Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies.

BMC Med Genomics. 2018 Jun 20;11(1):55

Authors: Sá ACC, Webb A, Gong Y, McDonough CW, Shahin MH, Datta S, Langaee TY, Turner ST, Beitelshees AL, Chapman AB, Boerwinkle E, Gums JG, Scherer SE, Cooper-DeHoff RM, Sadee W, Johnson JA

Abstract
BACKGROUND: Recently, 34 genes had been associated with differential expression relative to blood pressure (BP)/ hypertension (HTN). We hypothesize that some of the genes associated with BP/HTN are also associated with BP response to antihypertensive treatment with thiazide diuretics.
METHODS: We assessed these 34 genes for association with differential expression to BP response to thiazide diuretics with RNA sequencing in whole blood samples from 150 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. PEAR white and PEAR-2 white and black participants (n = 50 for each group) were selected based on the upper and lower quartile of BP response to hydrochlorothiazide (HCTZ) and to chlorthalidone.
RESULTS: FOS, DUSP1 and PPP1R15A were differentially expressed across all cohorts (meta-analysis p-value < 2.0 × 10- 6), and responders to HCTZ or chlorthalidone presented up-regulated transcripts. Rs11065987 in chromosome 12, a trans-eQTL for expression of FOS, PPP1R15A and other genes, is also associated with BP response to HCTZ in PEAR whites (SBP: β = - 2.1; p = 1.7 × 10- 3; DBP: β = - 1.4; p = 2.9 × 10- 3).
CONCLUSIONS: These findings suggest FOS, DUSP1 and PPP1R15A as potential molecular determinants of antihypertensive response to thiazide diuretics.
TRIAL REGISTRATION: NCT00246519 , NCT01203852 www.clinicaltrials.gov.

PMID: 29925376 [PubMed - in process]

Single-tube multiplex real-time PCR assay for rapid and reliable detection of HLA-A*31:01 allele.

Pharmacogenomics. 2018 Jun 21;:

Authors: Zhang T, Xiao Y, Wang Y, Li Y, Zhang L, Chen C, Wang H

Abstract
AIM: HLA-A*31:01 has been associated with carbamazepine-induced hypersensitivity reactions. HLA-A*31:01 genetic testing is recommended before the initiation of carbamazepine therapy.
METHODS: A novel real-time PCR assay was designed for HLA-A*31:01 detection by allele-specific primers and TaqMan minor groove binding probes.
RESULTS: The genotyping results in 100 subjects by the established method who were in 100% agreement with the sequencing-based typing method. The assay presents a sensitivity of 1 (95% CI: 0.69-1.00), a specificity of 1 (95% CI: 0.96-1.00) and a positive and negative predictive value of 1. The carrier rates of HLA-A*31:01 in Tibetan (n = 45), Han Chinese (n = 100), Miaos (n = 48) and Khalkhas (n = 48) were 22.2, 10, 4.2 and 18.8%, respectively.
CONCLUSION: This assay is reliable to detect HLA-A*31:01 and would be useful to prevent carbamazepine-induced hypersensitivity reactions.

PMID: 29925289 [PubMed - as supplied by publisher]

Fat label compared with fat content: gastrointestinal symptoms and brain activity in functional dyspepsia patients and healthy controls.

Am J Clin Nutr. 2018 Jun 18;:

