Genotyping and phenotyping CYP3A4\CYP3A5: no association with antiplatelet effect of clopidogrel.

Mol Biol Rep. 2019 May 17;:

Authors: Mirzaev KB, Samsonova KI, Potapov PP, Andreev DA, Grishina EA, Ryzhikova KA, Sychev DA

Abstract
The objective of this study was to determine the impact of polymorphism of CYP3A subfamily isoenzymes (allelic variants of CYP3A4*22 and CYP3A5*3) on the efficacy clopidogrel in patients with an acute coronary syndrome (ACS), who have undergone percutaneous coronary intervention (PCI). Platelet activity was determined on a VerifyNow P2Y12 test system in 81 patients with ACS aged 37-91 who had PCI. The activity of CYP3A4/5 was expressed as the ratio of the concentrations of cortisol and 6β-hydroxycortisol was performed by using high performance liquid chromatography. Genotyping was performed by using real-time polymerase real-time chain reaction. The frequencies for the CYP3A5 gene, rs 776746, were identified as follows: 77 (95.1%)-CC, 4 (4.9%)-CT; the allele frequencies by loci for the CYP3A4, rs rs35599367, were as follows: 78 (96.3%)-GG, 3 (3.7%)-AG. There was no statistically significant genotype-dependent difference between the presence of a minor T and G alleles and the presence of clopidogrel resistance (OR 3.53; 95% CI 0.46-26.94; p = 0.233 and p = 0.443, respectively). The average level of the metabolic relationship (6β-hydroxycortisol/cortisol) between the clopidogrel-resistant group and the normal platelet reactivity group was not statistically significantly different: 3.3 ± 2.8 versus 3.2 ± 3.2; p = 0.947. So, the activity of CYP3A4/5 was not related to platelet aggregation rates in this model. Genotyping and phenotyping CYP3A4\CYP3A5 does not predict the antiplatelet effect of clopidogrel. More extensive research is required to establish their clinical relevance.

PMID: 31102151 [PubMed - as supplied by publisher]

Optimising migraine treatment: from drug-drug interactions to personalized medicine.

J Headache Pain. 2019 May 17;20(1):56

Authors: Pomes LM, Guglielmetti M, Bertamino E, Simmaco M, Borro M, Martelletti P

Abstract
Migraine is the most disabling and expensive chronic disorders, the etiology of which is still not fully known. The neuronal systems, (glutammatergic, dopaminergic, serotoninergic and GABA-ergic) whose functionality is partly attributable to genetically determined factors, has been suggested to play an important role. The treatment of acute attacks and the prophylactic management of chronic forms include the use of different category of drugs, and it is demonstrated that not each subject has the same clinical answer to them. The reason of this is to be searched in different functional capacity and quantity of phase I enzymes (such as different isoforms of CYP P450), phase II enzymes (such as UDP-glucuronosyltransferases), receptors (such as OPRM1 for opioids) and transporters (such as ABCB1) involved in the metabolic destiny of each drug, all of these dictated by DNA and RNA variations. The general picture is further exacerbated by the need for polytherapies, often also to treat comorbidities, which may interfere with the pharmacological action of anti-migraine drugs. Personalized medicine has the objective of setting the optimal therapies in the light of the functional biochemical asset and of the comorbidities of the individual patient, in order to obtain the best clinical response. Novel therapeutic perspectives in migraine includes biotechnological drugs directed against molecules (such as CGRP and its receptor) that cause vasodilatation at the peripheral level of the meningeal blood vessels and reflex stimulation of the parasympathetic system. Drug-drug interactions and the possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale. Drug-drug interactions and their possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale.

PMID: 31101004 [PubMed - in process]

Association study of polymorphisms within inflammatory genes and methylation status in treatment response in major depression.

Eur Psychiatry. 2019 May 14;60:7-13

Authors: Draganov M, Arranz MJ, Salazar J, de Diego-Adeliño J, Gallego-Fabrega C, Jubero M, Carceller-Sindreu M, Portella MJ

