B6*4 carriers. CYP2C19 and P450 oxidoreductase variants did not influence bupropion enantiomers hydroxylation or plasma concentrations. Results show that clinical hydroxylation of both bupropion enantiomers was equivalently influenced by CYP2B6 allelic variation. CYP2B6 polymorphisms affect S-bupropion bioactivation, which may affect therapeutic outcomes. This article is protected by copyright. All rights reserved.

PMID: 29756345 [PubMed - as supplied by publisher]

Disease-Associated Changes in Drug Transporters May Impact the Pharmacokinetics and/or Toxicity of Drugs: A White Paper from the International Transporter Consortium.

Clin Pharmacol Ther. 2018 May 14;:

Authors: Evers R, Piquette-Miller M, Polli JW, Russel FGM, Sprowl JA, Tohyama K, Ware JA, de Wildt SN, Xie W, Brouwer KLR, International Transporter Consortium

PMID: 29756222 [PubMed - as supplied by publisher]

A genotype-directed comparative effectiveness trial of Bucindolol and metoprolol succinate for prevention of symptomatic atrial fibrillation/atrial flutter in patients with heart failure: Rationale and design of the GENETIC-AF trial.

Am Heart J. 2018 May;199:51-58

Authors: Piccini JP, Connolly SJ, Abraham WT, Healey JS, Steinberg BA, Al-Khalidi HR, Dignacco P, van Veldhuisen DJ, Sauer WH, White M, Wilton SB, Anand IS, Dufton C, Marshall DA, Aleong RG, Davis GW, Clark RL, Emery LL, Bristow MR

Abstract
BACKGROUND: Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non-selective beta-blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized trials.
METHODS/DESIGN: The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded "seamless" phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred.
CONCLUSIONS: GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.govNCT01970501).

PMID: 29754666 [PubMed - in process]

Toward personalized medicine in Bardet-Biedl syndrome.

Per Med. 2017 Sep;14(5):447-456

Authors: Kenny J, Forsythe E, Beales P, Bacchelli C

Abstract
Personalized medicine is becoming routine in the treatment of common diseases such as cancer, but has lagged behind in the field of rare diseases. It is currently in the early stages for the treatment of Bardet-Biedl syndrome. Advances in the understanding of ciliary biology and diagnostic techniques have opened up the prospect of treating BBS in a patient-specific manner. Owing to their structure and function, cilia provide an attractive therapeutic target and genetic therapies are being explored in ciliopathy treatment. Promising avenues include gene therapy, gene editing techniques and splice-correcting and read-through therapies. Targeted drug design has been successful in the treatment of genetic disease and research is underway in the discovery of known and novel drugs to treat Bardet-Biedl syndrome.

PMID: 29754569 [PubMed - in process]

Primary care physician experiences with integrated pharmacogenomic testing in a community health system.

Per Med. 2017 Sep;14(5):389-400

Authors: Lemke AA, Hutten Selkirk CG, Glaser NS, Sereika AW, Wake DT, Hulick PJ, Dunnenberger HM

Abstract
AIM: To explore primary care physicians' views of the utility and delivery of direct access to pharmacogenomics (PGx) testing in a community health system.
METHODS: This descriptive study assessed the perspectives of 15 healthcare providers utilizing qualitative individual interviews.
RESULTS: Three main themes emerged: perceived value and utility of PGx testing; challenges to implementation in practice; and provider as well as patient needs.
CONCLUSION: While providers in this study viewed benefits of PGx testing as avoiding side effects, titrating doses more quickly, improving shared decision-making and providing psychological reassurance, challenges will need to be addressed such as privacy concerns, cost, insurance coverage and understanding the complexity of PGx test results.

PMID: 29754567 [PubMed - in process]

A phase II study evaluating the efficacy of zoledronic acid in prevention of aromatase inhibitor-associated musculoskeletal symptoms: the ZAP trial.

