Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions.

Annu Rev Pharmacol Toxicol. 2018 Aug 22;:

Authors: Karnes JH, Miller MA, White KD, Konvinse KC, Pavlos RK, Redwood AJ, Peter JG, Lehloenya R, Mallal SA, Phillips EJ

Abstract
Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen (HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 30134124 [PubMed - as supplied by publisher]

Elevated amylase in plasma represents an adverse prognostic marker in patients with metastatic pancreatic cancer : A retrospective analysis.

Wien Klin Wochenschr. 2018 Aug 21;:

Authors: Asamer E, Szkandera J, Gibiser P, Lembeck AL, Stojakovic T, Kornprat P, Lackner C, Winder T, Schlick K, Stöger H, Gerger A, Pichler M, Stotz M

Abstract
BACKGROUND AND AIM: The aim of this study was to investigate the prognostic relevance of plasma amylase and lipase concerning survival of patients suffering from metastatic pancreatic cancer (PC).
METHOD: This retrospective study included 351 patients with metastatic PC, who were treated in a single academic institution. Cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method. To further evaluate the prognostic significance of lipase and amylase, univariate and multivariate values were calculated using Cox proportional models.
RESULTS: In univariate analysis, an increased amylase level was associated with shorter CSS in PC patients (hazard ratio HR = 1.258; 95% confidence interval CI = 1.011-1.566; p = 0.039). In multivariate analysis, including gender, age, CA19-9 and administration of chemotherapy, increased amylase levels prevailed as an independent prognostic factor for CSS (HR = 1.373; 95%CI = 1.004-1.878; p = 0.047).
CONCLUSIONS: Plasma amylase was found to be an independent prognostic factor in patients with metastatic PC. The results indicate that amylase might represent a novel and useful marker for better patient stratification in PC management.

PMID: 30132196 [PubMed - as supplied by publisher]

CD200 expression is a feature of solid pseudopapillary neoplasms of the pancreas.

Virchows Arch. 2018 Aug 21;:

Authors: Lawlor RT, Daprà V, Girolami I, Pea A, Pilati C, Nottegar A, Piccoli P, Parolini C, Sperandio N, Capelli P, Scarpa A, Luchini C

Abstract
CD200 has been recently indicated as a robust marker of well-differentiated neuroendocrine neoplasms. Here, we evaluate its role in differential diagnosis of solid pancreatic neoplasms. We immunostained for CD200 22 solid pseudopapillary neoplasms (SPNs), 8 acinar carcinomas (ACs), 2 pancreatoblastomas (PBs), 138 neuroendocrine tumors (PanNETs), and 48 ductal adenocarcinomas. All SPNs showed strong cytoplasmic and membranous staining for CD200, while only one case of AC had focal positivity. The two PBs showed focal CD200 positivity, mainly located in squamoid nests. The vast majority of PanNETs (96%) showed strong cytoplasmic and membranous staining for CD200, whereas all PDACs were negative. As both PanNETs and SPNs express CD200, it has no role in the differential diagnosis between these two entities.

PMID: 30132130 [PubMed - as supplied by publisher]

Association of Variability and Pharmacogenomics With Bioequivalence of Gefitinib in Healthy Male Subjects.

Front Pharmacol. 2018;9:849

Authors: Zhang H, Li Q, Zhu X, Wu M, Li C, Li X, Liu C, Shen Z, Ding Y, Hua S

Abstract
Objective: The aim of the study was to explore the association of pharmacokinetic variability and pharmacogenomics with the bioequivalence of orally administered gefitinib (Iressa®, AstraZeneca) provided by three sponsors in healthy subjects. Methods: The study designs were randomized, open-label, and two-period crossover studies in both fasting and fed healthy subjects. In one fasting study, the sample size was enlarged from 30 to 60 for the failing study. Each study subject received a 250-mg gefitinib tablet with a 21-day washout. The plasma concentrations were measured using LC-MS/MS, and pharmacokinetic parameters were determined by noncompartmental methods. Genetic analyses of CYP3A4, CYP3A5, and CYP2D6 alleles were carried out by the polymerase chain reaction (PCR). Results: Two hundred and sixty healthy male subjects were enrolled. The median maximum plasma concentration (Tmax) was 4-5 h, and the mean elimination half-life (t1/2) was 18-26 h. The maximum plasma concentration (Cmax) and area under the curve (AUC) increased but Tmax and t1/2 were unaffected by the intake of high-fat food. Three fed and two fasting studies achieved a plausible bioequivalence. The intake of high-fat food decreased the intra-subject variability significantly. In addition, CYP2D6 was associated with gefitinib exposure and may contribute to the high inter-subject variability, but it did not influence the bioequivalence result. Conclusions: Gefitinib is well tolerated, and the bioequivalence is easier to achieve under fed conditions compared to fasting conditions. The 90% confidence interval (CI) of geometric mean ratio (GMR) can be narrowed when the sample size is enlarged without changing the formulation-related technology.

