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Pharmacogenomics Journal

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https://www.readbyqxmd.com/read/29160303/the-pnpla3-i148m-variant-is-associated-with-transaminase-elevations-in-type-2-diabetes-patients-treated-with-basal-insulin-peglispro
#1
S Pillai, S Duvvuru, P Bhatnagar, W Foster, M Farmen, S Shankar, C Harris, E Bastyr, B Hoogwerf, A Haupt
Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials...
November 21, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29160302/role-of-cyp24a1-vdr-and-gc-gene-polymorphisms-on-deferasirox-pharmacokinetics-and-clinical-outcomes
#2
S Allegra, J Cusato, S De Francia, A Arduino, F Longo, E Pirro, D Massano, A De Nicolò, A Piga, A D'Avolio
β-Thalassemia patients develop deficiency in vitamin D absorption and liver hydroxylation, resulting in extremely low calcitriol levels. We explored the role of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism, transport and activity on deferasirox pharmacokinetics and outcomes (effectiveness trough levels (Ctrough) and the area under the curve (AUC) cutoffs of 20 μg ml(-1) and 360 μg ml(-1) h(-1), respectively; nonresponse AUC limit of 250 μg ml(-1) h(-1)). Ninety-nine β-thalassemic patients were enrolled...
November 21, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29160301/new-insights-into-the-pharmacogenomics-of-antidepressant-response-from-the-gendep-and-star-d-studies-rare-variant-analysis-and-high-density-imputation
#3
C Fabbri, K E Tansey, R H Perlis, J Hauser, N Henigsberg, W Maier, O Mors, A Placentino, M Rietschel, D Souery, G Breen, C Curtis, L Sang-Hyuk, S Newhouse, H Patel, M Guipponi, N Perroud, G Bondolfi, M O'Donovan, G Lewis, J M Biernacka, R M Weinshilboum, A Farmer, K J Aitchison, I Craig, P McGuffin, R Uher, C M Lewis
Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation...
November 21, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29160300/genome-wide-association-study-identifies-the-common-variants-in-cyp3a4-and-cyp3a5-responsible-for-variation-in-tacrolimus-trough-concentration-in-caucasian-kidney-transplant-recipients
#4
W S Oetting, B Wu, D P Schladt, W Guan, R P Remmel, R B Mannon, A J Matas, A K Israni, P A Jacobson
The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study...
November 21, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29053139/chronic-fluoxetine-upregulates-activity-protein-and-mrna-levels-of-cytosolic-phospholipase-a2-in-rat-frontal-cortex
#5
J S Rao, R N Ertley, H-J Lee, S I Rapoport, R P Bazinet
This corrects the article DOI: 10.1038/sj.tpj.6500391.
October 17, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28607508/systematic-review-and-meta-analysis-pharmacogenetics-of-anti-tnf-treatment-response-in-rheumatoid-arthritis
#6
REVIEW
S Bek, A B Bojesen, J V Nielsen, J Sode, S Bank, U Vogel, V Andersen
Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects ~1% of the Caucasian population. Over the last decades, the availability of biological drugs targeting the proinflammatory cytokine tumour necrosis factor α, anti-TNF drugs, has improved the treatment of patients with RA. However, one-third of the patients do not respond to the treatment. We wanted to evaluate the status of pharmacogenomics of anti-TNF treatment. We performed a PubMed literature search and all studies reporting original data on associations between genetic variants and anti-TNF treatment response in RA patients were included and results evaluated by meta-analysis...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28607506/cost-effectiveness-of-pharmacogenetic-guided-treatment-are-we-there-yet
#7
REVIEW
M Verbelen, M E Weale, C M Lewis
Pharmacogenetics (PGx) has the potential to personalize pharmaceutical treatments. Many relevant gene-drug associations have been discovered, but PGx-guided treatment needs to be cost-effective as well as clinically beneficial to be incorporated into standard health-care. We reviewed economic evaluations for PGx associations listed in the US Food and Drug Administration (FDA) Table of Pharmacogenomic Biomarkers in Drug Labeling. We determined the proportion of evaluations that found PGx-guided treatment to be cost-effective or dominant over the alternative strategies, and estimated the impact on this proportion of removing the cost of genetic testing...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27995989/pharmacogenetic-variants-associated-with-outcome-in-patients-with-advanced-gastric-cancer-treated-with-fluoropyrimidine-and-platinum-based-triplet-combinations-a-pooled-analysis-of-three-prospective-studies
#8
D Meulendijks, E A Rozeman, A Cats, K Sikorska, M Joerger, M J Deenen, J H Beijnen, J H M Schellens
The main treatment for advanced gastric cancer is fluoropyrimidine and platinum-based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P<0.0026. TYMS VNTR (variable number of 28-bp tandem repeats) 3 R/3 R genotype was formally associated with inferior ORR (odds ratio (OR) 0...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27573236/hedgehog-pathway-overexpression-in-pancreatic-cancer-is-abrogated-by-new-generation-taxoid-sb-t-1216
#9
B Mohelnikova-Duchonova, M Kocik, B Duchonova, V Brynychova, M Oliverius, J Hlavsa, E Honsova, J Mazanec, Z Kala, I Ojima, D J Hughes, J E Doherty, H A Murray, M A Crockard, R Lemstrova, P Soucek
