Pharmacogenetics of anticoagulants used for stroke prevention in patients with atrial fibrillation.

Expert Opin Drug Metab Toxicol. 2019 May 23;:

Authors: Kampouraki E, Kamali F

Abstract
Introduction: The inclusion of pharmacogenetics alongside clinical information in anticoagulant therapy offers the opportunity for a tailored approach to treatment according to individual patient characteristics. Areas covered: Literature was searched using PubMed database, focusing on pharmacogenetics of oral anticoagulants. Original research articles and review articles in English language were included in the literature reviewed. This article includes all information available for the genetic cause of inter-individual variability in anticoagulation response to oral anticoagulant drugs. The pharmacogenetics of VKAs and NOACs are described in detail. Expert opinion: There have been numerous studies focusing on the pharmacogenetics of VKAs, particularly warfarin. Current evidence suggests that known genetic and clinical factors explain a large proportion of the inter-individual variability in response to warfarin. Pharmacogenetic-based algorithms have been validated to determine their clinical utility with equivocal results. To date only a limited number of mostly small studies on the pharmacogenetics of NOACs exists. The latter have highlighted genetic polymorphisms in specific genes that may affect clinical outcomes. Further evaluations of these polymorphisms are needed before firm conclusions can be drawn about the significance of pharmacogenetics on NOAC therapy.

PMID: 31120800 [PubMed - as supplied by publisher]

RasGRP1 is a target for VEGF to induce angiogenesis and involved in the endothelial-protective effects of metformin under high glucose in HUVECs.

IUBMB Life. 2019 May 23;:

Authors: Xu J, Liu M, Yu M, Shen J, Zhou J, Hu J, Zhou Y, Zhang W

Abstract
Impaired angiogenesis in endothelial cells is a hallmark of diabetes vascular complications. Ras guanine-releasing protein 1 (RasGRP1) is a guanine nucleotide exchange factor for Ras, and its role in endothelial angiogenesis has not been investigated. Given the importance of Ras in vascular endothelial growth factor (VEGF)-induced angiogenesis, we hypothesized that RasGRP1 may be a critical pathway downstream of VEGF and involved in endothelial angiogenesis. Furthermore, we investigate whether RasGRP1-dependent VEGF signaling was downregulated under high glucose conditions mimicking diabetes and required for the endothelial protective action of metformin in human umbilical vein endothelial cells (HUVECs). HUVECs were transfected with either RasGRP1 small interfering RNA (siRNA) or pEnter-RasGRP1 plasmid to down- and upregulate RasGRP1 expression before different treatments, such as added VEGF or not, exposed to high glucose (35 mM) or normal glucose (5 mM) in the presence or absence of metformin. Expression of VEGF, RasGRP1, and their signaling targets were analyzed by Western blot; migration and tube formation were detected by transwell chamber assay and Matrigel angiogenesis assay, respectively. Knockdown of RasGRP1 significantly attenuated VEGF-induced migration and tube formation activities of HUVECs and activation of AKT pathway. The expression of VEGF, RasGRP1, and AKT phosphorylation was downregulated in HUVECs exposed to high glucose compared with normal glucose, whereas metformin upregulated the RasGRP1-dependent VEGF signaling and ameliorates the impaired angiogenesis caused by high glucose. RasGRP1 is involved in the VEGF-induced angiogenesis and the pro-angiogenesis effects of metformin under hyperglycemia. © 2019 IUBMB Life, 2019.

PMID: 31120617 [PubMed - as supplied by publisher]

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Nature. 2019 May 22;:

Authors: Flannick J, Mercader JM, Fuchsberger C, Udler MS, Mahajan A, Wessel J, Teslovich TM, Caulkins L, Koesterer R, Barajas-Olmos F, Blackwell TW, Boerwinkle E, Brody JA, Centeno-Cruz F, Chen L, Chen S, Contreras-Cubas C, Córdova E, Correa A, Cortes M, DeFronzo RA, Dolan L, Drews KL, Elliott A, Floyd JS, Gabriel S, Garay-Sevilla ME, García-Ortiz H, Gross M, Han S, Heard-Costa NL, Jackson AU, Jørgensen ME, Kang HM, Kelsey M, Kim BJ, Koistinen HA, Kuusisto J, Leader JB, Linneberg A, Liu CT, Liu J, Lyssenko V, Manning AK, Marcketta A, Malacara-Hernandez JM, Martínez-Hernández A, Matsuo K, Mayer-Davis E, Mendoza-Caamal E, Mohlke KL, Morrison AC, Ndungu A, Ng MCY, O'Dushlaine C, Payne AJ, Pihoker C, Broad Genomics Platform, Post WS, Preuss M, Psaty BM, Vasan RS, Rayner NW, Reiner AP, Revilla-Monsalve C, Robertson NR, Santoro N, Schurmann C, So WY, Soberón X, Stringham HM, Strom TM, Tam CHT, Thameem F, Tomlinson B, Torres JM, Tracy RP, van Dam RM, Vujkovic M, Wang S, Welch RP, Witte DR, Wong TY, Atzmon G, Barzilai N, Blangero J, Bonnycastle LL, Bowden DW, Chambers JC, Chan E, Cheng CY, Cho YS, Collins FS, de Vries PS, Duggirala R, Glaser B, Gonzalez C, Gonzalez ME, Groop L, Kooner JS, Kwak SH, Laakso M, Lehman DM, Nilsson P, Spector TD, Tai ES, Tuomi T, Tuomilehto J, Wilson JG, Aguilar-Salinas CA, Bottinger E, Burke B, Carey DJ, Chan JCN, Dupuis J, Frossard P, Heckbert SR, Hwang MY, Kim YJ, Kirchner HL, Lee JY, Lee J, Loos RJF, Ma RCW, Morris AD, O'Donnell CJ, Palmer CNA, Pankow J, Park KS, Rasheed A, Saleheen D, Sim X, Small KS, Teo YY, Haiman C, Hanis CL, Henderson BE, Orozco L, Tusié-Luna T, Dewey FE, Baras A, Gieger C, Meitinger T, Strauch K, Lange L, Grarup N, Hansen T, Pedersen O, Zeitler P, Dabelea D, Abecasis G, Bell GI, Cox NJ, Seielstad M, Sladek R, Meigs JB, Rich SS, Rotter JI, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES, Altshuler D, Burtt NP, Scott LJ, Morris AP, Florez JC, McCarthy MI, Boehnke M

Abstract
Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

PMID: 31118516 [PubMed - as supplied by publisher]

Genetics and adverse events with irinotecan treatment: what do we know?

Pharmacogenomics. 2019 Apr;20(6):393-395

Authors: Páez D

PMID: 31117929 [PubMed - in process]

VKORC1 variants as significant predictors of warfarin dose in Emiratis.

Pharmgenomics Pers Med. 2019;12:47-57

Authors: Al-Mahayri ZN, Al Jaibeji HS, Saab Y, Soliman K, Al-Gazali L, Patrinos GP, Ali BR

Abstract
Purpose: Variability in response to warfarin is one of the main obstacles challenging its use in clinical practice. Vitamin K epoxide reductase complex (VKORC) is the target enzyme of warfarin, and variations in the form of single nucleotide polymorphisms (SNPs) in VKORC1, coding for this enzyme, are known to cause resistance to warfarin treatment. This study aimed to explore VKORC1 variants in Emirati patients receiving warfarin treatment and to correlate their genotypes at the studied SNPs to their maintenance warfarin dose. Patients and methods: Sanger sequencing of the majority of the VKORC1 gene was applied to samples from 90 patients and 117 normal individuals recruited from Tawam Hospital, Al-Ain, UAE. Genotypes at the following variants were determined (rs9923231, rs188009042, rs61742245, rs17708472, rs9934438, rs8050894, rs2359612, rs7294). Statistical analysis was applied, including ANOVA, cross-tabulation, and multiple linear regression analysis, to determine the ability of nongenetic factors (age and gender) and genetic factors (VKORC1 genotypes) to explain variability in warfarin dose in patients. Results: Different frequencies of minor alleles were detected in the selected SNPs. Significant variation among genotypes at six VKORC1 variants were identified (rs9923231, rs9934438, rs8050894, rs2359612, rs7294). The main predictors for warfarin dose were rs9923231, age, and rs61742245 with 50.7% of the average warfarin dose in our sample could be explained by a regression model built on these three factors. Conclusion: This is the first report of the explanatory power of VKORC1 genotypes and nongenetic factors (age and gender) on warfarin dose among Emiratis. Also, this study highlighted the positive effect of considering rare pharmacogenomic variants on explaining warfarin dose variability.