Authors: Lee IS, Kullmann S, Scheffler K, Preissl H, Enck P

Abstract
Background: High-fat meals are associated with dyspeptic symptoms in functional dyspepsia (FD) patients. It is still unclear how fat is processed, or how FD symptoms and neuronal activities are modulated by psychological factors.
Objective: We investigated brain activity by functional magnetic resonance imaging (fMRI) after the ingestion of high- and low-fat foods with correct/incorrect fat information.
Design: We compared 12 FD patients and 14 healthy controls (HCs). We recorded resting-state fMRI on four different days before and after ingestion of four yogurts (200 mL, 10% or 0.1% fat, "low fat" or "high fat" label).
Results: FD patients showed more pronounced dyspeptic symptoms than did HCs, and symptoms were relieved less after consuming high fat-labeled yogurt than low fat-labeled yogurt, irrespective of the actual fat content. This is indicative of either a placebo effect of low-fat information or a nocebo effect of high-fat information on symptom expression. FD patients showed greater activity than did HCs in occipital areas before and after ingestion regardless of fat content and label, as well as greater activity in the middle frontal gyrus before ingestion. In addition, functional connectivity (FC) from the insula to the occipital cortex (I-O) increased after high fat ingestion and decreased after low fat ingestion in FD patients. FC from the insula to the precuneus (I-P) was higher in FD patients than in HCs after ingestion of low fat-labeled yogurt. In FD patients, I-O FC negatively correlated with nausea and I-P FC with FD symptom intensity, food craving, and depression.
Conclusions: Our results endorse the importance of psychological perception of food on the incidence of dyspeptic symptoms and on the altered brain activities. These findings show the importance of cognitive components in perceptions of fat, food craving, depression, and brain functions in pathophysiologic mechanisms of FD. This trial was registered at clinicaltrials.gov as NCT02618070.

PMID: 29924294 [PubMed - as supplied by publisher]

NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.

J Gastroenterol. 2018 Jun 19;:

Authors: Kakuta Y, Kawai Y, Okamoto D, Takagawa T, Ikeya K, Sakuraba H, Nishida A, Nakagawa S, Miura M, Toyonaga T, Onodera K, Shinozaki M, Ishiguro Y, Mizuno S, Takahara M, Yanai S, Hokari R, Nakagawa T, Araki H, Motoya S, Naito T, Moroi R, Shiga H, Endo K, Kobayashi T, Naganuma M, Hiraoka S, Matsumoto T, Nakamura S, Nakase H, Hisamatsu T, Sasaki M, Hanai H, Andoh A, Nagasaki M, Kinouchi Y, Shimosegawa T, Masamune A, Suzuki Y, MENDEL study group

Abstract
BACKGROUND: Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.
METHODS: Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.
RESULTS: We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively).
CONCLUSIONS: Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.

PMID: 29923122 [PubMed - as supplied by publisher]

Application of pharmacogenetics in clinical practice: problems and solutions.

J Neural Transm (Vienna). 2018 Jun 19;:

Authors: Baskys A

Abstract
This paper discusses difficulties of pharmacogenomic data integration into clinical practice. It emphasizes the need for developing simple and easy to use bioinformatics tools to help prescribers to rapidly access and use genetic data in clinical decision-making at the point of encounter.

PMID: 29922908 [PubMed - as supplied by publisher]

Characterization CYP1A2, CYP2C9, CYP2C19 and CYP2D6 polymorphisms using HRMA in Psychiatry patients with schizophrenia and bipolar disease for personalized medicine.

Comb Chem High Throughput Screen. 2018 Jun 19;:

Authors: Yenilmez ED, Tamam L, Karaytug O, Tuli A

Abstract
BACKGROUND: The interindividual genetic variations in drug metabolizing enzymes effects the impact and toxicity in plenty of drugs.
OBJECTIVE: The CYP1A2, CYP2C9, CYP2C19 and CYP2D6 gene polymorphisms characterized using high resolution melting analysis (HRMA) in follow-up patients in psychiatry clinic as a preliminary preparation for personalized medicine.
METHOD: Genotyping of CYP1A2*1F, CYP2C9 *2, *3, CYP2C19 *2, *3 and *17 and CYP2D6 *3, *4 was conducted in 101 patients using HRMA. Genotype and allele frequencies of the CYP variants were found to be in equilibrium with the Hardy-Weinberg equation.
RESULTS: The frequency of the CYP1A2*1F allele in schizophrenia and bipolar disease was 0.694 and 0.255, respectively. The CYP2C9 allele frequencies were 0.087 (CYP2C9*2), and 0.549 (CYP2C9*3) for bipolar; 0.278 (CYP2C9*2) and 0.648 (CYP2C9*3) in schizophrenias. The CYP2C19*2 and *17 allele frequencies was 0.111 and 0.185 in schizophrenia and variant *2 was 0.117 and variant *17 was 0.255 in bipolar group. The frequency of the CYP2D6*3 allele was 0.027 in schizophrenias. The frequencies for the CYP2D6*4 variant was 0.092 and 0.096 in schizophrenia and bipolar groups, respectively.
CONCLUSION: The knowledge in pharmacogenomics and also the developments in molecular genetics are growing rapidly. In the future this can be expected to provide new methodologies in the prediction of the activity in drug metabolizing enzymes. The HRMA is a rapid and useful technique to identify the genotypes for drug dosage adjustment before therapy in psychiatry patients.