PMID: 30131694 [PubMed]

A non-functional galanin receptor-2 in a multiple sclerosis patient.

Pharmacogenomics J. 2018 Aug 22;:

Authors: Garcia-Rosa S, Trivella DB, Marques VD, Serafim RB, Pereira JG, Lorenzi JC, Molfetta GA, Christo PP, Olival GS, Marchitto VB, Brum DG, Sabedot TS, Noushmehr H, Farias AS, Santos LM, Nogueira-Machado JA, Souza JE, Romano CM, Conde RM, Santos AC, Guerreiro CT, Schreuder WH, Gleber-Netto FO, Amorim M, Valieris R, Silva ITD, Silva WA, Nunes DN, Oliveira PS, Valente V, Arruda MA, Hill SJ, Barreira AA, Dias-Neto E

Abstract
Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease that affects approximately 2.5 million people globally. Even though the etiology of MS remains unknown, it is accepted that it involves a combination of genetic alterations and environmental factors. Here, after performing whole exome sequencing, we found a MS patient harboring a rare and homozygous single nucleotide variant (SNV; rs61745847) of the G-protein coupled receptor (GPCR) galanin-receptor 2 (GALR2) that alters an important amino acid in the TM6 molecular toggle switch region (W249L). Nuclear magnetic resonance imaging showed that the hypothalamus (an area rich in GALR2) of this patient exhibited an important volumetric reduction leading to an enlarged third ventricle. Ex vivo experiments with patient-derived blood cells (AKT phosphorylation), as well as studies in recombinant cell lines expressing the human GALR2 (calcium mobilization and NFAT mediated gene transcription), showed that galanin (GAL) was unable to stimulate cell signaling in cells expressing the variant GALR2 allele. Live cell confocal microscopy showed that the GALR2 mutant receptor was primarily localized to intracellular endosomes. We conclude that the W249L SNV is likely to abrogate GAL-mediated signaling through GALR2 due to the spontaneous internalization of this receptor in this patient. Although this homozygous SNV was rare in our MS cohort (1:262 cases), our findings raise the potential importance of impaired neuroregenerative pathways in the pathogenesis of MS, warrant future studies into the relevance of the GAL/GALR2 axis in MS and further suggest the activation of GALR2 as a potential therapeutic route for this disease.

PMID: 30131588 [PubMed - as supplied by publisher]

Lithium-associated anterior cingulate neurometabolic profile in euthymic Bipolar I disorder: A 1H-MRS study.

J Affect Disord. 2018 Aug 10;241:192-199

Authors: Soeiro-de-Souza MG, Otaduy MCG, Machado-Vieira R, Moreno RA, Nery FG, Leite C, Lafer B

Abstract
OBJECTIVE: In the treatment of Bipolar disorder (BD), achieving euthymia is highly complex and usually requires a combination of mood stabilizers. The mechanism of action in stabilizing mood has not been fully elucidated, but alterations in N-Acetylaspartate (NAA), Myo-Inositol (mI) and Choline (Cho) have been implicated. Proton magnetic resonance spectroscopy (1H-MRS) is the gold standard technique for measuring brain NAA, Cho and mI in vivo. The objective of this study was to investigate the association of lithium use in BD type I and brain levels of NAA, mI and Cho in the (anterior cingulate cortex) ACC.
METHODS: 129 BD type I subjects and 79 healthy controls (HC) were submitted to a 3-Tesla brain magnetic resonance imaging scan (1H-MRS) using a PRESS ACC single voxel (8cm3) sequence.
RESULTS: BD patients exhibited higher NAA and Cho levels compared to HC. Lithium prescription was associated with lower mI (combination + monotherapy) and higher NAA levels (monotherapy).
CONCLUSION: The results observed add to the knowledge about the mechanisms of action of mood stabilizers on brain metabolites during euthymia. Additionally, the observed decrease in mI levels associated with lithium monotherapy is an in vivo finding that supports the inositol-depletion hypothesis of lithium pharmacodynamics.