Breast Cancer Res Treat. 2018 May 11;:

Authors: Santa-Maria CA, Bardia A, Blackford AL, Snyder C, Connolly RM, Fetting JH, Hayes DF, Jeter SC, Miller RS, Nguyen A, Quinlan K, Rosner GL, Slater S, Storniolo AM, Wolff AC, Zorzi J, Henry NL, Stearns V

Abstract
PURPOSE: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are common adverse events of AIs often leading to drug discontinuation. We initiated a prospective clinical trial to evaluate whether bisphosphonates are associated with reduced incidence of AIMSS.
METHODS: In the single-arm trial, the Zoledronic Acid Prophylaxis (ZAP) trial, we compared the incidence of AIMSS against historical controls from the Exemestane and Letrozole Pharmacogenomics (ELPh) trial. Eligible women were postmenopausal with stage 0-III breast cancer planning to receive adjuvant AIs. AIMSS was assessed using the Health Assessment Questionnaire and Visual Analog Scale over 12 months in both trials. Participants in the ZAP trial received zoledronic acid prior to initiating letrozole and after 6 months; ELPh participants included in the analysis were taking letrozole but not bisphosphonates. We analyzed patient-reported outcomes (PROs) and bone density in the ZAP trial using mixed-effects linear regression models and paired t tests, respectively.
RESULTS: From 2011 to 2013, 59 postmenopausal women enrolled in ZAP trial. All 59 (100%) women received baseline and 52 (88%) received 6-month zoledronic acid, and had similar characteristics to historical controls from the ELPh trial (n = 206). Cumulatively during the first year of AI, 37 and 67% of ZAP and ELPh participants reported AIMSS (p < 0.001), respectively. Within the ZAP trial, we did not observe significant changes in other PROs; however, we report improvements in bone mineral density.
CONCLUSIONS: Compared to historical controls, zoledronic acid administered concomitantly with adjuvant AIs was associated with a reduced incidence of AIMSS. A randomized controlled trial is required to confirm these findings.

PMID: 29752687 [PubMed - as supplied by publisher]

Discovering novel SNPs that are correlated with patient outcome in a Singaporean cancer patient cohort treated with gemcitabine-based chemotherapy.

BMC Cancer. 2018 May 11;18(1):555

Authors: Limviphuvadh V, Tan CS, Konishi F, Jenjaroenpun P, Xiang JS, Kremenska Y, Mu YS, Syn N, Lee SC, Soo RA, Eisenhaber F, Maurer-Stroh S, Yong WP

Abstract
BACKGROUND: Single Nucleotide Polymorphisms (SNPs) can influence patient outcome such as drug response and toxicity after drug intervention. The purpose of this study is to develop a systematic pathway approach to accurately and efficiently predict novel non-synonymous SNPs (nsSNPs) that could be causative to gemcitabine-based chemotherapy treatment outcome in Singaporean non-small cell lung cancer (NSCLC) patients.
METHODS: Using a pathway approach that incorporates comprehensive protein-protein interaction data to systematically extend the gemcitabine pharmacologic pathway, we identified 77 related nsSNPs, common in the Singaporean population. After that, we used five computational criteria to prioritize the SNPs based on their importance for protein function. We specifically selected and screened six candidate SNPs in a patient cohort with NSCLC treated with gemcitabine-based chemotherapy.
RESULT: We performed survival analysis followed by hematologic toxicity analyses and found that three of six candidate SNPs are significantly correlated with the patient outcome (P < 0.05) i.e. ABCG2 Q141K (rs2231142), SLC29A3 S158F (rs780668) and POLR2A N764K (rs2228130).
CONCLUSIONS: Our computational SNP candidate enrichment workflow approach was able to identify several high confidence biomarkers predictive for personalized drug treatment outcome while providing a rationale for a molecular mechanism of the SNP effect.
TRIAL REGISTRATION: NCT00695994. Registered 10 June, 2008 'retrospectively registered'.

PMID: 29751792 [PubMed - in process]

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pharmacogenomics

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12 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 2018/05/11

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.

Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury.