PMID: 31114289 [PubMed]

Pharmacogenomics in Palliative Medicine.

Indian J Palliat Care. 2019 Apr-Jun;25(2):169-171

Authors: Rao M

PMID: 31114099 [PubMed]

Sequencing XMET genes to promote genotype-guided risk assessment and precision medicine.

Sci China Life Sci. 2019 May 20;:

Authors: Jin Y, Chen G, Xiao W, Hong H, Xu J, Guo Y, Xiao W, Shi T, Shi L, Tong W, Ning B

Abstract
High-throughput next generation sequencing (NGS) is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known reference genome or by de novo assembly without reference genome. This technology has led researchers to conduct an explosion of sequencing related projects in multidisciplinary fields of science. However, due to the limitations of sequencing-based chemistry, length of sequencing reads and the complexity of genes, it is difficult to determine the sequences of some portions of the human genome, leaving gaps in genomic data that frustrate further analysis. Particularly, some complex genes are difficult to be accurately sequenced or mapped because they contain high GC-content and/or low complexity regions, and complicated pseudogenes, such as the genes encoding xenobiotic metabolizing enzymes and transporters (XMETs). The genetic variants in XMET genes are critical to predicate inter-individual variability in drug efficacy, drug safety and susceptibility to environmental toxicity. We summarized and discussed challenges, wet-lab methods, and bioinformatics algorithms in sequencing "complex" XMET genes, which may provide insightful information in the application of NGS technology for implementation in toxicogenomics and pharmacogenomics.

PMID: 31114935 [PubMed - as supplied by publisher]

Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of amlodipine, olmesartan, and rosuvastatin in healthy adult subjects.

Drug Des Devel Ther. 2019;13:991-997

Authors: Oh M, Shin JG, Ahn S, Kim BH, Kim JY, Shin HJ, Shin HJ, Ghim JL

Abstract
Objective: The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of a fixed dose combination (FDC) formulation and co-administration of amlodipine, olmesartan, and rosuvastatin. Materials and methods: This study was an open-label, randomized, cross-over design conducted in healthy male volunteers. All subjects received either a single FDC tablet containing amlodipine 10 mg/olmesartan 40 mg/rosuvastatin 20 mg, or were co-administered an FDC tablet containing amlodipine 10 mg/olmesartan 40 mg and a tablet containing rosuvastatin 20 mg, for each period, with 14-day washout periods. Plasma concentrations of amlodipine, olmesartan, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was evaluated by measuring vital signs, clinical laboratory parameters, physical examinations, and medical interviews. Results: Sixty-four subjects were enrolled, and 54 completed the study. The geometric mean ratios and 90% CI for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 1.0716 (1.0369,1.1074) and 1.0497 (1.0243,1.0757) for amlodipine, 1.0396 (0.9818,1.1009) and 1.0138 (0.9716,1.0578) for olmesartan, and 1.0257 (0.9433,1.1152) and 1.0043 (0.9453,1.0669) for rosuvastatin. Fourteen cases of adverse events occurred in 12 subjects. There was no statistically significant clinical difference between the formulation groups. Conclusion: The 90% CI of the primary PK parameters were within the acceptance bioequivalence criteria, which is ln (0.8) and ln (1.25). These results indicate that the FDC formulation and co-administration of amlodipine, olmesartan and rosuvastatin are pharmacokinetically bioequivalent and have similar safety profiles.

PMID: 31114155 [PubMed - in process]

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial.