PMID: 30130684 [PubMed - as supplied by publisher]

Trends in herbgenomics.

Sci China Life Sci. 2018 Aug 14;:

Authors: Xin T, Zhang Y, Pu X, Gao R, Xu Z, Song J

Abstract
From Shen Nong's Herbal Classic (Shennong Bencao Jing) to the Compendium of Materia Medica (Bencao Gangmu) and the first scientific Nobel Prize for the mainland of China, each milestone in the historical process of the development of traditional Chinese medicine (TCM) involves screening, testing and integrating. After thousands of years of inheritance and development, herbgenomics (bencaogenomics) has bridged the gap between TCM and international advanced omics studies, promoting the application of frontier technologies in TCM. It is a discipline that uncovers the genetic information and regulatory networks of herbs to clarify their molecular mechanism in the prevention and treatment of human diseases. The main theoretical system includes genomics, functional genomics, proteomics, transcriptomics, metabolomics, epigenomics, metagenomics, synthetic biology, pharmacogenomics of TCM, and bioinformatics, among other fields. Herbgenomics is mainly applicable to the study of medicinal model plants, genomic-assisted breeding, herbal synthetic biology, protection and utilization of gene resources, TCM quality evaluation and control, and TCM drug development. Such studies will accelerate the application of cutting-edge technologies, revitalize herbal research, and strongly promote the development and modernization of TCM.

PMID: 30128965 [PubMed - as supplied by publisher]

ZNF542P is a pseudogene associated with LDL response to simvastatin treatment.

Sci Rep. 2018 Aug 20;8(1):12443

Authors: Kim K, Theusch E, Kuang YL, Dose A, Mitchel K, Cubitt C, Chen YI, Krauss RM, Medina MW

Abstract
Statins are the most commonly prescribed cardiovascular disease drug, but their inter-individual efficacy varies considerably. Genetic factors uncovered to date have only explained a small proportion of variation in low-density lipoprotein cholesterol (LDLC) lowering. To identify novel markers and determinants of statin response, we used whole transcriptome sequence data collected from simvastatin and control incubated lymphoblastoid cell lines (LCLs) established from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial. We looked for genes whose statin-induced expression changes were most different between LCLs derived from individuals with high versus low plasma LDLC statin response during the CAP trial. We created a classification model of 82 "signature" gene expression changes that distinguished high versus low LDLC statin response. One of the most differentially changing genes was zinc finger protein 542 pseudogene (ZNF542P), the signature gene with changes most correlated with statin-induced change in cellular cholesterol ester, an in vitro marker of statin response. ZNF542P knock-down in a human hepatoma cell line increased intracellular cholesterol ester levels upon simvastatin treatment. Together, these findings imply a role for ZNF542P in LDLC response to simvastatin and, importantly, highlight the potential significance of noncoding RNAs as a contributing factor to variation in drug response.

PMID: 30127457 [PubMed - in process]

Methylation analysis for multiple gene promoters in non-small cell lung cancers in high indoor air pollution region in China.

Bull Cancer. 2018 Aug 17;:

Authors: Huang X, Wu C, Fu Y, Guo L, Kong X, Cai H

Abstract
AIM: The prevalence and mortality rates of lung cancer in Xuanwei, Yunnan, China, are the highest in the world. The severe indoor air pollution caused by smoky coals with high benzo (a)pyrene (BaP) and quartz levels is the main environmental factor. The aim of this study was to investigate methylation profiles of promoters in eight genes in primary non-small cell lung cancers (NSCLC) exposed to smoky coals.
MATERIALS AND METHODS: Candidate genes including CDKN2A, DLEC1, CDH1, DAPK, RUNX3, APC, WIF1 and MGMT were determined for the promoter methylation status using Nested methylation-specific PCR (nMSP) in primary 23NSCLC tissues and in circulating tumor DNA (ctDNA) isolated from 42plasma samples (9matched to tissues) as well as 10healthy plasma samples, using Sanger sequencing to verify the results.
RESULTS: Seven of the 8genes, except MGMT, had relatively high methylation frequencies ranging from 39%-74% in tissues. Moreover, methylation frequencies in five genes identified in lung cancer plasma were 45% for CDKN2A, 48% for DLEC1, 76% for CDH1, 14% for DAPK, 29% for RUNX3, with a relatively good concordance of methylation among 9 tissues and paired plasma. However, the genes from all healthy plasma showed no methylation.
CONCLUSIONS: A panel of genes including CDKN2A, DLEC1, CDH1, DAPK and RUNX3 may be used as potential epigenetic biomarkers for early lung cancer detection. CDH1 promoter methylation was associated with lung cancer metastasis in areas of air pollution from buring of smoky coals. DLEC1 and CDH1 exhibited specific high methylation frequencies, different from previous reports.

PMID: 30126609 [PubMed - as supplied by publisher]

Integrative Analysis of DNA Methylation and Gene Expression Identify a Three-Gene Signature for Predicting Prognosis in Lower-Grade Gliomas.

Cell Physiol Biochem. 2018;47(1):428-439

Authors: Zeng WJ, Yang YL, Liu ZZ, Wen ZP, Chen YH, Hu XL, Cheng Q, Xiao J, Zhao J, Chen XP

Abstract
BACKGROUND/AIMS: In the current study, we performed an integrated analysis of genome-wide methylation and gene expression data to find novel prognostic genes for lower-grade gliomas (LGGs).
METHODS: First, TCGA methylation data were used to identify prognostic genes associated with promoter methylation. Second, candidate genes that were stably regulated by promoter methylation were explored. Third, Cox proportional hazards regression analysis was used to generate a prognostic signature, and the signature genes were used to construct a survival risk score system.
RESULTS: Three genes (EMP3, GSX2 and EMILIN3) were selected as signature genes. These three signature genes were used to construct a survival risk score system. The high-risk group exhibited significantly worse overall survival (OS) and relapse-free survival (RFS) as compared to the low-risk group in the TCGA dataset. The association of the three-gene prognostic signature with patient' survival was then validated using the CGGA dataset. Moreover, Kaplan-Meier plots showed that the three-gene prognostic signature risk remarkably stratified grade II and grade III patients in terms of both OS and RFS in the TCGA cohort. There was also a significant difference between the low- and high-risk groups in IDH wild-type glioma patients, indicating that the three-gene signature may be able to help in predicting prognosis for patients with IDH wild-type gliomas.
CONCLUSION: We identified and validated a three-gene (EMP3, GSX2 and EMILIN3) prognostic signature in LGGs by integrating multidimensional genomic data from the TCGA and CGGA datasets, which may help in fine-tuning the current histology-based tumors classification system and providing better stratification for future clinical trials.

PMID: 29794476 [PubMed - indexed for MEDLINE]

SLC6A4 5HTTLPR Polymorphism Affects Insulin Secretion in Patients with Polycystic Ovary Syndrome.

Int J Endocrinol. 2018;2018:6130487

Authors: Šenk B, Goričar K, Kravos NA, Jensterle Sever M, Janež A, Dolžan V

Abstract
Purpose: To investigate in a pilot study of genetic polymorphisms in serotonin system influencing basal- and glucose-stimulated insulin secretion in women with polycystic ovary syndrome (PCOS).
Methods: A cross-sectional study included 65 female patients with PCOS followed up at the endocrine outpatient clinic of the University Medical Center Ljubljana and a control group of 94 young healthy female blood donors. Oral glucose tolerance test was performed only in PCOS patients and basal- and glucose-stimulated blood glucose and insulin levels were measured. All the subjects were genotyped for 5HTR1A rs6295, 5HTR1B rs13212041, and SLC6A4 5HTTLPR polymorphisms in the serotonin system.
Results: Genotype distributions were in accordance with the Hardy-Weinberg equilibrium (HWE), except for 5HTR1A rs6295 in healthy controls and 5HTR1B rs13212041 in PCOS patients that were not consistent with HWE. SLC6A4 5HTTLPR polymorphism was significantly associated with insulin secretion (p = 0.030) and with the area under the curve of insulin blood levels during OGTT (p = 0.021). None of the investigated polymorphisms was significantly associated with basal- or glucose-stimulated blood glucose levels at any point in time during OGTT or with the basal insulin concentration.
Conclusions: Serotonin system may play a role in glucose-stimulated insulin secretion in patients with insulin resistance (IR) and decreased insulin sensitivity. Further studies are needed to conclude whether the observed effect is characteristic for PCOS-related metabolic disturbances or for the identified mutation in different high metabolic risk populations.