PMID: 29921201 [PubMed - as supplied by publisher]

Extranodal extension of nodal metastases is a poor prognostic moderator in non-small cell lung cancer: a meta-analysis.

Virchows Arch. 2018 Jun;472(6):939-947

Authors: Luchini C, Veronese N, Nottegar A, Cheng M, Kaneko T, Pilati C, Tabbò F, Stubbs B, Pea A, Bagante F, Demurtas J, Fassan M, Infante M, Cheng L, Scarpa A

Abstract
Extranodal extension (ENE) of nodal metastasis is defined as the extension of metastatic cells through the nodal capsule into the perinodal tissue. This morphological parameter, recently proposed as an important prognostic factor in different types of malignancy, has not been included in the TNM staging system for non-small cell lung cancer (NSCLC). In this systematic review with meta-analysis, we weighted the prognostic role of ENE in patients with lymph node-positive NSCLC. Two independent authors searched SCOPUS and PubMed through 28 February 2017. Prospective and retrospective studies on NSCLC, comparing patients with presence of ENE (ENE+) ENE+) vs. only intranodal extension (ENE-) and including data regarding prognosis, were considered as eligible. Data were summarized using risk ratios (RR) for the number of deaths/recurrences, and hazard ratios (HR) with 95% confidence intervals (CI) for time-dependent risk related to ENE+, adjusted for potential confounders. We identified 13 studies, including 1709 patients (573 ENE+ and 1136 ENE-) with a median follow-up of 60 months. ENE was associated with a significantly increased risk of mortality of all causes (RR = 1.39, 95% CI: 1.18-1.65, P < 0.0001, I2 = 70%; HR = 1.30, 95% CI: 1.01-1.67, P = 0.04, I2 = 0%) and of disease recurrence (RR = 1.32, 95% CI: 1.04-1.68, P = 0.02, I2 = 42%; HR = 1.93, 95% CI: 1.53-2.44, P < 0.0001, I2 = 0%). We conclude that in NSCLC, requirements for assessment of ENE should be included in gross sampling and ENE status should be included in the pathology report. Inclusion of ENE status in oncology staging systems will allow further assessment of its role as prognostic parameter.

PMID: 29392400 [PubMed - indexed for MEDLINE]

Genetic addiction risk score (GARS) ™, a predictor of vulnerability to opioid dependence.

Front Biosci (Elite Ed). 2018 01 01;10:175-196

Authors: Blum K, Chen ALC, Thanos PK, Febo M, Demetrovics Z, Dushaj K, Kovoor A, Baron D, Smith DE, Roy AK, Fried L, Chen TJH, Chapman E, Modestino EJ, Steinberg B, Badgaiyan RD

