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Pharmacogenomics Journal

Yaowaluck Hongkaew, Sadeep Medhasi, Ekawat Pasomsub, Nattawat Ngamsamut, Apichaya Puangpetch, Natchaya Vanwong, Monpat Chamnanphon, Penkhae Limsila, Chuthamanee Suthisisang, Bob Wilffert, Chonlaphat Sukasem
The aim of this study was to investigate the association of drug-metabolizing enzyme and transporter (DMET) polymorphisms with the risperidone-induced prolactin response using an overlapping gene model between serum prolactin level and hyperprolactinemia in autism spectrum disorder (ASD) patients. Eighty-four ASD patients who were receiving risperidone for at least 1 month were recruited and then assigned to either the normal prolactin group or the hyperprolactinemia group based on their serum prolactin level...
June 29, 2018: Pharmacogenomics Journal
Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Chiara Cremolini, Sara Lonardi, Francesca Bergamo, Yang Ning, Noriko Yamamoto, Satoshi Okazaki, Martin D Berger, Yuji Miyamoto, Roel Gopez, Afsaneh Barzi, Toshiharu Yamaguchi, Sebastian Stintzing, Volker Heinemann, Fotios Loupakis, Alfredo Falcone, Heinz-Josef Lenz
PIN1-mediated substrate isomerization plays a role in the repair of DNA double-strand breaks. We hypothesized that genetic polymorphisms in PIN1-related pathways may affect tumor sensitivity to oxaliplatin or irinotecan in metastatic colorectal cancer (mCRC) patients. We analyzed genomic DNA from five cohorts of mCRC patients (total 950) treated with different first-line treatments: oxaliplatin cohorts 1 (n = 146) and 2 (n = 70); irinotecan cohorts 1 (n = 228), and 2 (n = 276); and combination cohort (n = 230)...
June 21, 2018: Pharmacogenomics Journal
Marguerite R Irvin, Colleen M Sitlani, Raymond Noordam, Christie L Avery, Joshua C Bis, James S Floyd, Jin Li, Nita A Limdi, Vinodh Srinivasasainagendra, James Stewart, Renée de Mutsert, Dennis O Mook-Kanamori, Leonard Lipovich, Erica L Kleinbrink, Albert Smith, Traci M Bartz, Eric A Whitsel, Andre G Uitterlinden, Kerri L Wiggins, James G Wilson, Degui Zhi, Bruno H Stricker, Jerome I Rotter, Donna K Arnett, Bruce M Psaty, Leslie A Lange
We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10-8 ) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1...
June 1, 2018: Pharmacogenomics Journal
Marijana Vujkovic, Scarlett L Bellamy, Athena F Zuppa, Marc R Gastonguay, Ganesh S Moorthy, Bakgaki Ratshaa, Xiaoyan Han, Andrew P Steenhoff, Mosepele Mosepele, Brian L Strom, Gregory P Bisson, Richard Aplenc, Robert Gross
Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance...
June 1, 2018: Pharmacogenomics Journal
Chiara De Leonibus, Philip Murray, Terence Garner, Daniel Hanson, Peter Clayton, Adam Stevens
Response to recombinant human growth hormone (r-hGH) in the first year of therapy has been associated with single-nucleotide polymorphisms (SNPs) in children with GH deficiency (GHD). Associated SNPs were screened for regulatory function using a combination of in silico techniques. Four SNPs in regulatory sequences were selected for the analysis of in vitro transcriptional activity (TA). There was an additive effect of the alleles in the four genes associated with good growth response. For rs3110697 within IGFBP3, rs1045992 in CYP19A1 and rs2888586 in SOS1, the variant associated with better growth response showed higher TA with r-hGH treatment...