PMID: 30123264 [PubMed]

Usefulness of Pharmacogenetic Analysis in Psychiatric Clinical Practice: A Case Report.

Clin Psychopharmacol Neurosci. 2018 Aug 31;16(3):349-357

Authors: Franco-Martin MA, Sans F, García-Berrocal B, Blanco C, Llanes-Alvarez C, Isidoro-García M

Abstract
There are many factors involved in the effectiveness and efficiency of psychiatric drug treatment. One of them is psychotropic drug metabolism, which takes place mostly in the liver through the P450 enzyme system. However, there are genotypic variants of this system's enzymes that can directly affect both the efficacy and the onset of side effects of a given therapeutic regimen. These genotypic changes could partly explain the lack of efficacy of treatment in certain patients. We report the case of a patient diagnosed with bipolar type I disorder that presented multiple and frequent manic episodes in which the efficacy and tolerability of several pharmacological regimens with mood stabilizers and antipsychotics was scarce. The choice of medical treatment should be based on its efficacy and side effect profile. This decision can be made more accurately using the information provided by pharmacogenetic analysis. This case illustrates the importance of pharmacogenetic studies in clinical practice. The results of pharmacogenetic analysis helped to decide on a better treatment plan to achieve clinical improvement and reduce drug-induced adverse effects.

PMID: 30121988 [PubMed]

NOS3 895G>T and CBR3 730G>A Are Associated with Recurrence Risk in Non-Muscle-Invasive Bladder Cancer with Intravesical Instillations of THP.

Chemotherapy. 2018 Aug 17;63(4):191-197

Authors: Zhou Q, Ding W, Weng Y, Ding G, Xia G, Xu J, Xu K, Ding Q

Abstract
OBJECTIVES: To analyze the correlation between pharmacogenomic biomarkers and the efficacy of pirarubicin (THP, also named 4'-O-tetrahydropyranyl-adriamycin) and to explore potential associations of individual genetic backgrounds with the clinical outcomes of non-muscle-invasive bladder cancer (NMIBC) patients.
METHODS: Between July 2003 and June 2011, a total of 91 patients were treated with transurethral resection (TUR) of the bladder tumor and were histopathologically confirmed to have NMIBC. Patients received an immediate instillation and maintenance therapy with THP. All patients underwent follow-up for recurrence. We genotyped 13 single nucleotide polymorphisms (SNPs) from blood and saliva DNA samples of all patients.
RESULTS: The associations of patients' genotypes with tumor recurrence risks were analyzed by survival analysis. A total of 16 (17.6%) of the 91 patients with NMIBC had tumor recurrences with a median follow-up of 17 months (range, 2-83 months). We confirmed the effect of the European Organization for Research and Treatment of Cancer (EORTC) risk score for predicting tumor recurrence (p = 0.002, log-rank test). We adjusted for the EORTC score and found that 2 SNPs, NOS3 895G>T (rs1799983) (p = 0.02, HR = 4.32, 95% CI, 1.30-14.39, GT+TT vs. GG) and CBR3 730G>A (rs1056892) (p = 0.04, HR = 2.57, 95% CI, 1.07-6.18, GA+AA vs. GG), were significantly associated with a higher recurrence risk after TUR and instillations of THP in NMIBC patients.
CONCLUSIONS: Our results suggest that NOS3 895G>T and CBR3 730G>A are genetic markers that can be used to predict tumor recurrence in NMIBC patients receiving intravesical instillations of THP. The effects of those 2 SNPs are independent of the EORTC scores. Further studies with larger sample sizes and longer follow-ups are needed to confirm our results.

PMID: 30125887 [PubMed - as supplied by publisher]

Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics of Efavirenz 400 mg Once Daily During Pregnancy and Post-Partum.