Abstract
The interaction of neurotransmitters and genes that control the release of dopamine is the Brain Reward Cascade (BRC). Variations within the BRC, whether genetic or epigenetic, may predispose individuals to addictive behaviors and altered pain tolerance. This discussion authored by a group of concerned scientists and clinicians examines the Genetic Addiction Risk Score (GARS), the first test to accurately predict vulnerability to pain, addiction, and other compulsive behaviors, defined as Reward Deficiency Syndrome (RDS). Innovative strategies to combat epidemic opioid, iatrogenic prescription drug abuse and death, based on the role of dopaminergic tone in pain pathways, are proposed. Sensitivity to pain may reside in the mesolimbic projection system, where genetic polymorphisms associate with a predisposition to pain vulnerability or tolerance. They provide unique therapeutic targets that could assist in the treatment of pain, and identify risk for subsequent addiction. Pharmacogenomic testing of candidate genes like CB1, mu receptors, and PENK might result in pharmacogenomic, personalized solutions, and improved clinical outcomes. Genetically identifying risk for all RDS behaviors, especially in compromised populations, may be a frontline tool to assist municipalities to provide better resource allocation.

PMID: 28930612 [PubMed - indexed for MEDLINE]

Genome-wide association study of neovascular age-related macular degeneration in the Thai population.

J Hum Genet. 2017 Nov;62(11):957-962

Authors: Ruamviboonsuk P, Tadarati M, Singhanetr P, Wattanapokayakit S, Kunhapan P, Wanitchanon T, Wichukchinda N, Mushiroda T, Akiyama M, Momozawa Y, Kubo M, Mahasirimongkol S

Abstract
We performed a genome-wide association study on 377 cases of neovascular age-related macular degeneration (AMD) and 1074 controls to determine the association of previously reported genetic variants associated with neovascular AMD in the Thai population. All patients were of Thai ancestry. We confirmed the association of age-related maculopathy susceptibility 2 (ARMS2) rs10490924 (P=7.38 × 10-17), HTRA1 rs11200638 (P=5.47 × 10-17) and complement factor H gene (CFH) rs800292 (P=2.53 × 10-8) with neovascular AMD, all loci passing the genome-wide significance level (P<5.22 × 10-8). We also found association of the previously reported CFH rs10737680 (P=1.76 × 10-6) locus in the discovery sample. Two loci not previously reported to be associated with neovascular AMD were selected for replication in 222 cases and 623 controls. The loci included LINCO1317 rs6733379 and rs2384550 on chromosome 12. LINCO1317 rs6733379 (P=3.85 × 10-2) remained significantly associated with neovascular AMD after replication. In conclusion, we confirm that ARMS2, HTRA1 and CFH variants are associated with neovascular AMD in the Thai population. Findings from this study also suggest that variants contributing to the susceptibility of neovascular AMD in the Thai population are mostly similar to other Asians with additional local genetic risks that may specifically be identified in Thai population.

PMID: 28703135 [PubMed - indexed for MEDLINE]

A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML.

Leukemia. 2017 06;31(6):1466-1470

Authors: Kats LM, Vervoort SJ, Cole R, Rogers AJ, Gregory GP, Vidacs E, Li J, Nagaraja R, Yen KE, Johnstone RW

PMID: 28280273 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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

pharmacogenomics

These pubmed results were generated on 2018/06/20

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.

Progression of Chronic Kidney Disease Affects HDL Impact on Lipoprotein Lipase (LPL)-Mediated VLDL Lipolysis Efficiency.

Kidney Blood Press Res. 2018 Jun 15;43(3):970-978

Authors: Ćwiklińska A, Cackowska M, Wieczorek E, Król E, Kowalski R, Kuchta A, Kortas-Stempak B, Gliwińska A, Dąbkowski K, Zielińska J, Dębska-Ślizień A, Jankowski M