Crit Care Med. 2018 May 07;:

Authors: Hagos FT, Empey PE, Wang P, Ma X, Poloyac SM, Bayır H, Kochanek PM, Bell MJ, Clark RSB

Abstract
OBJECTIVES: To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment.
DESIGN: Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board-approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009).
SETTING: Thirty-six-bed PICU in a university-affiliated children's hospital.
PATIENTS AND SUBJECTS: Twelve children 2-18 years old after severe traumatic brain injury and five age-matched control subjects.
INTERVENTION: Probenecid (25 mg/kg) and N-acetylcysteine (140 mg/kg) or placebo administered via naso/orogastric tube.
MEASUREMENTS AND MAIN RESULTS: The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation.
CONCLUSIONS: This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children.

PMID: 29742587 [PubMed - as supplied by publisher]

Analyzing the clinical actionability of germline pharmacogenomic findings in oncology.

Cancer. 2018 May 09;:

Authors: Wellmann R, Borden BA, Danahey K, Nanda R, Polite BN, Stadler WM, Ratain MJ, O'Donnell PH

Abstract
BACKGROUND: Germline and tumor pharmacogenomics impact drug responses, but germline markers less commonly guide oncology prescribing. The authors hypothesized that a critical number of clinically actionable germline pharmacogenomic associations exist, representing clinical implementation opportunities.
METHODS: In total, 125 oncology drugs were analyzed for positive germline pharmacogenomic associations in journals with impact factors ≥5. Studies were assessed for design and genotyping quality, clinically relevant outcomes, statistical rigor, and evidence of drug-gene effects. Associations from studies of high methodologic quality were deemed potentially clinically actionable, and translational summaries were written as point-of-care clinical decision support (CDS) tools and formally evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument.
RESULTS: The authors identified germline pharmacogenomic results for 56 of 125 oncology drugs (45%) across 173 publications. Actionable associations were detected for 12 drugs, including 6 that had germline pharmacogenomic information within US Food and Drug Administration labels or published guidelines (capecitabine/fluorouracil/dihydropyrimidine dehydrogenase [DPYD], irinotecan/uridine diphosphate glucuronosyltransferase family 1 member A1 [UGT1A1], mercaptopurine/thioguanine/thiopurine S-methyltransferase [TPMT], tamoxifen/cytochrome P450 [CYP] family 2 subfamily D member 6 [CYP2D6]), and 6 others were novel (asparaginase/nuclear factor of activated T-cells 2 [NFATC2]/human leukocyte antigen D-related β1 [HLA-DRB1], cisplatin/acylphosphatase 2 [ACYP2], doxorubicin/adenosine triphosphate-binding cassette subfamily C member 2/Rac family small guanosine triphosphatase 2/neutrophil cytosolic factor 4 [ABCC2/RAC2/NCF4], lapatinib/human leukocyte antigen DQ α1 [HLA-DQA1], sunitinib/cytochrome P450 family 3 subfamily A member 5 [CYP3A5], vincristine/centrosomal protein 72 [CEP72]). By using AGREE II, the developed CDS summaries had high mean ± standard deviation scores (maximum score, 100) for scope and purpose (92.7 ± 5.1) and rigour of development (87.6 ± 7.4) and moderate yet robust scores for clarity of presentation (58.6 ± 25.1) and applicability (55.9 ± 24.6). The overall mean guideline quality score was 5.2 ± 1.0 (maximum score, 7). Germline pharmacogenomic CDS summaries for these 12 drugs were recommended for implementation.
CONCLUSIONS: Several oncology drugs have actionable germline pharmacogenomic information, justifying their delivery through institutional pharmacogenomic implementations to determine clinical utility. Cancer 2018. © 2018 American Cancer Society.

PMID: 29742281 [PubMed - as supplied by publisher]

Genomics and electronic health record systems.

Hum Mol Genet. 2018 May 01;27(R1):R48-R55

Authors: Ohno-Machado L, Kim J, Gabriel RA, Kuo GM, Hogarth MA

Abstract
Several reviews and case reports have described how information derived from the analysis of genomes are currently included in electronic health records (EHRs) for the purposes of supporting clinical decisions. Since the introduction of this new type of information in EHRs is relatively new (for instance, the widespread adoption of EHRs in the United States is just about a decade old), it is not surprising that a myriad of approaches has been attempted, with various degrees of success. EHR systems undergo much customization to fit the needs of health systems; these approaches have been varied and not always generalizable. The intent of this article is to present a high-level view of these approaches, emphasizing the functionality that they are trying to achieve, and not to advocate for specific solutions, which may become obsolete soon after this review is published. We start by broadly defining the end goal of including genomics in EHRs for healthcare and then explaining the various sources of information that need to be linked to arrive at a clinically actionable genomics analysis using a pharmacogenomics example. In addition, we include discussions on open issues and a vision for the next generation systems that integrate whole genome sequencing and EHRs in a seamless fashion.

