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

pharmacogenomics

These pubmed results were generated on 2017/05/24

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.

Association Study of Serotonin 3 Receptor Subunit Gene Variants in Antipsychotic-Induced Weight Gain.

Neuropsychobiology. 2017 May 23;74(3):169-175

Authors: Zai CC, Tiwari AK, Chowdhury NI, Brandl EJ, Shaikh SA, Freeman N, Lieberman JA, Meltzer HY, Kennedy JL, Müller DJ

Abstract
BACKGROUND: Schizophrenia (SCZ) is a chronic severe neuropsychiatric disorder, where pharmacological treatment has been hindered by adverse effects, including antipsychotic-induced weight gain (AIWG) and related complications. Genetic studies have been exploring the appetite regulation and energy homeostasis pathways in AIWG with some promising leads. The serotonin system has been shown to participate in these pathways.
METHODS: In the current study, we examined single nucleotide polymorphisms across the serotonin receptor genes HTR3A and HTR3B. Prospective weight change was assessed for a total of 149 SCZ patients of European ancestry.
RESULTS: We did not find the tested HTR3A or HTR3B gene markers to be associated with AIWG in our sample.
CONCLUSION: Our preliminary findings suggest that these receptors may not play a major role in predicting AIWG.

PMID: 28531893 [PubMed - as supplied by publisher]

Hypothalamic regulation of the sleep/wake cycle.

Neurosci Res. 2017 May 16;:

Authors: Ono D, Yamanaka A

Abstract
Sleep is one of the most important physiological functions in mammals. It is regulated by not only homeostatic regulation but also circadian clock. Several neuropeptide-producing neurons located in the hypothalamus are implicated in the regulation of sleep/wakefulness. Among them, orexin/hypocretin-producing neurons (orexin neurons) are a crucial component for maintenance of wakefulness, because lack of orexin function results in narcolepsy, which is a sleep disorder. Recent findings have identified substances that excite or inhibit neural activity of orexin neurons. Furthermore neural projections of the neurons which release these substances have been revealed. In addition to orexin, melanin concentrating hormone (MCH)-producing neurons in the lateral hypothalamic area (LHA) are also implicated in the regulation of sleep/wakefulness. MCH neurons are active during sleep but become silent during wakefulness. Recently developed innovative methods including optogenetics and pharmacogenetics have provided substantial insights into the regulation of sleep/wakefulness. In vivo optical recordings and retrograde and anterograde tracing methods will allow us to understand additional details regarding important interactions between these two types of neurons in the LHA and other neurons in the brain. Finally we discuss the circadian clock and sleep/wakefulness cycle. Understanding of the neural networks and its circadian modulation of sleep/wakefulness cycles remain to be investigated.

PMID: 28526553 [PubMed - as supplied by publisher]

Pharmacogenomics in Pain Management.

Anesthesiol Clin. 2017 Jun;35(2):295-304

Authors: Saba R, Kaye AD, Urman RD

Abstract
There is interpatient variability to analgesic administration. Much can be traced to pharmacogenomics variations between individuals. Certain ethnicities are more prone to reduced function of CYP2D6. Weak opioids are subject to interpatient variation based on their CYP2D6 type. Strong opioids have variations based on their transport and individual metabolism. Several cytochrome enzymes have been found to be involved with ketamine but there is no strong evidence of individual polymorphisms manifesting in clinical outcomes. Nonsteroidal anti-inflammatory drugs have adverse outcomes that certain CYP variants are more prone toward. There are now recommendations for dosing based on specific genomic makeup.

PMID: 28526150 [PubMed - in process]

Pharmacogenomics in Anesthesia.

Anesthesiol Clin. 2017 Jun;35(2):285-294

Authors: Saba R, Kaye AD, Urman RD

Abstract
A significant number of commonly administered medications in anesthesia show wide clinical interpatient variability. Some of these include neuromuscular blockers, opioids, local anesthetics, and inhalation anesthetics. Individual genetic makeup may account for and predict cardiovascular outcomes after cardiac surgery. These interactions can manifest at any point in the perioperative period and may also only affect a specific system. A better understanding of pharmacogenomics will allow for more individually tailored anesthetics and may ultimately lead to better outcomes, decreased hospital stays, and improved patient satisfaction.