June 1, 2018: Pharmacogenomics Journal
Chad A Bousman, Boadie W Dunlop
The degree of agreement between four commercial pharmacogenetic-based decision support tools (DSTs) was examined in five outpatients with major depressive disorder and at least two previous antidepressant failures. Comparisons were made across seven pharmacokinetic (CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, and UGT2B15) and seven pharmacodynamic (BDNF, COMT, HLA-A, HTR2A, HTR2C, OPRM1, and SLC6A4) genes that were included on ≥2 of the four DST testing panels. Among these overlapping genes, genotype (33-100%) and predicted phenotype (20-100%) agreement varied substantially...
May 25, 2018: Pharmacogenomics Journal
Ruowang Li, Dokyoon Kim, Heather E Wheeler, Scott M Dudek, M Eileen Dolan, Marylyn D Ritchie
Identifying genetic variants associated with chemotherapeutic induced toxicity is an important step towards personalized treatment of cancer patients. However, annotating and interpreting the associated genetic variants remains challenging because each associated variant is a surrogate for many other variants in the same region. The issue is further complicated when investigating patterns of associated variants with multiple drugs. In this study, we used biological knowledge to annotate and compare genetic variants associated with cellular sensitivity to mechanistically distinct chemotherapeutic drugs, including platinating agents (cisplatin, carboplatin), capecitabine, cytarabine, and paclitaxel...
May 25, 2018: Pharmacogenomics Journal
John C Taylor, Tim Bongartz, Jonathan Massey, Borbala Mifsud, Athina Spiliopoulou, Ian C Scott, Jianmei Wang, Michael Morgan, Darren Plant, Marco Colombo, Peter Orchard, Sarah Twigg, Iain B McInnes, Duncan Porter, Jane E Freeston, Jackie L Nam, Heather J Cordell, John D Isaacs, Jenna L Strathdee, Donna Arnett, Maria J H de Hair, Paul P Tak, Stella Aslibekyan, Ronald F van Vollenhoven, Leonid Padyukov, S Louis Bridges, Costantino Pitzalis, Andrew P Cope, Suzanne M M Verstappen, Paul Emery, Michael R Barnes, Felix Agakov, Paul McKeigue, Taisei Mushiroda, Michiaki Kubo, Richard Weinshilboum, Anne Barton, Ann W Morgan, Jennifer H Barrett
Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28)...
May 25, 2018: Pharmacogenomics Journal
Fernando F P Mafra, Pedro P Gattai, Michel M Macedo, Marcelo A Mori, Ronaldo C Araujo
Angiotensin-I-converting enzyme (ACE) is involved in the synthesis and degradation of important bioactive peptides. The ACE gene has a 287-bp insertion/deletion polymorphism that controls ACE expression through a mechanism that remains elusive. In this study, we found that the 287-bp polymorphic element of the ACE gene, a member of the AluYa5 sub-family of Alu elements, codes for an RNA molecule that controls the levels of ACE mRNA. Transient transfection of a plasmid containing a CMV promoter upstream of the ACE polymorphic element resulted in significant expression of an AluYa5 RNA and reduced ACE mRNA expression as well as ACE enzymatic activity in AD 293 cells...
May 23, 2018: Pharmacogenomics Journal
Ambily Sivadas, Vinod Scaria
The Arabs represent one of the most genetically heterogeneous populations characterized by a high prevalence of Mendelian disorders due to consanguinity. Population-scale genomic datasets provide a unique opportunity to understand the epidemiology of variants associated with differential therapeutic response. We analyzed publicly available genomic data for 1005 Qatari individuals encompassing five subpopulations. The frequencies of known and novel pharmacogenetic variants were compared with global populations...