PMID: 29741693 [PubMed - in process]

Inter-individual variation in imatinib disposition: any role for prevalent variants of CYP1A2, CYP2C8, CYP2C9, and CYP3A5 in Nigerian CML patients?

Leuk Lymphoma. 2018 May 09;:1-6

Authors: Adehin A, Adeagbo BA, Kennedy MA, Bolaji OO, Olugbade TA, Bolarinwa RA, Durosinmi MA

Abstract
Imatinib has been successful in the management of chronic myeloid leukemia (CML) but some patients experience adverse reactions or develop resistance to its use. The roles of some polymorphisms in genes encoding enzymes critical for the biotransformation of imatinib have been previously examined. This study, hence, evaluated some other unstudied functionally significant polymorphisms in CYP1A2, CYP2C8, CYP2C9, and CYP3A5. Trough imatinib blood levels and genotypes were determined in 42 CML patients by an HPLC-UV technique and a Sequenom iPLEX assay, respectively. Statistical analysis of the influence of genetic polymorphisms on standardized trough level detected no significant relationship. However, higher trough levels were observed in two homozygous carriers of CYP2C8*2 while diminished imatinib levels were seen in two homozygous carriers of CYP3A5*7. The study findings suggest that polymorphisms in drug metabolizing enzymes may be significant for imatinib therapy only in instances where all copies of the relevant studied genes are functionally impaired.

PMID: 29741432 [PubMed - as supplied by publisher]

Overexpression of Fn14 in gliomas: tumor progression and poor prognosis.

Future Oncol. 2018 May 09;:

Authors: Tan D, Pang FM, Li D, Zhang L, Wu J, Liu ZQ, Li X, Yan H

Abstract
AIM: To confirm whether the expression level of Fn14 could affect progression or prognosis of glioma patients.
METHODS: Glioma cohorts in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas databases were comprehensively analyzed.
RESULTS: Low-grade patients had lower expression level of Fn14, while patients with higher expression of Fn14 tended to harbor shorter overall survival and disease-free survival. The expression level of Fn14 was downregulated by IDH1/IDH2 mutations while its gene body methylation was upregulated. After adjusting age, the expression level of Fn14 was still significantly associated with overall survival and disease-free survival in low-grade gliomas. In a cell line data analysis, Fn14 expression was positively correlated with temozolomide dosage.
CONCLUSION: Fn14 was an independent predictive biomarker for the progression and prognosis in low-grade gliomas.

PMID: 29741404 [PubMed - as supplied by publisher]

Race and Beta-Blocker Survival Benefit in Patients With Heart Failure: An Investigation of Self-Reported Race and Proportion of African Genetic Ancestry.

J Am Heart Assoc. 2018 May 08;7(10):

Authors: Luzum JA, Peterson E, Li J, She R, Gui H, Liu B, Spertus JA, Pinto YM, Williams LK, Sabbah HN, Lanfear DE