PMID: 28526149 [PubMed - in process]

SurvivalGWAS_SV: software for the analysis of genome-wide association studies of imputed genotypes with "time-to-event" outcomes.

BMC Bioinformatics. 2017 May 19;18(1):265

Authors: Syed H, Jorgensen AL, Morris AP

Abstract
BACKGROUND: Analysis of genome-wide association studies (GWAS) with "time to event" outcomes have become increasingly popular, predominantly in the context of pharmacogenetics, where the survival endpoint could be death, disease remission or the occurrence of an adverse drug reaction. However, methodology and software that can efficiently handle the scale and complexity of genetic data from GWAS with time to event outcomes has not been extensively developed.
RESULTS: SurvivalGWAS_SV is an easy to use software implemented using C# and run on Linux, Mac OS X & Windows operating systems. SurvivalGWAS_SV is able to handle large scale genome-wide data, allowing for imputed genotypes by modelling time to event outcomes under a dosage model. Either a Cox proportional hazards or Weibull regression model is used for analysis. The software can adjust for multiple covariates and incorporate SNP-covariate interaction effects.
CONCLUSIONS: We introduce a new console application analysis tool for the analysis of GWAS with time to event outcomes. SurvivalGWAS_SV is compatible with high performance parallel computing clusters, thereby allowing efficient and effective analysis of large scale GWAS datasets, without incurring memory issues. With its particular relevance to pharmacogenetic GWAS, SurvivalGWAS_SV will aid in the identification of genetic biomarkers of patient response to treatment, with the ultimate goal of personalising therapeutic intervention for an array of diseases.

PMID: 28525968 [PubMed - in process]

Inference of the Genetic Polymorphisms of CYP2D6 in Six Subtribes of the Malaysian Orang Asli from Whole-Genome Sequencing Data.

Genet Test Mol Biomarkers. 2017 May 19;:

Authors: Yu CY, Ang GY, Subramaniam V, Johari James R, Ahmad A, Abdul Rahman T, Mohd Nor F, Shaari SA, Teh LK, Salleh MZ

Abstract
AIMS: CYP2D6 is one of the major enzymes in the cytochrome P450 monooxygenase system. It metabolizes ∼25% of prescribed drugs and hence, the genetic diversity of CYP2D6 gene has continued to be of great interest to the medical and pharmaceutical industries. This study aims to perform a systematic analysis of the CYP2D6 gene in six subtribes of the Malaysian Orang Asli.
METHODS: Genomic DNAs were extracted from the blood samples followed by whole-genome sequencing. The reads were aligned to the reference human genome hg19 and variants in the CYP2D6 gene were analyzed. CYP2D6*5 and duplication of CYP2D6 were analyzed using previously established methods.
RESULTS: A total of 72 single-nucleotide polymorphisms were identified. CYP2D6*1, *2, *4, *5, *10,*41, and duplication of the gene were found in the Orang Asli, whereby CYP2D6*2 and *41 alleles are reported for the first time in the Malaysian population.
CONCLUSION: The findings in this study provide insights into the genetic polymorphisms of CYP2D6 in Orang Asli of Peninsular Malaysia.

PMID: 28525288 [PubMed - as supplied by publisher]

siRNA-mediated inhibition of SREBP cleavage-activating protein reduces dyslipidemia in spontaneously dysmetabolic rhesus monkeys.