The Hedgehog pathway is one of the major driver pathways in pancreatic ductal adenocarcinoma. This study investigated prognostic importance of Hedgehog signaling pathway in pancreatic cancer patients who underwent a radical resection. Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 45 patients with histologically verified pancreatic cancer. The effect of experimental taxane chemotherapy on the expression of Hedgehog pathway was evaluated in vivo using a mouse xenograft model prepared using pancreatic cancer cell line Paca-44...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27241063/influence-of-abcb1-and-abcg2-polymorphisms-on-the-antiemetic-efficacy-in-patients-with-cancer-receiving-cisplatin-based-chemotherapy-a-triple-pharmacogenomics-study
#10
D Tsuji, M Yokoi, K Suzuki, T Daimon, M Nakao, H Ayuhara, Y Kogure, K Shibata, T Hayashi, K Hirai, K Inoue, T Hama, K Takeda, M Nishio, K Itoh
Resistance to antiemetic treatment with 5-hydroxytryptamine-3 receptor antagonist is an issue. This study evaluated the potential roles of ABCB1 and ABCG2 polymorphisms in antiemetic treatment resistance in patients with cancer previously enrolled in a randomized controlled trial. A total of 156 patients were evaluated for their responses to antiemetic therapy and then subdivided into granisetron or palonosetron groups. The genotypes were evaluated for their association with antiemetic efficacy in each treatment groups...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27241059/genetic-epidemiology-of-pharmacogenetic-variants-in-south-east-asian-malays-using-whole-genome-sequences
#11
A Sivadas, M Z Salleh, L K Teh, V Scaria
Expanding the scope of pharmacogenomic research by including multiple global populations is integral to building robust evidence for its clinical translation. Deep whole-genome sequencing of diverse ethnic populations provides a unique opportunity to study rare and common pharmacogenomic markers that often vary in frequency across populations. In this study, we aim to build a diverse map of pharmacogenetic variants in South East Asian (SEA) Malay population using deep whole-genome sequences of 100 healthy SEA Malay individuals...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27217051/clinical-pharmacogenetic-predictive-models-for-mtx-discontinuation-due-to-adverse-events-in-rheumatoid-arthritis
#12
B Jenko, L Lusa, M Tomsic, S Praprotnik, V Dolzan
We describe a novel approach to investigate and evaluate combined effect of a large number of clinical and pharmacogenetic factors on treatment outcome. We have used this approach to investigate predictors of methotrexate (MTX)-induced adverse events (AEs) leading to treatment discontinuation in rheumatoid arthritis (RA) patients. In total, 333 RA patients were genotyped for 34 polymorphisms in MTX transporters, folate and adenosine pathways. The effect of clinical and pharmacogenetic factors was assessed with penalized regression in the cause-specific Cox proportional hazards model...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27168101/genetic-risk-factors-for-clozapine-induced-neutropenia-and-agranulocytosis-in-a-dutch-psychiatric-population
#13
K van der Weide, H Loovers, K Pondman, J Bogers, T van der Straaten, E Langemeijer, D Cohen, J Commandeur, J van der Weide
Prescription of clozapine is complicated by the occurrence of clozapine-induced reduction of neutrophils. The aim of this study was to identify genetic risk factors in a population of 310 Dutch patients treated with clozapine, including 38 patients developing neutropenia and 31 patients developing agranulocytosis. NQO2 1541AA (NRH quinone oxidoreductase 2; protects cells against oxidative metabolites) was present at a higher frequency in agranulocytosis patients compared with control (23% versus 7%, P=0.03), as was ABCB1 (ABC-transporter-B1; drug efflux transporter) 3435TT (32% versus 20%, P=0...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27168100/gene-gene-interactions-in-the-nampt-pathway-plasma-visfatin-nampt-levels-and-antihypertensive-therapy-responsiveness-in-hypertensive-disorders-of-pregnancy
#14
M R Luizon, A C T Palei, V A Belo, L M Amaral, R Lacchini, G Duarte, R C Cavalli, V C Sandrim, J E Tanus-Santos
Nicotinamide phosphorybosil transferase (NAMPT) polymorphisms affect visfatin/NAMPT levels and may affect the responsiveness to therapy in hypertensive disorders of pregnancy. We examined whether NAMPT polymorphisms (rs1319501 T>C and rs3801266 A>G), or haplotypes, and gene-gene interactions in the NAMPT pathway affect plasma visfatin/NAMPT levels and the response to antihypertensive therapy in 205 patients with preeclampsia (PE) and 174 patients with gestational hypertension. We also studied 207 healthy pregnant controls...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27139154/emergent-biomarker-derived-from-next-generation-sequencing-to-identify-pain-patients-requiring-uncommonly-high-opioid-doses
#15
D Kringel, A Ultsch, M Zimmermann, J-P Jansen, W Ilias, R Freynhagen, N Griessinger, A Kopf, C Stein, A Doehring, E Resch, J Lötsch
Next-generation sequencing (NGS) provides unrestricted access to the genome, but it produces 'big data' exceeding in amount and complexity the classical analytical approaches. We introduce a bioinformatics-based classifying biomarker that uses emergent properties in genetics to separate pain patients requiring extremely high opioid doses from controls. Following precisely calculated selection of the 34 most informative markers in the OPRM1, OPRK1, OPRD1 and SIGMAR1 genes, pattern of genotypes belonging to either patient group could be derived using a k-nearest neighbor (kNN) classifier that provided a diagnostic accuracy of 80...