Abstract
BACKGROUND: Although pharmacogenetics for major depressive disorder (MDD) is gaining momentum, the role of genetics in differences in response to antidepressant treatment is controversial, as they depend on multifactorial and polygenic phenotypes. Previous studies focused on the genes of the serotonergic system, leaving apart other pathological factors such as the inflammatory pathway. The main objective of the study was to assess whether treatment response might be associated with specific inflammation-related genetic variants or their methylation status.
METHODS: 41 SNPs in 8 inflammatory genes: interleukin (IL) 1-β, IL2, IL6, IL6R, IL10, IL18, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were genotyped in 153 patients with MDD, who were evaluated with the Mausdley Staging Method to determine treatment response profiles. Pyrosequencing reactions and methylation quantification were performed in a PyroMark Q24 in 5 selected CpG islands of IL1- β, IL6 and IL6R. Linear and logistic regression analyses were conducted, including age and gender as covariates using PLINK 1.07.
RESULTS: Allelic distribution of IL1- β rs1143643 was significantly associated with MSM scores (FDR corrected p = 0.04). Allelic distribution of IL6R rs57569414 showed a trend towards significance with MSM scores (p = 0.002; FDR corrected p = 0.07). Haplotype analyses showed associations between allelic combinations of IL1-β and IL10 with treatment response (FDR corrected p < 0.01). Methylation percentage of treatment responders was only higher in an IL6R CpG island (p < 0.05).
CONCLUSIONS: These exploratory findings suggest that IL1-β and, marginally, IL6R polymorphisms may affect treatment response in major depression. If confirmed, these results may account for the heterogeneous phenotypes of major depression that underlie differences in treatment response.

PMID: 31100612 [PubMed - as supplied by publisher]

Pharmacogenetics of treatments for pancreatic cancer.

Expert Opin Drug Metab Toxicol. 2019 May 17;:

Authors: El Hassouni B, Li Petri G, Liu D, Cascioferro S, Parrino B, Hassan W, Diana P, Ali A, Frampton AE, Giovannetti E

Abstract
INTRODUCTION: Despite many clinical efforts, pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate. The scarcity of effective therapies can be reflected by the lack of reliable biomarkers to adapt the prescription of anticancer drugs to tumors' and patients' features. Areas covered: Pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best matches the individual and tumor genetic profile, but it has not yet led to gains in clinical outcome. The present review describes the main findings on PDAC pharmacogenetics, critically reappraising the studies on polymorphisms and -omics profiles correlated to response to gemcitabine, FOLFIRINOX and nab-paclitaxel combinations, as well as limitations of targeted therapies. Further, the authors question whether these personalized approaches will benefit patients to any significant degree, supporting the need of new strategies within well-designed trials and validated genomic tests for treatment decision-making. Expert Opinion: A major challenge in PDAC is the identification of subgroups of patients who will benefit from specific treatments. Ideally, minimally-invasive tests to analyze biomarkers of drug sensitivity/toxicity should be developed alongside anticancer treatments. However, progress might fall below expectations because of the challenges of tumor heterogeneity and clonal evolution. Whole-genome sequencing and liquid biopsies, as well as prospective validation in selected cohorts of patients, should overcome the limitations of the traditional pharmacogenetic approaches.

PMID: 31100206 [PubMed - as supplied by publisher]

Precision Medicine in Autoimmune Hepatitis.

J Dig Dis. 2019 May 17;:

Authors: Chen RL, Wang QX, Ma X

Abstract
Autoimmune hepatitis (AIH) is an autoimmune liver disease induced by environmental factors in genetically susceptible individuals. AIH is characterized by hypergammaglobulinemia, elevation of serum autoantibodies and transaminases and interface hepatitis. Because of its diverse clinical manifestations, a high heterogenicity of AIH in clinical diagnosis and treatment makes it significant to perform personalized therapy. Precision medicine has recently been a novel therapeutic pattern other than evidence-based medicine, with the aim of achieving personalized therapy. In this review we demonstrated the research progress of precision medicine in AIH through an exploration of genetic susceptible genes, precision diagnosis and prognosis, pharmacogenomics and precision medication, and precision treatment of special types.

PMID: 31099976 [PubMed - as supplied by publisher]

Personalized Nutrition: Translating the Science of NutriGenomics Into Practice: Proceedings From the 2018 American College of Nutrition Meeting.

J Am Coll Nutr. 2019 May-Jun;38(4):287-301

Authors: Aruoma OI, Hausman-Cohen S, Pizano J, Schmidt MA, Minich DM, Joffe Y, Brandhorst S, Evans SJ, Brady DM

Abstract
Adverse reactions to foods and adverse drug reactions are inherent in product defects, medication errors, and differences in individual drug exposure. Pharmacogenetics is the study of genetic causes of individual variations in drug response and pharmacogenomics more broadly involves genome-wide analysis of the genetic determinants of drug efficacy and toxicity. The similarity of nutritional genomics and pharmacogenomics stems from the innate goal to identify genetic variants associated with metabolism and disease. Thus, nutrigenomics can be thought of as encompassing gene-diet interactions involving diverse compounds that are present in even the simplest foods. The advances in the knowledge base of the complex interactions among genotype, diet, lifestyle, and environment is the cornerstone that continues to elicit changes in current medical practice to ultimately yield personalized nutrition recommendations for health and risk assessment. This information could be used to understand how foods and dietary supplements uniquely affect the health of individuals and, hence, wellness. The individual's gut microbiota is not only paramount but pivotal in embracing the multiple-functional relationships with complex metabolic mechanisms involved in maintaining cellular homeostasis. The genetic revolution has ushered in an exciting era, one in which many new opportunities are expected for nutrition professionals with expertise in nutritional genomics. The American College of Nutrition's conference focused on "Personalized Nutrition: Translating the Science of NutriGenomics Into Practice" was designed to help to provide the education needed for the professional engagement of providers in the personalized medicine era.