Metabolism. 2017 Jun;71:202-212

Authors: Murphy BA, Tadin-Strapps M, Jensen K, Mogg R, Liaw A, Herath K, Bhat G, McLaren DG, Previs SF, Pinto S

Abstract
BACKGROUND: SREBP cleavage-activating protein (SCAP) is a cholesterol binding endoplasmic reticulum (ER) membrane protein that is required to activate SREBP transcription factors. SREBPs regulate genes involved in lipid biosynthesis. They also influence lipid clearance by modulating the expression of LDL receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Inhibiting SCAP decreases circulating PCSK9, triglycerides (TG), and LDL-cholesterol (LDL-C), both in vitro and in vivo. Type 2 diabetics with dyslipidemia are at high risk for cardiovascular diseases. These patients present a unique pathophysiological lipid profile characterized by moderately elevated LDL-C, elevated TG and reduced HDL-cholesterol (HDL-C). The spontaneous dysmetabolic rhesus monkey model (DysMet RhM) recapitulates this human dyslipidemia and therefore is an attractive preclinical model to evaluate SCAP inhibition as a therapy for this disease population. The objective to of this study was to assess the effect of SCAP inhibition on the lipid profile of DysMet RhM.
METHOD: We assessed the effect of inhibiting hepatic SCAP on the lipid profile of DysMet RhM using an siRNA encapsulated lipid nanoparticle (siRNA-LNP).
RESULTS: The SCAP siRNA-LNP significantly reduced LDL-C, PCSK9 and TG in DysMet RhM; LDL-C was reduced by ≥20%, circulating PCSK9 by 30-40% and TG by >25%. These changes by the SCAP siRNA-LNP agree with the predicted effect of SCAP inhibition and reduced SREBP tone on these endpoints.
CONCLUSION: These data demonstrate that a SCAP siRNA-LNP improved the lipid profile in a clinically relevant preclinical disease model and provide evidence for SCAP inhibition as a therapy for diabetic dyslipidemic patients.

PMID: 28521874 [PubMed - in process]

Effect of CYP2C19*2 and *3 on clinical outcome in ischemic stroke patients treated with clopidogrel.

J Neurol Sci. 2016 Oct 15;369:216-9

Authors: Wang Y, Cai H, Zhou G, Zhang Z, Liu X

Abstract
BACKGROUND: Despite clopidogrel has been widely applied to patients with ischemic stroke combined with aspirin, decreased metabolic activation of clopidogrel still occurs because of genetic variations in CYP2C19.
METHODS: Three hundred twenty-one patients completed a genetic test for CYP2C19 loss of function (LOF) alleles in hospital. Cox regression models were used to assess the relationship between CYP2C19 genotypes with the primary endpoint, which was a composite of nonfatal ischemic stroke, myocardial infarction, or vascular death. Functional outcome was measured by the modified Rankin Scale (mRS) at 3months, 6months and 12months intervals. Binary logistic regression was used to analyze the correlation between poor functional outcome and CYP2C19 LOF alleles.
RESULTS: The CYP2C19 LOF alleles were independently associated with the primary endpoint. There was no significant association between poor functional outcome and CYP2C19 LOF allele (*2 and *3) in overall patients. After the participants were stratified by stent treatment into two groups, the polymorphisms of CYP2C19 had significant impact on poor prognosis at 3months and 6months but not at 12months in patients without stent. No correlation was found in patients with stent.
CONCLUSIONS: The CYP2C19 LOF alleles may increase the recurrent risk of ischemic events. The polymorphisms of CYP2C19 may be predictors of poor functional outcome of patients without stent, and the effect may be weakened by time.

PMID: 27653892 [PubMed - indexed for MEDLINE]

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.