Abstract
BACKGROUND: It remains unclear whether beta-blockade is similarly effective in black patients with heart failure and reduced ejection fraction as in white patients, but self-reported race is a complex social construct with both biological and environmental components. The objective of this study was to compare the reduction in mortality associated with beta-blocker exposure in heart failure and reduced ejection fraction patients by both self-reported race and by proportion African genetic ancestry.
METHODS AND RESULTS: Insured patients with heart failure and reduced ejection fraction (n=1122) were included in a prospective registry at Henry Ford Health System. This included 575 self-reported blacks (129 deaths, 22%) and 547 self-reported whites (126 deaths, 23%) followed for a median 3.0 years. Beta-blocker exposure (BBexp) was calculated from pharmacy claims, and the proportion of African genetic ancestry was determined from genome-wide array data. Time-dependent Cox proportional hazards regression was used to separately test the association of BBexp with all-cause mortality by self-reported race or by proportion of African genetic ancestry. Both sets of models were evaluated unadjusted and then adjusted for baseline risk factors and beta-blocker propensity score. BBexp effect estimates were protective and of similar magnitude both by self-reported race and by African genetic ancestry (adjusted hazard ratio=0.56 in blacks and adjusted hazard ratio=0.48 in whites). The tests for interactions with BBexp for both self-reported race and for African genetic ancestry were not statistically significant in any model (P>0.1 for all).
CONCLUSIONS: Among black and white patients with heart failure and reduced ejection fraction, reduction in all-cause mortality associated with BBexp was similar, regardless of self-reported race or proportion African genetic ancestry.

PMID: 29739794 [PubMed - in process]

Analytical validation of a psychiatric pharmacogenomic test.

Per Med. 2018 Feb 07;:

Authors: Jablonski MR, King N, Wang Y, Winner JG, Watterson LR, Gunselman S, Dechairo BM

Abstract
AIM: The aim of this study was to validate the analytical performance of a combinatorial pharmacogenomics test designed to aid in the appropriate medication selection for neuropsychiatric conditions.
MATERIALS & METHODS: Genomic DNA was isolated from buccal swabs. Twelve genes (65 variants/alleles) associated with psychotropic medication metabolism, side effects, and mechanisms of actions were evaluated by bead array, MALDI-TOF mass spectrometry, and/or capillary electrophoresis methods (GeneSight Psychotropic, Assurex Health, Inc.).
RESULTS: The combinatorial pharmacogenomics test has a dynamic range of 2.5-20 ng/μl of input genomic DNA, with comparable performance for all assays included in the test. Both the precision and accuracy of the test were >99.9%, with individual gene components between 99.4 and 100%.
CONCLUSION: This study demonstrates that the combinatorial pharmacogenomics test is robust and reproducible, making it suitable for clinical use.

PMID: 29739269 [PubMed - as supplied by publisher]

Anthropometric and Dietary Factors as Predictors of DNA Damage in Obese Women.

Nutrients. 2018 May 08;10(5):

Authors: Włodarczyk M, Jabłonowska-Lietz B, Olejarz W, Nowicka G

Abstract
Enhanced DNA damage and disturbances in DNA repair mechanisms are reported to be involved in the pathogenesis of chronic diseases like obesity, atherosclerosis, metabolic syndrome, diabetes, and cancer. The aim of the present study was to evaluate whether anthropometric factors and dietary habits are related to endogenous DNA damage. One hundred and fourteen premenopausal, apparently healthy women were included in the study: 88 obese individuals and 26 controls. The comet assay was used to measure basal DNA damage. Biochemical measurements included lipids, apolipoproteinAI, fasting insulin, glucose, and C-reactive protein high sensitivity (CRP-hs). Dietary intakes were assessed by 3-day food records. The mean level of DNA damage was almost two times higher in obese than in non-obese women (p < 0.001). Regression modeling showed that body mass index (BMI), daily intakes of energy, and vitamin C are key predictors of variance in basal DNA damage. Our data demonstrate the impact of obesity-associated inflammation on DNA damage and indicate that regardless of obesity, the level of DNA damage can be reduced by adequate intakes of vitamins C and E. It suggests that particular attention should be paid to the content of antioxidants in the diet of obese people and further studies are needed to modify dietary guidelines to prevent DNA damage in obese individuals.

PMID: 29738492 [PubMed - in process]

Pharmacogenetic testing by polymorphic markers 681G>A and 636G>A CYP2C19 gene in patients with acute coronary syndrome and gastric ulcer in the Republic of Sakha (Yakutia).