PMID: 31099726 [PubMed - in process]

Renal Fibrosis, Immune Cell Infiltration and Changes of TRPC Channel Expression after Unilateral Ureteral Obstruction in Trpc6-/- Mice.

Cell Physiol Biochem. 2019;52(6):1484-1502

Authors: Kong W, Haschler TN, Nürnberg B, Krämer S, Gollasch M, Markó L

Abstract
BACKGROUND/AIMS: The transient receptor potential cation channel subfamily C member 6 (TRPC6) is a Ca2+-permeable nonselective cation channel and has received recent attention because of its capability to promote chronic kidney disease (CKD). The aims of this study were (i) to examine whether deletion of TRPC6 impacts on renal fibrosis and inflammatory cell infiltration in an early CKD model of unilateral ureter obstruction (UUO) in mice; and (ii) whether TRPC6-deficiency as well as UUO affect the regulation of TRPC expression in murine kidneys.
METHODS: Wild-type (WT), Trpc6-knockout (Trpc6-/-) and New Zealand obese (NZO) mice underwent sham operation or unilateral ureteral obstruction (UUO). The kidneys were harvested 7 days after surgery. We examined renal fibrosis and inflammatory cell infiltration by histological and immunohistochemical staining. The mRNA expression of TRPC members and markers of fibrosis and inflammation in kidney were assessed by using real-time quantitative reverse transcription PCR.
RESULTS: Histological and immunohistochemical analyses revealed less inflammatory cell infiltration (F4/80 and CD3) in UUO kidneys of Trpc6-/- mice compared to UUO kidneys of WT mice as well as less fibrosis. Genomic deletion of TRPC6 also affected the expression of pro-fibrotic genes in UUO Trpc6-/- kidneys compared to UUO WT kidneys while the expression of pro-inflammatory genes did not differ. UUO caused marked up-regulation of Trpc6 and down-regulation of Trpc1 mRNA in kidneys of WT and NZO mice. Trpc3 mRNA expression was significantly elevated in kidneys of Trpc6-/- mice underwent UUO while the levels did not change in kidneys of neither WT nor in NZO mice underwent UUO.
CONCLUSION: TRPC6 contributes to renal fibrosis and immune cell infiltration in the UUO mouse model. Therefore, inhibition of TRPC6 emerges as a promising novel therapeutic strategy for treatment of chronic kidney failure in chronic obstructive nephropathy. However, confounding genomic and non-genomic effects of other TRPC channels should be taken into consideration to fully comprehend the renoprotective potential of targeting TRPC6 therapeutically under chronic kidney damaging conditions.

PMID: 31099508 [PubMed - in process]

Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway.

Science. 2019 05 17;364(6441):

Authors: Lee YR, Chen M, Lee JD, Zhang J, Lin SY, Fu TM, Chen H, Ishikawa T, Chiang SY, Katon J, Zhang Y, Shulga YV, Bester AC, Fung J, Monteleone E, Wan L, Shen C, Hsu CH, Papa A, Clohessy JG, Teruya-Feldstein J, Jain S, Wu H, Matesic L, Chen RH, Wei W, Pandolfi PP

Abstract
Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain-containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1 appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.

PMID: 31097636 [PubMed - in process]

Transforming growth factor alpha promotes tumorigenesis and regulates epithelial-mesenchymal transition modulation in colon cancer.

Biochem Biophys Res Commun. 2018 12 02;506(4):901-906

Authors: Yu CY, Chang WC, Zheng JH, Hung WH, Cho EC

Abstract
Colon cancer is one of the most common cancers in the developed countries. The association between transforming growth factor TGFα and human cancer incidence has been suggested, yet, the regulatory roles of TGFα and the molecular mechanisms remain unknown, especially in colon cancer. We aim to investigate the functional regulations of TGFα in colon cancer progression. Two colon cancer cell lines were applied, and plasmid overexpression and siRNA-mediated depletion techniques were used to verify the role of TGFα in colon cancer. Cell proliferation was analyzed by MTS assay and colony formation assay, and western blot assay was used to examine protein expression. Migration, invasion, and reporter assays were also carried out to study the regulations of TGFα in colon cancer. Our results evidenced that expression of TGFα facilitates short-term and long-term proliferations of colon cancer cells. Moreover, TGFα was suggested as a migration-and-invasion promoting factor of colon cancer. Finally, our data indicated that TGFα modulates epithelial-mesenchymal transition (EMT) markers and NFκB signaling pathway in colon cancer cells. We provide the first time evidence of the promoting role TGFα plays in colon cancer tumorigenesis with proposed regulatory mechanisms involving EMT alteration and NFκB signaling pathway.