Blood Cancer J. 2019 May 21;9(6):51

Authors: Rafiee R, Chauhan L, Alonzo TA, Wang YC, Elmasry A, Loken MR, Pollard J, Aplenc R, Raimondi S, Hirsch BA, Bernstein ID, Gamis AS, Meshinchi S, Lamba JK

Abstract
Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p > 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.

PMID: 31113932 [PubMed - in process]

Could polymorphisms in ABCB1 gene represent a genetic risk factor for the development of mammary tumors in dogs?

Vet J. 2019 Jun;248:58-63

Authors: Maués T, El-Jaick KB, Costa FB, Freitas PVS, Moreira AS, Castro L, Ferreira MLG, Ferreira AMR

Abstract
The ABCB1 gene encodes the P-glycoprotein (P-gp) which regulates distribution and bioavailability of many endogenous and exogenous substrates, acting as a cellular mechanism of protection against these substances. Some studies have shown evidence that P-gp is related to carcinogenesis. In this study, we performed PCR and direct sequencing of ABCB1 exons 9 and 26 in 47 tissue DNA samples from canine mammary tumors. A statistically significant correlation between distinct canine breeds and the frequency of ABCB1 polymorphisms (c.985T > A and c.3442A > G SNP in ABCB1exons 9 and 26, respectively) was observed (P = 0.0015). In contrast, the TNM clinical staging, age, histological type and grade, as well as other histopathological characteristics, did not present statistically significant difference in relation to one or both SNP found in exons 9 and 26. These findings raise questions about the role of the canine ABCB1 polymorphisms in the development of mammary tumors, since the Poodle breed, which is the most common dog breed affected by mammary tumors in Brazil, presented the highest frequency of these variants. Notwithstanding, additional studies comprising a number of samples expressing the ABCB1 gene from healthy dogs, with advanced age and from different breeds, will be necessary to confirm the association of ABCB1polymorphisms and the development of mammary tumors.

PMID: 31113564 [PubMed - in process]

Promoter methylation of the MGAT3 and BACH2 genes correlates with the composition of the immunoglobulin G glycome in inflammatory bowel disease.

Clin Epigenetics. 2018;10:75

Authors: Klasić M, Markulin D, Vojta A, Samaržija I, Biruš I, Dobrinić P, Ventham NT, Trbojević-Akmačić I, Šimurina M, Štambuk J, Razdorov G, Kennedy NA, Satsangi J, Dias AM, Pinho S, Annese V, Latiano A, D'Inca R, IBD consortium, Lauc G, Zoldoš V

Abstract
Background: Many genome- and epigenome-wide association studies (GWAS and EWAS) and studies of promoter methylation of candidate genes for inflammatory bowel disease (IBD) have demonstrated significant associations between genetic and epigenetic changes and IBD. Independent GWA studies have identified genetic variants in the BACH2, IL6ST, LAMB1, IKZF1, and MGAT3 loci to be associated with both IBD and immunoglobulin G (IgG) glycosylation.
Methods: Using bisulfite pyrosequencing, we analyzed CpG methylation in promoter regions of these five genes from peripheral blood of several hundred IBD patients and healthy controls (HCs) from two independent cohorts, respectively.
Results: We found significant differences in the methylation levels in the MGAT3 and BACH2 genes between both Crohn's disease and ulcerative colitis when compared to HC. The same pattern of methylation changes was identified for both genes in CD19+ B cells isolated from the whole blood of a subset of the IBD patients. A correlation analysis was performed between the MGAT3 and BACH2 promoter methylation and individual IgG glycans, measured in the same individuals of the two large cohorts. MGAT3 promoter methylation correlated significantly with galactosylation, sialylation, and bisecting GlcNAc on IgG of the same patients, suggesting that activity of the GnT-III enzyme, encoded by this gene, might be altered in IBD. The correlations between the BACH2 promoter methylation and IgG glycans were less obvious, since BACH2 is not a glycosyltransferase and therefore may affect IgG glycosylation only indirectly.
Conclusions: Our results suggest that epigenetic deregulation of key glycosylation genes might lead to an increase in pro-inflammatory properties of IgG in IBD through a decrease in galactosylation and sialylation and an increase of bisecting GlcNAc on digalactosylated glycan structures. Finally, we showed that CpG methylation in the promoter of the MGAT3 gene is altered in CD3+ T cells isolated from inflamed mucosa of patients with ulcerative colitis from a third smaller cohort, for which biopsies were available, suggesting a functional role of this glyco-gene in IBD pathogenesis.