Am J Hum Genet. 2016 Jul 07;99(1):56-75

Authors: Liu CT, Raghavan S, Maruthur N, Kabagambe EK, Hong J, Ng MC, Hivert MF, Lu Y, An P, Bentley AR, Drolet AM, Gaulton KJ, Guo X, Armstrong LL, Irvin MR, Li M, Lipovich L, Rybin DV, Taylor KD, Agyemang C, Palmer ND, Cade BE, Chen WM, Dauriz M, Delaney JA, Edwards TL, Evans DS, Evans MK, Lange LA, Leong A, Liu J, Liu Y, Nayak U, Patel SR, Porneala BC, Rasmussen-Torvik LJ, Snijder MB, Stallings SC, Tanaka T, Yanek LR, Zhao W, Becker DM, Bielak LF, Biggs ML, Bottinger EP, Bowden DW, Chen G, Correa A, Couper DJ, Crawford DC, Cushman M, Eicher JD, Fornage M, Franceschini N, Fu YP, Goodarzi MO, Gottesman O, Hara K, Harris TB, Jensen RA, Johnson AD, Jhun MA, Karter AJ, Keller MF, Kho AN, Kizer JR, Krauss RM, Langefeld CD, Li X, Liang J, Liu S, Lowe WL, Mosley TH, North KE, Pacheco JA, Peyser PA, Patrick AL, Rice KM, Selvin E, Sims M, Smith JA, Tajuddin SM, Vaidya D, Wren MP, Yao J, Zhu X, Ziegler JT, Zmuda JM, Zonderman AB, Zwinderman AH, AAAG Consortium, CARe Consortium, COGENT-BP Consortium, eMERGE Consortium, MEDIA Consortium, Adeyemo A, Boerwinkle E, Ferrucci L, Hayes MG, Kardia SL, Miljkovic I, Pankow JS, Rotimi CN, Sale MM, Wagenknecht LE, Arnett DK, Chen YD, Nalls MA, MAGIC Consortium, Province MA, Kao WH, Siscovick DS, Psaty BM, Wilson JG, Loos RJ, Dupuis J, Rich SS, Florez JC, Rotter JI, Morris AP, Meigs JB

Abstract
Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

PMID: 27321945 [PubMed - indexed for MEDLINE]

Association between rs9930506 polymorphism of the fat mass & obesity-associated (FTO) gene & onset of obesity in Polish adults.

Indian J Med Res. 2016 Mar;143(3):281-7

Authors: Wrzosek M, Zakrzewska A, Ruczko L, Jabłonowska-Lietz B, Nowicka G

Abstract
BACKGROUND & OBJECTIVES: The fat mass and obesity-associated (FTO) gene is known to be associated with obesity. However, no data are available on the relation between FTO rs9930506 polymorphism and obesity in Polish population. The aim of this study was to evaluate an association between rs9930506 variants of the FTO gene and obesity in Polish adults.
METHODS: The study group consisted of 442 adults, aged 33.9 ±12.7 yr, with mean BMI 27.2 ± 5.4 kg/m2. The following variables were determined for each subject: fasting blood glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides. Real-time PCR was used to detect the A/G alleles of the rs9939506 polymorphism in the FTO gene. An association between the rs9930506 polymorphism and obesity was determined using codominant, dominant, and recessive models. The odds ratio (OR) was calculated to determine the risk of obesity associated with this polymorphism.
RESULTS: It was observed that the presence of FTO rs9939506 G allele was associated with increased risk for obesity and this association was found significant in both recessive (OR = 1.72, P = 0.014) and co-dominant (OR = 1.36, P = 0.031) models of inheritance. The FTO rs9939506 GG homozygotes had a significantly higher BMI than those with other genotypes.
INTERPRETATION & CONCLUSIONS: This study shows that FTO rs9939506 GG genotype is related to higher BMI and is associated with obesity in Polish adults.

PMID: 27241640 [PubMed - indexed for MEDLINE]

Role of the endocannabinoid system in vertebrates: Emphasis on the zebrafish model.

Dev Growth Differ. 2017 May 17;:

Authors: Oltrabella F, Melgoza A, Nguyen B, Guo S

Abstract
The endocannabinoid system (eCBs), named after the plant Cannabis sativa, comprises cannabinoid receptors, endogenous ligands known as "endocannabinoids", and enzymes involved in the biosynthesis and degradation of these ligands, as well as putative transporters for these ligands. ECBs proteins and small molecules have been detected in early embryonic stages of many vertebrate models. As a result, cannabinoid receptors and endogenous as well as exogenous cannabinoids influence development and behavior in many vertebrate species. Understanding the precise mechanisms of action for the eCBs will provide an invaluable guide towards elucidation of vertebrate development and will also help delineate how developmental exposure to marijuana might impact health and cognitive/executive functioning in adulthood. Here we review the developmental roles of the eCBs in vertebrates, focusing our attention on the zebrafish model. Since little is known regarding the eCBs in zebrafish, we provide new data on the expression profiles of eCBs genes during development and in adult tissue types of this model organism. We also highlight exciting areas for future investigations, including the synaptic regulation of eCBs, its role in reward and addiction, and in nervous system development and plasticity.