Clin Infect Dis. 2018 Aug 16;67(5):785-790

Authors: Lamorde M, Wang X, Neary M, Bisdomini E, Nakalema S, Byakika-Kibwika P, Mukonzo JK, Khan W, Owen A, McClure M, Boffito M

Abstract
Background: A clinical trial showed that efavirenz 400 mg once daily (EFV400) is as effective as the standard adult dose. World Health Organization recommends EFV400 as an alternative first-line agent, but data are lacking in the third trimester of pregnancy (TT). We investigated the pharmacokinetics, efficacy, and CYP2B6 pharmacogenetics in HIV-infected women (WLWH) on EFV400 during TT and post-partum (PP).
Methods: An open-label 2-center study (United Kingdom, Uganda) was conducted in WLWH receiving antiretroviral regimens containing efavirenz 600 mg, who had their efavirenz dose reduced to EFV400. Weekly therapeutic drug monitoring (TDM), steady-state pharmacokinetic profiles (TT and PP), safety, virological efficacy, and CYP2B6 polymorphisms at positions 516 (C > T) and 938 (T > C) were evaluated.
Results: Twenty-five WLWH of African origin were enrolled. All had viral loads <50 copies/mL at baseline, which were maintained throughout the study. No infant was HIV infected. No WLWH were withdrawn due to low EFV400 TDM results. Geometric mean ratios (TT/PP; 90% confidence interval) for EFV400 maximum observed plasma concentration, area under the curve, and plasma concentration measured 24 hours after the observed dose were 0.97 (.85-1.10), 0.87 (.76-.99), and 0.77 (.65-.91), respectively. Five of 25 WLWH were slow metabolizers.
Conclusions: Although EFV400 pharmacokinetic parameters were slightly lower for TT compared with PP values, efavirenz concentrations exceeded cutoff levels established by the study and those measured in antiretroviral-naive patients receiving EFV400 in ENCORE1. All subjects maintained a viral load <50 copies/mL, suggesting that EFV400 can be used in pregnant WLWH.

PMID: 30124823 [PubMed - in process]

Human Microbiome as an Approach to Personalized Medicine.

Altern Ther Health Med. 2017 Nov;23(6):8-9

Authors: Ejtahed HS, Hasani-Ranjbar S, Larijani B

Abstract
Personalized medicine is an approach for medical decisions, practices, and interventions that considers individual variations in genes, environment, and lifestyle for each person. Regarding complex metabolic patterns associated with different diseases, characterizing unique metabolic patterns of each patient seems like a practical approach. We can imagine a future in which routinely analyzing the microbiome allows us to predict individualized responses to different foods and drugs. Microbiome analysis of individuals may be added to future routine personalized medicine protocols after comparing the costs and benefits of microbiome-sequencing technology. Moreover, improved understanding of the human microbiome could lead to the development of novel therapeutic strategies for different diseases. Potential therapeutic agents, such as personalized probiotic and prebiotic supplements, dietary interventions, and fecal microbiota transplantation that can be used to reshape the gut microbiome, represent a reasonable strategy in an era of personalized medicine.

PMID: 28987073 [PubMed - indexed for MEDLINE]

The IDO genetic polymorphisms and postpartum depressive symptoms: an association study in Chinese parturients who underwent cesarean section.

Arch Womens Ment Health. 2018 Aug 18;:

Authors: Duan KM, Wang SY, Yin JY, Li X, Ma JH, Huang ZD, Zhou YY, Yu HY, Yang M, Zhou HH, Liu ZQ

Abstract
Postpartum depressive symptoms (PDS) are not an uncommon mood disorder in postpartum women. Our previous research indicated a role for increased tryptophan (TRP) metabolism along the kynurenine pathway (KP) in the pathogenesis of PDS. Accordingly, this study was going to investigate the association of indoleamine-2,3-dioxygenase (IDO, a key enzyme of KP) genetic polymorphisms with PDS. Seven hundred twenty-five women receiving cesarean section were enrolled in this study. PDS was determined by an Edinburgh Postnatal Depression Scale (EPDS) score ≥ 13. Subsequently, 48 parturients with PDS and 48 parturients without PDS were selected for investigation of perinatal serum concentrations of TRP, kynurenine (KYN), and KYN/TRP ratio, the latter is the representative of IDO activity. In addition, seven single nucleotide polymorphisms of the IDO gene were examined. Following this genotyping, 50 parturients carrying the IDO rs10108662 AA genotype and 50 parturients carrying the IDO rs10108662 AC + CC genotype were selected for comparisons of TRP, KYN, and KYN/TRP ratio levels. This study showed the PDS incidence of 6.9% in the Chinese population, with PDS characterized by increased IDO activity (p < 0.05), versus women without PDS. We also found that the variations of IDO1 gene rs10108662 were significantly related to PDS incidence (p < 0.05). Furthermore, there was a significant difference in IDO activity between the IDO rs10108662 CA + AA, versus CC, genotypes. Our findings indicate a role of the kynurenine pathway in the development of PDS, rs10108662 genetic polymorphism resulting in changes of IDO activity might contribute to PDS pathogenesis.