PMID: 29991969 [PubMed - indexed for MEDLINE]

Antidepressant pharmacogenetics in children and young adults: A systematic review.

J Affect Disord. 2019 May 14;254:98-108

Authors: Maruf AA, Greenslade A, Arnold PD, Bousman C

Abstract
OBJECTIVE: Antidepressants are frequently prescribed and are the first-line pharmacological treatments for psychiatric disorders in children and adolescents. Although antidepressants are generally effective and well-tolerated by children, between 31% to 48% will not respond and up to 25% will experience an adverse drug reaction. Evidence from adult populations suggests pharmacogenetic information can assist with identifying individuals at greatest risk for poor response or adverse drug reactions but the evidence base in pediatric populations is less clear.
METHOD: We systematically identified, reviewed, and critically evaluated the antidepressant pharmacogenetics literature among children and adolescents using standardized tools and consensus criteria.
RESULTS: We identified 24 studies, most of which were of fair to moderate quality. Collectively, the studies identified 25 significant gene-antidepressant associations involving 10 genes (ABCB1, BDNF, CYP2C19, CYP2D6, FKBP5, GNB3, HTR1B, HTR2A, SLC6A4, TPH2) and nine antidepressants (amitriptyline, citalopram, escitalopram, fluoxetine, fluvoxamine, nortriptyline, paroxetine, sertraline, and venlafaxine). None of the identified associations have been independently replicated in children.
LIMITATIONS: Included studies were heterogenous in terms of study design, genes and drugs assessed, and outcomes measured.
CONCLUSION: The antidepressant pharmacogenetics knowledge base in pediatric populations is still emerging, but results to date echo many of the gene-antidepressant associations identified in adult populations. Given ubiquitous prescribing of antidepressants in the care of children and adolescents with psychiatric disorders, further research on identifying new and confirming current gene-antidepressant associations are warranted.

PMID: 31112844 [PubMed - as supplied by publisher]

Disposition of oral delta-9 tetrahydrocannabinol (THC) in children receiving cannabis extracts for epilepsy.

Clin Toxicol (Phila). 2019 May 21;:1-5

Authors: Wang GS, Bourne DWA, Klawitter J, Sempio C, Chapman K, Knupp K, Wempe MF, Borgelt L, Christians U, Heard K, Bajaj L

Abstract
INTRODUCTION: Although over half of US states have legalized marijuana for medical indications, there is limited research in use in the pediatric population. The objective was to evaluate the disposition of oral tetrahydrocannabinol (THC) in children receiving cannabis extracts for pediatric epilepsy.
METHODS: Prospective, observational study, evaluating the disposition of oral THC in children receiving cannabis extracts. Subjects were less than 18 years of age, receiving oral cannabis for pediatric epilepsy. Subjects included in the study had at least 2 detectable THC and related metabolite plasma concentrations during serial blood draw over a 10-12 h study period.
RESULTS: Nine subjects with a median age of 11 years (IQR 4.75) were included in the study, with oral doses ranging from 0.02 mg/kg to 1.59 mg/kg. Peak plasma concentrations (0.8 to 3.6 ng/ml) in most patients were achieved within 2 hours, while acute phase elimination half-life ranged from 1 to 5 hours. THC-COOH and glucuronide remained elevated through the study period. There was significant variation between the dose ingested and peak concentrations (R2 = 0.05).
CONCLUSION: In pediatric patients receiving oral THC cannabis extracts, mean time to peak plasma concentrations was 2-7 hours, while mean acute phase elimination half-life was 4.0 hours. THC-COOH and THC-COOH glucuronide metabolites persisted throughout the 10-12 hour study period. Large variation and no correlation was noted between dose of THC by weight and peak concentrations, suggesting variation of bioavailability amongst pediatric population or inaccurate reporting of THC contents.