PMID: 28516445 [PubMed - as supplied by publisher]

DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously.

Front Mol Biosci. 2017;4:24

Authors: Smith M

Abstract
Delineation of underlying genomic and genetic factors in a specific disease may be valuable in establishing a definitive diagnosis and may guide patient management and counseling. In addition, genetic information may be useful in identification of at risk family members. Gene mapping and initial genome sequencing data enabled the development of microarrays to analyze genomic variants. The goal of this review is to consider different generations of sequencing techniques and their application to exome sequencing and whole genome sequencing and their clinical applications. In recent decades, exome sequencing has primarily been used in patient studies. Discussed in some detail, are important measures that have been developed to standardize variant calling and to assess pathogenicity of variants. Examples of cases where exome sequencing has facilitated diagnosis and led to improved medical management are presented. Whole genome sequencing and its clinical relevance are presented particularly in the context of analysis of nucleotide and structural genomic variants in large population studies and in certain patient cohorts. Applications involving analysis of cell free DNA in maternal blood for prenatal diagnosis of specific autosomal trisomies are reviewed. Applications of DNA sequencing to diagnosis and therapeutics of cancer are presented. Also discussed are important recent diagnostic applications of DNA sequencing in cancer, including analysis of tumor derived cell free DNA and exosomes that are present in body fluids. Insights gained into underlying pathogenetic mechanisms of certain complex common diseases, including schizophrenia, macular degeneration, neurodegenerative disease are presented. The relevance of different types of variants, rare, uncommon, and common to disease pathogenesis, and the continuum of causality, are addressed. Pharmogenetic variants detected by DNA sequence analysis are gaining in importance and are particularly relevant to personalized and precision medicine.

PMID: 28516087 [PubMed - in process]

[HAPTOGLOBIN POLYMORPHISM AS AN INDEPENDENT PREDICTOR OF DIABETIC NEPHROPATHY AND RETINOPATHY].

Harefuah. 2016 Jul;155(7):439-442

Authors: Dahan I, Thauho N, Nakhoul F, Nakhoul N, Jabaly H, Farber E

Abstract
INTRODUCTION: The antioxidant protein haptoglobin (Hp) plays a major role in the development of diabetic complications such as diabetic nephropathy and retinopathy. In humans, two alleles of Hp were identified: 1 and 2 with three possible genotypes: 1-1, 2-1, and 2-2. The Hp protein products differ in their biochemical and biophysical properties, such as their antioxidant capacity. The Hp1 protein is superior to the Hp2 protein in binding to free hemoglobin and neutralizing its oxidative potential and the accompanying renal and retinal injury. Hence, diabetic patients with different Hp phenotypes have variable susceptibility to developing diabetic nephropathy and retinopathy. In diabetes, the kidney and the retinal injury progress gradually over time. Thus, understanding the factors that mediate the aggravation and progression of these complications is of critical importance. One of the latest hypotheses regarding the involvement of haptoglobin in the development of diabetic complications is its contribution to impaired vitamin D activation in the kidney. Over the last few years, great efforts were made in the field to explore this notion and decrypt the mechanism behind it. The goal in this area is that the research findings will be translated into clinical practice and lead to the development of a pharmacogenomics clinical approach that will deal with diabetic complications by selective administration of vitamin D according to the Hp genotype.

PMID: 28514126 [PubMed - in process]

Mechanisms of Immune Tolerance in Leukemia and Lymphoma.