Abstract
BACKGROUND/AIMS: Hypertriglyceridaemia (HTG) and reduction and dysfunction of high density lipoprotein (HDL) are common lipid disturbances in chronic kidney disease (CKD). HTG in CKD is caused mainly by the decreased efficiency of lipoprotein lipase (LPL)-mediated very low density lipoprotein triglyceride (VLDL-TG) lipolysis. It has not been clarified whether HDL dysfunction in CKD contributes directly to HTG development; thus, the aim of this study was to assess the impact of CKD progression on the ability of HDL to enhance LPL-mediated VLDL-TG lipolysis efficiency.
METHODS: VLDL was isolated from non-dialysis patients in CKD stages 3 and 4 and from non-CKD patients. The VLDL was incubated with LPL at the constant LPL:VLDL-TG ratio, in the absence or presence of HDL. After incubation, the VLDL was separated and the percentage (%) of hydrolyzed TG was calculated.
RESULTS: HDL presence increased the lipolysis efficiency of VLDL isolated from CKD and non-CKD patients, for the VLDL-TG> 50 mg/dl. Its effect was dependent on the VLDL-TG and HDL-cholesterol concentrations in the reaction mixtures: the higher the concentrations of VLDL-TG and HDL-cholesterol, the greater the effect. The positive impact of HDL on VLDL lipolysis was modified by CKD progression: the percentage of lipolyzed VLDL-TG in the presence of HDL decreased with a reduction in eGFR (r=0.43, p=0.009), and for patients with stage 4 CKD, no positive impact of HDL on lipolysis was observed. The percentage of lipolyzed TG correlated negatively with apoE and apoCs content in VLDL, and positively with HDL-apoCII, as well as with VLDL and HDL apoCII/ apoCIII ratios. The progression of CKD was associated with unfavourable changes in VLDL and HDL composition; apoE and apoCs levels increased in VLDL with a decrease in eGFR whereas the HDL-cholesterol level decreased.
CONCLUSION: The progression of CKD affects lipoprotein composition and properties, and modulates the positive impact of HDL on VLDL lipolysis efficiency. In CKD patients, HDL deficiency and dysfunction can directly affect hypertriglyceridaemia development.

PMID: 29913451 [PubMed - as supplied by publisher]

Inter-individual differences in the susceptibility of primary human hepatocytes towards the cholestatic drug hepatotoxicity are compound and time dependent.

Toxicol Lett. 2018 Jun 15;:

Authors: Parmentier C, Hendriks DFG, Heyd B, Bachellier P, Ingelman-Sundberg M, Richert L

Abstract
Cholestasis represents a major subtype of drug-induced liver injury and novel preclinical models for its prediction are needed. Here we used primary human hepatocytes (PHH) from different donors in 2D-sandwich (2D-sw) and/or 3D-spheroid cultures to study inter-individual differences in response towards cholestatic hepatotoxins after short-term (48-72 h) and long-term repeated exposures (14 days). Cholestatic liabilities were determined by comparing cell viability upon exposure to the highest non-cytotoxic drug concentration in the presence and absence of a non-cytotoxic concentrated bile acid (BA) mixture. In 2D-sw culture, cyclosporine A and amiodarone presented clear cholestatic liabilities in all four PHH donors tested, whereas differences in the susceptibility of the various PHH donors towards the cholestatic toxicity of bosentan, chlorpromazine and troglitazone were observed. When PHH from one donor in which the cholestatic toxicity of chlorpromazine and troglitazone were not detected after a short-term exposure in 2D-sw culture, were maintained in 3D-spheroid culture, the cholestatic toxicity of chlorpromazine and troglitazone was only detected upon long-term repeated exposures, suggesting that cholestatic hepatotoxicity may require time to develop. In conclusion, inter-individual susceptibility exists towards drug-induced cholestasis, which depends on the choice of compounds as well as the exposure time.

PMID: 29913214 [PubMed - as supplied by publisher]

Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma.

Hum Reprod. 2018 Jun 15;:

Authors: Bourcigaux N, Rubino C, Berthaud I, Toubert ME, Donadille B, Leenhardt L, Petrot-Keller I, Brailly-Tabard S, Fromigué J, de Vathaire F, Simon T, Siffroi JP, Schlumberger M, Bouchard P, Christin-Maitre S