PMID: 30121843 [PubMed - as supplied by publisher]

Cause-specific risk of major adverse cardiovascular outcomes and hypoglycemic in patients with type 2 diabetes: a multicenter prospective cohort study.

Endocrine. 2018 Aug 18;:

Authors: Sun B, He F, Sun L, Zhou J, Shen J, Xu J, Wu B, Liu R, Wang X, Xu H, Chen X, Zhou H, Liu Z, Zhang W

Abstract
PURPOSE: Glycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) was identified to account for the risk of cardiovascular diseases in type 2 diabetic patients, but no study evaluated the risk based on both HbA1c and FPG levels. We described the risk of major adverse cardiovascular events (MACE) and hypoglycemic in type 2 diabetic patients according to both HbA1c and FPG levels.
METHODS: With the usage of databases of Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), 1815 patients from 61 centers in China was identified and grouped according to the criterion value of HbA1c and FPG: Good glycemic control (HbA1c < 6.5%, FPG < 6.1 mmol/L); Insufficient glycemic control (HbA1c < 6.5%, FPG ≥ 6.1 mmol/L or HbA1c ≥ 6.5%, FPG < 6.1 mmol/L); Poor glycemic control (HbA1c ≥ 6.5%, FPG ≥ 6.1 mmol/L). Time-varying multivariable Cox proportional hazards models were employed.
RESULTS: Average age was 64.8 ± 5.8 years, with a median of 4.8 years of follow-up. Overall, the incidence rates of MACE were 20.6 per 1000-person-years in Good glycemic control compared with 45.9 per 1000-person-years in Insufficient glycemic control (adjusted hazard ratio (aHR): 1.99; 95% CI 1.11-3.56; p = 0.02) and 54.7 per 1000-person-years in Poor glycemic control (aHR: 2.46; 95% CI 1.38-4.40; p = 0.002), respectively. The risk of hypoglycemic was highest in Insufficient glycemic control; 67.3 per 1000-person-years compared with 46.3 per 1000-person-years in Good glycemic control (aHR: 1.62; 95% CI 1.03-2.56; p = 0.04). Apart from this, we also observed that both MACE (aHR:1.41; 95% CI 1.13-1.77; p = 0.003) and hypoglycemic episodes (aHR: 1.82; 95% CI 1.48-2.24; p < 0.001) were sufficiently more frequent in the insulin-exposed group than the non-exposed group. In a post-hoc analysis, the risk of MACE (aHR:1.43; 95% CI 1.09-1.86; p = 0.01) and hypoglycemic (aHR: 1.99; 95% CI 1.46-2.69; p < 0.001) were more pronounced in Insufficient glycemic control with insulin exposure.
CONCLUSIONS: We observed a significant association of cause-specific risk of MACE and hypoglycemic with Insufficient glycemic control, particularly with insulin exposure.

PMID: 30121774 [PubMed - as supplied by publisher]

CHST3 and CHST13 polymorphisms as predictors of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension.

Pharmacol Res. 2018 Aug 14;:

Authors: Yorifuji K, Uemura Y, Horibata S, Tsuji G, Suzuki Y, Miyagawa K, Nakayama K, Hirata KI, Kumagai S, Emoto N