Trends Immunol. 2017 May 13;:

Authors: Curran EK, Godfrey J, Kline J

Abstract
The mechanisms through which immune responses are generated against solid cancers are well characterized and knowledge of the immune evasion pathways exploited by these malignancies has grown considerably. However, for hematological cancers, which develop and disseminate quite differently than solid tumors, the pathways that regulate immune activation or tolerance are less clear. Growing evidence suggests that, while numerous immune escape pathways are shared between hematological and solid malignancies, several unique pathways are exploited by leukemia and lymphoma. Below we discuss immune evasion mechanisms in leukemia and lymphoma, highlighting key differences from solid tumors. A more complete characterization of the mechanisms of immune tolerance in hematological malignancies is critical to inform the development of future immunotherapeutic approaches.

PMID: 28511816 [PubMed - as supplied by publisher]

Precision Medicine-Nobody Is Average.

Clin Pharmacol Ther. 2017 Mar;101(3):304-307

Authors: Vinks AA

Abstract
Medicine gets personal and tailor-made treatments are underway. Hospitals have started to advertise their advanced genomic testing capabilities and even their disruptive technologies to help foster a culture of innovation. The prediction in the lay press is that in decades from now we may look back and see 2017 as the year precision medicine blossomed. It is all part of the Precision Medicine Initiative that takes into account individual differences in people's genes, environments, and lifestyles.

PMID: 28194769 [PubMed - indexed for MEDLINE]

Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats.

Drug Des Devel Ther. 2016;10:3545-3553

Authors: Gudasheva TA, Povarnina P, Logvinov IO, Antipova TA, Seredenin SB

Abstract
BACKGROUND: Two dimeric dipeptides, bis-(N-monosuccinyl-l-seryl-l-lysine)hexamethylenediamide (GSB-106) and bis-(N-monosuccinyl-l-methionyl-l-serine) heptamethylenediamide (GSB-214), were designed based on the brain-derived neurotrophic factor (BDNF) loop 4 and loop 1 β-turn sequences, respectively. Earlier, both of these dipeptides were shown to exhibit neuroprotective activity in vitro (10(-5)-10(-8) M). The present study aimed to investigate the mechanisms of action of these peptides and their neuroprotective activity in an experimental stroke model.
METHODS: We used western blot and HT-22 hippocampal neuronal cell line to investigate whether these peptides induced phosphorylation of the TrkB receptor and the AKT and ERK kinases. Rat middle cerebral artery occlusion (MCAO) was used as a stroke model. GSB-106 and GSB-214 were administered intraperitoneally (0.1 mg (1.3×10(-7) mol)/kg) 4 hours after MCAO and daily for 7 days. The cerebral infarct volumes were measured with 2,3,5-triphenyltetrazolium chloride staining 21 days after MCAO.
RESULTS: Both compounds were shown to elevate the TrkB phosphorylation level while having different post-receptor signaling patterns. GSB-106 activated the PI3K/AKT and MAPK/ERK pathways simultaneously, whereas GSB-214 activated the PI3K/AKT only. In experimental stroke, the reduction of cerebral infarct volume by GSB-106 (∼66%) was significantly greater than that of GSB-214 (∼28% reduction), which could be explained by the fundamental role of the MAPK/ERK pathway in neurogenesis and neuroplasticity. Notably, between these two dipeptides, only GSB-106 exhibited antidepressant activity, as was found previously.
CONCLUSION: The results provided support for the beneficial pharmacological properties of BDNF loop 4 mimetic GSB-106, thereby suggesting a potential role for this dipeptide as a therapeutic agent.

PMID: 27843294 [PubMed - indexed for MEDLINE]

Novel Deleterious Dihydropyrimidine Dehydrogenase Variants May Contribute to 5-Fluorouracil Sensitivity in an East African Population.