Abstract
STUDY QUESTION: What are the consequences of radioactive iodine (RAI) therapy for testicular function?
SUMMARY ANSWER: A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities.
WHAT IS KNOWN ALREADY: Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function.
STUDY DESIGN, SIZE, DURATION: A longitudinal prospective multi-center study on testicular function performed in DTC patients before a single 131I ablative activity of 3.7 GBq (V0) and at 3 months (V3) and 13 months (V13) after treatment.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Forty male patients, aged 18-55 years, with DTC participated. Hormonal analysis included FSH, LH, testosterone and inhibin B serum levels at V0, V3 and V13. Furthermore, sperm parameters, DNA fragmentation and sperm chromosomal abnormalities were evaluated at each time points. The differences in all parameters, between V0-V3, V0-V13 and V3-V13, were analyzed, using a Wilcoxon test.
MAIN RESULTS AND THE ROLE OF CHANCE: Prior to RAI administration, all patients had normal gonadal function. At V3, a statistically significant increase in FSH levels and a decrease in inhibin B levels were observed and sperm concentration, as well as the percentage of morphologically normal spermatozoa, were significantly decreased (P < 0.0001). These modifications were transient as both sperm concentration and normal morphology rate returned to baseline values at V13. However, at this later time point, FSH and inhibin B levels were still impacted by RAI administration but remained in the normal range. Although no DNA fragmentation was observed at V3 nor V13, our study revealed a statistically significant increase in the number of sperm chromosomal abnormalities both at V3 (P < 0.001) and V13 (P = 0.01).
LIMITATIONS, REASONS FOR CAUTION: Among the 40 patients included in the study, only 24 had all the parameters available at all visits.
WIDER IMPLICATIONS OF THE FINDINGS: Prospective studies with longer term follow up would be helpful to determine whether the chromosome abnormalities persist. These studies would be required before sperm banking should be suggested for all patients. However, sperm preservation for DTC patients who require cumulative radioiodine activities higher than 3.7 GBq should be proposed.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Programme Hospitalier de Recherche Clinique, AP-HP (No. P040419). The authors report no conflict of interest in this work.
TRIAL REGISTRATION NUMBER: NCT01150318.

PMID: 29912343 [PubMed - as supplied by publisher]

Frequency of Common CYP2C9 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population.

Clin Appl Thromb Hemost. 2017 Oct;23(7):800-806

Authors: Qayyum A, Najmi MH, Mansoor Q, Farooqi ZU, Naveed AK, Hanif A, Kazmi SAR, Ismail M

Abstract
Polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9) gene result in interindividual variability in warfarin dose requirement. There is a need for characterization of genotype frequency distribution in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common CYP2C9 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations. Single blood sample was collected after informed consent. Genomic DNA was extracted, and genotype analysis for CYP2C9*2 and CYP2C9*3 polymorphisms was done by polymerase chain reaction-restriction fragment length polymorphism assay. A number of samples were also analyzed by direct DNA sequencing for validation of the results. Data were analyzed using SPSS version 20. Genotype frequency distribution of CYP2C9*2 and CYP2C9*3 was found to be different from other populations. Of these 2 polymorphisms, CYP2C9*2 did not demonstrate significant effect on warfarin dose requirement, whereas CYP2C9*3 did show significant effect ( P value = .012). It is concluded that there is a need to study genotype frequency distribution and their effect on warfarin dose variability among different populations due to diversity in outcome.

PMID: 27313202 [PubMed - indexed for MEDLINE]

Connecting the pharmacogenetics and personalised medicine community.

Drug Discov Today. 2018 Jun 13;:

Authors: McNamee C

PMID: 29908264 [PubMed - as supplied by publisher]

A Parallel Software Pipeline for DMET Microarray Genotyping Data Analysis.