October 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28786423/characterisation-of-the-hla-drb1-07-01-biomarker-for-lapatinib-induced-liver-toxicity-during-treatment-of-early-stage-breast-cancer-patients-with-lapatinib-in-combination-with-trastuzumab-and-or-taxanes
#16
C F Spraggs, L R Parham, L P Briley, L Warren, L S Williams, D J Fraser, Z Jiang, Z Aziz, S Ahmed, G Demetriou, A Mehta, N Jackson, J Byrne, M Andersson, M Toi, L Harris, J Gralow, J A Zujewski, R Crescenzo, A Armour, E Perez, M Piccart
HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10(-26), n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers...
August 8, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28762371/imatinib-induced-ophthalmological-side-effects-in-gist-patients-are-associated-with-the-variations-of-egfr-slc22a1-slc22a5-and-abcb1
#17
H-B Qiu, W Zhuang, T Wu, S Xin, C-Z Lin, H-L Ruan, X Zhu, M Huang, J-L Li, X-Y Hou, Z-W Zhou, X-D Wang
Imatinib-induced ophthalmological side-effects, including conjunctiva hemorrhage and periorbital oedema, although very common and still remain relatively little understood. The present study investigated the effects of genetic polymorphisms of drug targets and membrane transporters on these side effects. We found that the minor allele of EGFR rs10258429 and SLC22A1 rs683369 were significant risk determinants of conjunctival hemorrhage with OR of 7.061 (95%CI=1.791-27.837, P=0.005 for EGFR rs10258429 CT+TT vs CC), and 4...
August 1, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28762370/impact-of-cyp2d6-polymorphisms-on-endoxifen-concentrations-and-breast-cancer-outcomes
#18
REVIEW
G S Hwang, R Bhat, R D Crutchley, M V Trivedi
We investigated the impact of germline CYP2D6 genotyping done using the non-tumor specimen on endoxifen concentrations and/or clinical outcomes in breast cancer (BC) patients treated with tamoxifen in published studies. We evaluated published data from 13 001 patients in 29 studies. Mean±s.d. endoxifen concentrations were significantly lower in poor metabolizers (PM) versus extensive metabolizers (EM) (8.8±7.2 versus 22.3±11.8 ng ml(-1); P<0.05). The PM status did not influence clinical outcomes in majority of the studies...
August 1, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28719598/the-predictive-value-of-abcb1-abcg2-cyp3a4-5-and-cyp2d6-polymorphisms-for-risperidone-and-aripiprazole-plasma-concentrations-and-the-occurrence-of-adverse-drug-reactions
#19
C Rafaniello, M Sessa, F F Bernardi, M Pozzi, S Cheli, D Cattaneo, S Baldelli, M Molteni, R Bernardini, F Rossi, E Clementi, C Bravaccio, S Radice, A Capuano
We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c...
July 18, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28719597/pharmacogenomics-study-of-thiazide-diuretics-and-qt-interval-in-multi-ethnic-populations-the-cohorts-for-heart-and-aging-research-in-genomic-epidemiology
#20
A A Seyerle, C M Sitlani, R Noordam, S M Gogarten, J Li, X Li, D S Evans, F Sun, M A Laaksonen, A Isaacs, K Kristiansson, H M Highland, J D Stewart, T B Harris, S Trompet, J C Bis, G M Peloso, J A Brody, L Broer, E L Busch, Q Duan, A M Stilp, C J O'Donnell, P W Macfarlane, J S Floyd, J A Kors, H J Lin, R Li-Gao, T Sofer, R Méndez-Giráldez, S R Cummings, S R Heckbert, A Hofman, I Ford, Y Li, L J Launer, K Porthan, C Newton-Cheh, M D Napier, K F Kerr, A P Reiner, K M Rice, J Roach, B M Buckley, E Z Soliman, R de Mutsert, N Sotoodehnia, A G Uitterlinden, K E North, C R Lee, V Gudnason, T Stürmer, F R Rosendaal, K D Taylor, K L Wiggins, J G Wilson, Y-DI Chen, R C Kaplan, K Wilhelmsen, L A Cupples, V Salomaa, C van Duijn, J W Jukema, Y Liu, D O Mook-Kanamori, L A Lange, R S Vasan, A V Smith, B H Stricker, C C Laurie, J I Rotter, E A Whitsel, B M Psaty, C L Avery
Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment...
July 18, 2017: Pharmacogenomics Journal
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