PMID: 31111749 [PubMed - as supplied by publisher]

Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy.

Mol Genet Genomic Med. 2019 May 20;:e751

Authors: Jay K, Mitra A, Harding T, Matthes D, Van Ness B

Abstract
BACKGROUND: Autism spectrum disorder is commonly co-diagnosed intellectual disability, language disorder, anxiety, and epilepsy, however, symptom management is difficult due to the complex genetic nature of ASD.
METHODS: We present a next-generation sequencing-based case study with both de novo and inherited genetic variants and highlight the impact of structural variants on post-translational regulation of protein expression. Since management of symptoms has classically been through pharmaceutical therapies, a pharmacogenomics screen was also utilized to determine possible drug/gene interactions.
RESULTS: A de novo variant was identified within the FOXP1 3' untranslated regulatory region using exome sequencing. Additionally, inherited variants that likely contribute to the current and potential future traits were identified within the COMT, SLC6A4, CYP2C19, and CYP2D6 genes.
CONCLUSION: This study aims to elucidate how a collection of variant genotypes could potentially impact neural development resulting in a unique phenotype including ASD and epilepsy. Each gene's contribution to neural development is assessed, and the interplay of these genotypes is discussed. The results highlight the utility of exome sequencing in conjunction with pharmacogenomics screening when evaluating possible causes of and therapeutic treatments for ASD-related symptoms.

PMID: 31111659 [PubMed - as supplied by publisher]

Genome-Wide Association Study Confirming the Association of NAT2 with Susceptibility to Anti-tuberculosis Drug-Induced Liver Injury in Thai Patients.

Antimicrob Agents Chemother. 2019 May 20;:

Authors: Suvichapanich S, Wattanapokayakit S, Mushiroda T, Yanai H, Chuchottawon C, Kantima T, Suwankesawong W, Sonsupap C, Pannarunothai R, Tumpattanakul S, Bamrungram W, Chaiwong A, Mahasirimongkol S, Mameechai S, Panthong W, Klungtes N, Munsoo A, Chauychana U, Maneerat M, Fukunaga K, Omae Y, Tokunaga K

Abstract
BackgroundAnti-tuberculosis drug-induced liver injury (ATDILI) is a common side effect leading to tuberculosis (TB) treatment disruption. The mechanism of the disease remains poorly understood. We conducted a genome-wide association study (GWAS) to investigate all possible genetic factors of ATDILI in Thai patients.ResultsThis study was carried out in Thai TB patients, including 79 ATDILI cases and 239 tolerant controls from our network hospitals in Thailand. Nearly one million single nucleotide polymorphisms (SNPs) were genotyped across the whole genome using an Illumina OmniExpress Exome BeadChip Array. In the discovery stage, we identified strong association signals on chromosome 8 originating from the N-acetyltransferse (NAT2) region. The A allele of rs1495741, the top SNP in the intergenic region of NAT2 and PSD3 (14 kb from NAT2), was significantly associated with ATDILI (recessive model: odds ratio 6.01, 95% confidence interval 3.42-10.57, P = 6.86E-11). This particular SNP was reported as a tag SNP for NAT2 inferred phenotypes. The AA, AG, and GG genotypes represented NAT2 slow acetylators, intermediate acetylators, and fast acetylators, respectively. The tag SNP genotypes demonstrated a concordant rate of 94.98% with NAT2 acetylator phenotypes.ConclusionThis GWAS shows that NAT2 is the most important risk factor for ATDILI in the Thai population.

PMID: 31109976 [PubMed - as supplied by publisher]

Implementing a personalized medicine cancer program in a community cancer system.

Per Med. 2019 May 21;:

Authors: Dressler LG, Bell GC, Schuetze DP, Steciuk MR, Binns OA, Raab RE, Abernathy PM, Wilson CM, Kunutsor SE, Loveless MC, Ahearne PM, Messino MJ

PMID: 31109249 [PubMed - as supplied by publisher]

Continuous pharmacogenomics and genomic medicine education for healthcare professionals through electronic educational courses.