Drug Metab Pers Ther. 2018 May 08;:

Authors: Fedorinov DS, Mirzaev KB, Ivashchenko DV, Temirbulatov II, Sychev DA, Maksimova NR, Chertovskih JV, Popova NV, Tayurskaya KS, Rudykh ZA

Abstract
BACKGROUND: The focus of the study is to determine the prevalence of CYP2C19 alleles, associated with the risk of changes in the pharmacological response to clopidogrel and proton pump inhibitors in patients with acute coronary syndrome (ACS) and gastric ulcer from Russian and Yakut ethnic groups.
METHODS: The research included 411 patients with ACS (143 Russians and 268 Yakuts) and 204 patients with histologically confirmed gastric ulcer (63 Russians and 141 Yakuts). Genotyping of 681G>A and 636G>A polymorphisms was performed by using polymerase real-time chain reaction.
RESULTS: In both ethnic groups, Hardy-Weinberg equilibrium was followed in a distribution of alleles and genotypes in the population (p>0.05). The 681A allele frequency in the Yakut ethnic group was higher than in the Russian group: 17.53% vs. 8.39% (p=0.001). No statistically significant difference was found in the frequency of 636A in Yakuts and Russians with ACS: 3.92% vs. 3.50% (p=0.840). While comparing the frequency distribution of alleles 681A (13.49% vs. 14.54%, p=0.878) and 636A (7.94% vs. 7.80%, p=1) in patients with a gastric ulcer from Russian and Yakut ethnic groups, no significant difference was found in carrier frequency.
CONCLUSIONS: The results of the present study may be helpful for developing guidelines for CYPC19 genotype-directed antiplatelet therapy for Yakut and Russian patients.

PMID: 29738309 [PubMed - as supplied by publisher]

Impact of a non-synonymous Q281R polymorphism on structure of human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2 ).

J Cell Biochem. 2018 May 08;:

Authors: Gurung AB, Bhattacharjee A

Abstract
Non-synonymous single nucleotide polymorphisms (nsSNPs) are genetic variations at single base resulting in an amino acid change which have been associated with various complex human diseases. The human Lipoprotein-associated phospholipase A2 (Lp-PLA2 ) gene harbours a rare Q281R polymorphism which was previously reported to cause loss of enzymatic function. Lp-PLA2 is an important enzyme which catalyzes the hydrolysis of polar phospholipids releasing pro-atherogenic and pro-inflammatory mediators involved in the pathogenesis of atherosclerosis. Our current study is aimed at elucidating the structural and functional consequences of Q281R polymorphism on Lp-PLA2 . The Q281R mutation is classified as deleterious and causes protein instability as deduced from evolutionary, folding free energy changes and Support vector machine (SVM)-based methods. A Q281R mutant structure was deciphered using homology modelling approach and was validated using phi and psi dihedral angles distribution, ERRAT, Verify_3D scores, Protein Structure Analysis (ProSA) energ,y and Z-score. A decreased hydrophobic interactions and weaker substrate binding affinity was observed in the mutant compared to the wild- type (WT) using molecular docking. Further, the mutant displayed enhanced structural flexibility particularly in the low density lipoprotein (LDL) binding domain, decreased solvent accessibility of catalytic residues-Phe274 and Ser273 and increased Cɑ distance between Phe274 and Leu153 and large conformational entropy change as inferred from all-atom molecular dynamics (MD) simulation and essential dynamics (ED) studies. Our results corroborate well with previous experimental studies and thus these aberrations in the Q281R mutant structure may help explain the molecular basis of loss of enzyme activity.

PMID: 29737567 [PubMed - as supplied by publisher]

Age- and genotype-dependent variability in the protein abundance and activity of six major uridine diphosphate-glucuronosyltransferases in human liver.

Clin Pharmacol Ther. 2018 May 08;:

Authors: Bhatt DK, Mehrotra A, Gaedigk A, Chapa R, Basit A, Zhang H, Choudhari P, Boberg M, Pearce RE, Gaedigk R, Broeckel U, Leeder JS, Prasad B

Abstract
The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by LC-MS/MS proteomics to determine UGT protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age 18-67 years) donors. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 increased by ∼8, 55, 35, 33, 8 and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for UGT isoforms was between 2.6 to 10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple genetic variants possessing noticeable ontogeny-genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated for zidovudine and morphine. This article is protected by copyright. All rights reserved.

PMID: 29737521 [PubMed - as supplied by publisher]