High Throughput. 2018 Jun 14;7(2):

Authors: Agapito G, Guzzi PH, Cannataro M

Abstract
Personalized medicine is an aspect of the P4 medicine (predictive, preventive, personalized and participatory) based precisely on the customization of all medical characters of each subject. In personalized medicine, the development of medical treatments and drugs is tailored to the individual characteristics and needs of each subject, according to the study of diseases at different scales from genotype to phenotype scale. To make concrete the goal of personalized medicine, it is necessary to employ high-throughput methodologies such as Next Generation Sequencing (NGS), Genome-Wide Association Studies (GWAS), Mass Spectrometry or Microarrays, that are able to investigate a single disease from a broader perspective. A side effect of high-throughput methodologies is the massive amount of data produced for each single experiment, that poses several challenges (e.g., high execution time and required memory) to bioinformatic software. Thus a main requirement of modern bioinformatic softwares, is the use of good software engineering methods and efficient programming techniques, able to face those challenges, that include the use of parallel programming and efficient and compact data structures. This paper presents the design and the experimentation of a comprehensive software pipeline, named microPipe, for the preprocessing, annotation and analysis of microarray-based Single Nucleotide Polymorphism (SNP) genotyping data. A use case in pharmacogenomics is presented. The main advantages of using microPipe are: the reduction of errors that may happen when trying to make data compatible among different tools; the possibility to analyze in parallel huge datasets; the easy annotation and integration of data. microPipe is available under Creative Commons license, and is freely downloadable for academic and not-for-profit institutions.

PMID: 29904017 [PubMed]

Clinical application of antidepressant pharmacogenetics: considerations for the design of future studies.

Neurosci Lett. 2018 Jun 12;:

Authors: Fabbri C, Serretti A

Abstract
A frustrating inertia has affected the development of clinical applications of antidepressant pharmacogenetics and personalized treatments of depression are still lacking 20 years after the first findings. Candidate gene studies provided replicated findings for some polymorphisms, but each of them shows at best a small effect on antidepressant efficacy and the cumulative effect of different polymorphisms is unclear. Further, no candidate was immune by at least some negative studies. These considerations give rise to some concerns about the clinical benefits of currently available pharmacogenetic tests since they are based on the results of candidate gene studies. Clinical guidelines in fact suggest that only polymorphisms that alter cytochrome 2D6 or 2C19 enzymatic activity probably provide useful clinical indications, while variants in genes involved in antidepressant pharmacodynamics have no recommended clinical applications. The present review discusses possible strategies to facilitate the identification of genetic biomarkers with clinical usefulness in guiding antidepressant treatments. These include analysis methods for the study of the polygenic/omnigenic nature of antidepressant response, the prioritization of polymorphisms on the basis of functional considerations, the incorporation of clinical-demographic predictors in pharmacogenetic studies (e.g. mixed polygenic and clinical risk scores), the application of methodological improvements to the design of future studies in order to maximize the comparability of results and improve power.

PMID: 29906483 [PubMed - as supplied by publisher]

Liver Metabolomics in a Mouse Model of Erythropoietic Protoporphyria.

Biochem Pharmacol. 2018 Jun 12;:

Authors: Wang P, Sachar M, Guo GL, Shehu AI, Lu J, Zhong XB, Ma X

Abstract
Erythropoietic protoporphyria (EPP) is a genetic disease that results from the defective mutation in the gene encoding ferrochelatase (FECH), the enzyme that converts protoporphyrin IX (PPIX) to heme. Liver injury and even liver failure can occur in EPP patients because of PPIX accumulation in the liver. The current study profiled the liver metabolome in an EPP mouse model caused by a Fech mutation (Fech-mut). As expected, we observed the accumulation of PPIX in the liver of Fech-mut mice. In addition, our metabolomic analysis revealed the accumulation of bile acids and ceramide (Cer) in the liver of Fech-mut mice. High levels of bile acids and Cer are toxic to the liver. Furthermore, we found that the major phosphatidylcholines (PC) in the liver and the ratio of total PC to PPIX in the bile were decreased in Fech-mut mice compared to wild type mice. A decrease of the ratio of PC to PPIX in the bile can potentiate the accumulation of PPIX in the liver because PC increases PPIX solubility and excretion. These metabolomic findings suggest that the accumulation of PPIX, together with the disruption of the homeostasis of bile acids, Cer, and PC, contributes to EPP-associated liver injury.

PMID: 29906468 [PubMed - as supplied by publisher]