May 3, 2018: Pharmacogenomics Journal
Félix Javier Jiménez-Jiménez, Gara Esguevillas, Hortensia Alonso-Navarro, Martín Zurdo, Laura Turpín-Fenoll, Jorge Millán-Pascual, Teresa Adeva-Bartolomé, Esther Cubo, Francisco Navacerrada, Gemma Amo, Ana Rojo-Sebastián, Lluisa Rubio, Mónica Díez-Fairén, Pau Pastor, Marisol Calleja, José Francisco Plaza-Nieto, Belén Pilo-de-la-Fuente, Margarita Arroyo-Solera, Esteban García-Albea, José A G Agúndez, Elena García-Martín
The possible role of gammaaminobutyric acid (GABA) in the pathophysiology of restless legs syndrome (RLS) is suggested by the symptomatic improvement achieved with GABAergic drugs. Thalamic GABA levels have shown positive correlation with periodic limb movements indices and with RLS severity. We tried to investigate the possible association between the most common single nucleotide polymorphisms (SNPs) in the GABA receptors (GABR) genes rho1, 2, and 3 (GABRR1, GABRR2, GABRR3), alpha4 (GABRA4), epsilon (GABRE), and theta (GABRQ) with the risk of developing RLS...
May 3, 2018: Pharmacogenomics Journal
Fernanda Rodrigues-Soares, Fernanda S G Kehdy, Julia Sampaio-Coelho, Poliana X C Andrade, Carolina Céspedes-Garro, Camila Zolini, Marla M Aquino, Mauricio L Barreto, Bernardo L Horta, Maria Fernanda Lima-Costa, Alexandre C Pereira, Adrián LLerena, Eduardo Tarazona-Santos
We present allele frequencies involving 39 pharmacogenetic biomarkers studied in Brazil, and their distribution on self-reported race/color categories that: (1) involve a mix of perceptions about ancestry, morphological traits, and cultural/identity issues, being social constructs pervasively used in Brazilian society and medical studies; (2) are associated with disparities in access to health services, as well as in their representation in genetic studies, and (3), as we report here, explain a larger portion of the variance of pharmaco-allele frequencies than geography...
May 1, 2018: Pharmacogenomics Journal
D I Staquicini, S D'Angelo, F Ferrara, K Karjalainen, G Sharma, T L Smith, C A Tarleton, D E Jaalouk, A Kuniyasu, W B Baze, B K Chaffee, P W Hanley, K F Barnhart, E Koivunen, S Marchiò, R L Sidman, J E Cortes, H M Kantarjian, W Arap, R Pasqualini
Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D(KLAKLAK)2-containing class of agents...
May 22, 2018: Pharmacogenomics Journal
W C Tan-Koi, P C Leow, Y Y Teo
With rapid developments of pharmacogenomics (PGx) and regulatory science, it is important to understand the current PGx integration in product life cycle, impact on clinical practice thus far and opportunities ahead. We conducted a cross-sectional review on PGx-related regulatory documents and implementation guidelines in the United States and Europe. Our review found that although PGx-related guidance in both markets span across the entire product life cycle, the scope of implementation guidelines varies across two continents...
May 22, 2018: Pharmacogenomics Journal
J Jack, G W Small, C C Brown, T M Havener, H L McLeod, A A Motsinger-Reif, K L Richards
Elucidating resistance mechanisms for therapeutic monoclonal antibodies (MAbs) is challenging, because they are difficult to study in non-human models. We therefore developed a strategy to genetically map in vitro drug sensitivity, identifying genes that alter responsiveness to rituximab, a therapeutic anti-CD20 MAb that provides significant benefit to patients with B-cell malignancies. We discovered novel loci with genome-wide mapping analyses and functionally validated one of these genes, CBLB, which causes rituximab resistance when knocked down in lymphoma cells...
May 22, 2018: Pharmacogenomics Journal
G Visani, F Loscocco, A Ruzzo, S Galimberti, F Graziano, M T Voso, E Giacomini, C Finelli, E Ciabatti, E Fabiani, S Barulli, A Volpe, D Magro, P Piccaluga, F Fuligni, M Vignetti, P Fazi, A Piciocchi, E Gabucci, M Rocchi, M Magnani, A Isidori
We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0...
May 22, 2018: Pharmacogenomics Journal
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...
May 22, 2018: Pharmacogenomics Journal
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...
May 22, 2018: Pharmacogenomics Journal
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...
May 22, 2018: Pharmacogenomics Journal
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...
May 22, 2018: Pharmacogenomics Journal
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