Per Med. 2019 May 21;:

Authors: Tsermpini EE, Stamopoulou T, Kordou Z, Barba E, Siamoglou S, Stathoulias A, Patrinos GP

PMID: 31109241 [PubMed - as supplied by publisher]

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The association of a single nucleotide polymorphism in the nuclear factor erythroid derived-2 like 2 (Nrf-2) gene with adverse drug reactions, multimorbidity and frailty in older people.

J Gerontol A Biol Sci Med Sci. 2019 May 18;:

Authors: Scutt G, Overall A, Bakrania P, Krasteva E, Parekh N, Ali K, Davies JG, Rajkumar C

Abstract
Susceptibility to adverse drug reactions (ADRs), multimorbidity, and frailty are associated with human ageing, yet there is wide variation in the severity and age at which individuals are afflicted. Identifying genetic markers of increased risk of this phenotype would help stratify individuals to specialist interventions. Nuclear factor erythroid derived-2 like 2 (Nrf2) regulates a cell's response to stressors, including the expression of enzymes involved in drug-metabolism. Its expression has been shown to decline in animal ageing models. In this study we tested the hypothesis that Nrf2 gene transcription/translation decline in human ageing, and that single nucleotide polymorphisms (SNPs) in the Nrf2 gene are associated with increased ADR risk, multi-morbidity, and frailty in older people. Gene expression and protein levels were measured in peripheral blood mononuclear cells (PBMCs) donated from healthy patients aged 18-80 years old. Nrf2 genotypes were determined at three loci in a sub-population of patients recruited to the PRIME study (a multicentre prospective cohort study that followed older adults for 8-weeks post-discharge to determine ADR). Both Nrf2 gene and protein expression declined significantly with age in human PBMCs. In the PRIME sub-study population, the rs35652124 Nrf2 SNP was associated with increased ADR risk, and decreased frailty and multi-morbidity scores.

PMID: 31102514 [PubMed - as supplied by publisher]

LncRNA FOXD1-AS1 acts as a potential oncogenic biomarker in glioma.

CNS Neurosci Ther. 2019 May 17;:

Authors: Gao YF, Liu JY, Mao XY, He ZW, Zhu T, Wang ZB, Li X, Yin JY, Zhang W, Zhou HH, Liu ZQ

Abstract
AIMS: Altered activities of long noncoding RNAs (lncRNAs) have been associated with cancer development, and lncRNA FOXD1-AS1 (FOXD1-AS1) is the antisense transcript of the gene encoding for FOXD1, known for its role as an oncogene in several tumor types including glioma. However, the role of FOXD1-AS1 in the differentiation and progression of glioma is not well known.
METHODS: Expression profile chip and qPCR were used to screen and identify FOXD1-AS1. Glioma cells were transfected with siRNA or eukaryotic expression vector to observe FOXD1-AS1 function in vitro and in vivo. Dual luciferase reporter gene analysis, Western blot, and ChIRP-MS were used to detect microRNAs and protein that combine with FOXD1-AS1.
RESULTS: FOXD1-AS1 was upregulated and directly correlated with the glioma grade, and it was localized in both the nucleus and the cytoplasm of the glioma cell. FOXD1-AS1 silencing caused tumor suppressive effects via inhibiting cell proliferation, migration, and apoptosis, while FOXD1-AS1 overexpression resulted in opposite effects. Additionally, in vivo experiments showed that FOXD1-AS1 knockdown reduced tumor volume and weight. More importantly, mechanical studies revealed that FOXD1-AS1 targeted both miR339-5p and miR342-3p (miR339/342). Furthermore, protein eukaryotic translation initiation factor 5 subunit A (eIF5a) resulted a direct target of FOXD1-AS1.
CONCLUSIONS: These data indicated that FOXD1-AS1, a miR339/342 target, affected biological processes via protein eIF5a; thus, it might be considered as a new therapeutic target for glioblastoma.

PMID: 31102349 [PubMed - as supplied by publisher]