Abstract
Bosentan, an endothelin receptor antagonist, has been widely used as a first-line drug for the treatment of pulmonary arterial hypertension (PAH). In addition, bosentan is approved for patients with digital ulcers related to systemic sclerosis. Liver dysfunction is a major adverse effect of bosentan and may lead to discontinuation of therapy. The purpose of this study was to identify genomic biomarkers to predict bosentan-induced liver injury. A total of 69 PAH patients were recruited into the study. An exploratory analysis of 1,936 single-nucleotide polymorphisms (SNPs) in 231 genes involved in absorption, distribution, metabolism, and elimination of multiple medications using Affimetrix DMET™ (Drug Metabolism Enzymes and Transporters) chips was performed. We extracted 16 SNPs (P <  0.05) using the Jonckheere-Terpstra trend test and multiplex logistic analysis; we identified two SNPs in two genes, CHST3 and CHST13, which are responsible for proteoglycan sulfation and were significantly associated with bosentan-induced liver injury. We constructed a predictive model for bosentan-induced liver injury (area under the curve [AUC]: 0.89, sensitivity: 82.61%, specificity: 86.05%) via receiver operating curve (ROC) analysis using 2 SNPs and 2 non-genetic factors. Two SNPs were identified as potential predictive markers for bosentan-induced liver injury in Japanese patients with pulmonary arterial hypertension. This is the first pharmacogenomics study linking proteoglycan sulfating genes to drug-induced liver dysfunction, a frequently observed clinical adverse effect of bosentan therapy. These results may provide a way to personalize PAH medicine as well as provide novel mechanistic insights to drug-induced liver dysfunction.

PMID: 30118797 [PubMed - as supplied by publisher]

Association study of Disrupted-In-Schizophrenia-1 Gene variants and Tardive Dyskinesia.

Neurosci Lett. 2018 Aug 14;:

Authors: Lu JY, Tiwari AK, Zai GC, Rastogi A, Shaikh SA, Mueller DJ, Voineskos AN, Potkin SG, Lieberman JA, Meltzer HY, Remington G, Wong AHC, Kennedy JL, Zai CC

Abstract
Tardive dyskinesia (TD) is an involuntary movement disorder that occurs in ~20% of patients after extended antipsychotic use. Its pathophysiology is unclear; however, familial patterns and gene association studies indicate an inherited component to risk. The disrupted in schizophrenia 1 (DISC1) gene was selected for analysis because it interacts with and regulates two important proteins involved in antipsychotic medication action: the dopamine D2 receptor and the cAMP phosphodiesterase type IVB (PDE4B). The D2 receptor is the obligate target of all existing antipsychotic medications, and PDE4B hydrolyzes cAMP, a core signaling molecule activated by agonist binding to the D2 receptor. Notably, PDE4B inhibitors such as rolipram have been shown to reduce TD-like behaviours in animal models. Nine single-nucleotide polymorphisms (SNPs) in the DISC1 gene were investigated in a sample of 193 chronic schizophrenia patients for association with the presence and severity of TD, with age and sex as additional variables. TD severity was measured using the Abnormal Involuntary Movement Scale (AIMS). Two DISC1 SNPs were associated with TD severity (uncorrected p < 0.05), but these findings did not survive correction for multiple testing. This preliminary investigation suggests that DISC1 gene variants do not affect risk for TD or severity.

PMID: 30118782 [PubMed - as supplied by publisher]

Oncology Nurses' Knowledge of Pharmacogenomics Before and After Implementation of an Education Module.

Oncol Nurs Forum. 2018 Sep 01;45(5):575-580

Authors: Dodson C

Abstract
OBJECTIVES: To assess the efficacy of an interactive continuing education module in improving knowledge of pharmacogenomics in oncology nursing practice.
SAMPLE &AMP; SETTING: 434 inpatient and outpatient oncology nurses from a large teaching hospital in Florida and oncology nurses who practice in North Carolina.
METHODS &AMP; VARIABLES: An interactive continuing education module was created based on key information elicited from a focus group of inpatient and outpatient oncology nurses regarding their lack of knowledge on pharmacogenomics. A pre-/post-test design was implemented. Purposive sampling of oncology nurses was used.
RESULTS: The mean pretest score was 72.7 and the post-test score was 85.9. A statistically significant difference was found between these scores. No difference in scores were found between the oncology nurses employed at urban hospitals compared to nurses at community hospitals or outpatient settings.
IMPLICATIONS FOR NURSING: Educational opportunities for pharmacogenomics should be threaded throughout nursing competencies. The continuing education module in the current article has been shown to significantly improve oncology nurses' knowledge of genomic and pharmacogenomic information.

PMID: 30118446 [PubMed - in process]