Clin Pharmacol Ther. 2017 Mar;101(3):382-390

Authors: Elraiyah T, Jerde CR, Shrestha S, Wu R, Nie Q, Giama NH, Sarangi V, Roberts LR, Offer SM, Diasio RB

Abstract
Clinical studies have identified specific genetic variants in dihydropyrimidine dehydrogenase (DPD; DPYD gene) as predictors of severe adverse toxicity to the commonly used chemotherapeutic 5-fluorouracil (5-FU); however, these studies have focused on European and European-American populations. Our laboratory recently demonstrated that additional variants in non-European haplotypes are predictive of 5-FU toxicity. The objective of this study was to identify potential risk variants in an understudied East African population relevant to our institution's catchment area. The DPYD protein-coding region was sequenced in 588 individuals of Somali or Kenyan ancestry living in central/southeast Minnesota. Twelve novel nonsynonymous variants were identified, seven of which significantly decreased DPD activity in vitro. The commonly reported toxicity-associated variants, *2A, D949V, and I560S, were not detected in any individuals. Overall, this study demonstrates a critical limitation in our knowledge of pharmacogenetic predictors of 5-FU toxicity, which has been based on clinical studies conducted in populations of limited diversity.

PMID: 27727460 [PubMed - indexed for MEDLINE]

Implementing Algorithm-Guided Warfarin Dosing in an Ethnically Diverse Patient Population Using Electronic Health Records and Preemptive CYP2C9 and VKORC1 Genetic Testing.

Clin Pharmacol Ther. 2016 Nov;100(5):427-430

Authors: Obeng AO, Kaszemacher T, Abul-Husn NS, Gottesman O, Vega A, Waite E, Myers K, Cho J, Bottinger EP, Ellis SB, Scott SA

Abstract
Implementation of pharmacogenetic-guided warfarin dosing has been hindered by inconsistent results from reported clinical trials and a lack of available algorithms that include alleles prevalent in non-white populations. However, current evidence indicates that algorithm-guided dosing is more accurate than empirical dosing. To facilitate multiethnic algorithm-guided warfarin dosing using preemptive genetic testing, we developed a strategy that accounts for the complexity of race and leverages electronic health records for algorithm variables and deploying point-of-care dose recommendations.

PMID: 27393744 [PubMed - indexed for MEDLINE]

Combined administration of propranolol + AG490 offers better effects on portal hypertensive rats with cirrhosis.

J Gastroenterol Hepatol. 2016 May;31(5):1037-44

Authors: Wang D, Wang Q, Yin J, Dong R, Wang Q, Du X, Lu J

Abstract
BACKGROUND AND AIMS: AG490, the specific inhibitor of JAK2/STAT3 signaling, has been shown to decrease portal pressure, splanchnic hyperdynamic circulation and liver fibrosis in cirrhotic rats. Nonselective betablockers such as propranolol are the only drugs recommended in the treatment of portal hypertension. The aim of this study was to explore the combinative effect of treatment with propranolol and AG490 on portal hypertension.
METHODS: Rats induced by common bile duct ligation were treated with vehicle, AG490, propranolol, or AG490 + propranolol for 2 weeks. Hemodynamics parameters were assessed. Expressions of phospho-STAT3 protein and its down-regulated cytokines in splanchnic organs were detected by ELISA or western blot. Lipopolysaccharide binding protein (LBP) and IL-6 were assessed by ELISA or western blot. Characterization of liver and mesentery was performed by histological analyses.
RESULTS: Highly expressed phospho-STAT3 protein in cirrhotic rats could successfully be inhibited by AG490 or AG490 + propranolol treatments but not by propranolol alone. Both AG490 and propranolol significantly reduced portal pressure and hyperdynamic splanchnic circulation, and combination of AG490 and propranolol achieved an additive effect than with either drug alone. AG490, alone or in combination with propranolol, inhibited liver fibrosis, splenomegaly and splanchnic angiogenesis. Increased markers of bacterial translocation (LBP and IL6) were greatly reduced by propranolol but not by AG490.
CONCLUSIONS: The combination of propranolol and AG490 caused a greater improvement of portal hypertension and might therefore offer a potentially promising therapy in the portal hypertension treatment.

PMID: 26487394 [PubMed - indexed for MEDLINE]