PMID: 30392905 [PubMed - indexed for MEDLINE]

Drug-induced interstitial lung disease: role of pharmacogenetics in predicting cytotoxic mechanisms and risks of side effects.

Curr Opin Pulm Med. 2019 May 06;:

Authors: Jessurun NT, Drent M, van Puijenbroek EP, Bekers O, Wijnen PA, Bast A

Abstract
PURPOSE OF REVIEW: The diagnosis of drug-induced interstitial lung disease (DI-ILD) is challenging and mainly made by exclusion of other possible causes. Toxicity can occur as a cause of drug(s) or drug-drug interactions. In this review, we summarize the possible role of pharmacogenetics of metabolizing enzymes in DI-ILD.
RECENT FINDINGS: Knowledge of the genetic predispositions of enzymes involved in drug metabolization and their relation with proposed cytotoxic mechanisms of DI-ILD, in particular direct cell toxicity and free oxygen radical production is increasing. The cytochrome P450 enzyme family and other enzymes play an important role in the metabolism of all sorts of ingested, injected, or inhaled xenobiotic substances. The liver is the major site for metabolism. Metabolic cytotoxic mechanisms have however also been detected in lung tissue. Polymorphisms in genes coding for enzymes that influence metabolic activity may lead to localized (toxic) reactions and tissue damage. This knowledge may be helpful in preventing the risk of DI-ILD.
SUMMARY: Drug toxicity can be the consequence of absence or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, it is recommended to reduce the dose or to prescribe an alternative drug, which is metabolized by a different, unaffected enzyme system to prevent toxic side effects. However, enhanced enzyme activity may lead to excessive formation of toxic and sometimes reactive metabolites. Therefore, knowing a patient's drug-metabolizing profile before drug prescription is a promising way to prevent or explain DI-ILD.

PMID: 31094717 [PubMed - as supplied by publisher]

The European Association for Clinical Pharmacology and Therapeutics-25 years' young and going strong.

Eur J Clin Pharmacol. 2019 May 16;:

Authors: Coleman JJ, Samer C, Zeitlinger M, van Agtmael M, Rongen GA, Marquet P, Simon T, Singer D, Manolopoulos VG, Böttiger Y

Abstract
Clinical pharmacology as a scientific discipline and medical specialty was unarguably born in the twentieth century. Whilst pharmacology-the science behind the treatment of disease-had been in evolution since at least medieval times, the clinical discipline of pharmacology has had a more recent genesis and rather insidious evolution. During the 1900s, there were some clear father (parent) figures of clinical pharmacology in Europe that emerged and were responsible for the development of the specialty in this continent. This was a time when there were parallel developments in geographically dispersed academic departments (around the globe), during an age of excitement in drug discovery and clinical application of new therapeutic agents. It was the meeting of minds of some of these progenitors of the specialty that led to the development of the European Association for Clinical Pharmacology and Therapeutics (EACPT) 25 years ago arising from a working party supported by the World Health Organization in Europe. The EACPT now includes all major national organizations for clinical pharmacology in Europe, representing over 4000 individual professionals interested in clinical pharmacology and therapeutics. The EACPT has a major interest in promoting the safe use of medicines across Europe and internationally and has supported these aims since 1995, through biennial international scientific congresses and summer schools with delegates and presenters from around the world as well as various working group activities. In this article, the current executive committee members of EACPT recall this history, describe the evolution of the association over the last quarter of a century, and provide an update on the activities and ambitions of the association today.

PMID: 31093706 [PubMed - as supplied by publisher]

The Role of Early-Phase Design-Letter.

Clin Cancer Res. 2019 May 15;25(10):3190

Authors: Ratain MJ

PMID: 31092614 [PubMed - in process]

Fifteen-minute consultation: Pharmacogenomics: a guide for busy clinicians.

Arch Dis Child Educ Pract Ed. 2019 May 15;:

Authors: Parry CM, Hawcutt D

Abstract
The ultimate goal of pharmacogenomics is to understand how the effects of interindividual genetic variation impact on the response of patients to treatments and in turn optimise those treatments while minimising potential side effects. This review article provides a brief overview of pharmacogenomics, focusing on the methods used to understand how genes of interest are identified, how pharmacogenomics is currently used within paediatric clinical practice within the UK, potential areas for future use and some of the caveats specific to paediatric medicine.

PMID: 31092398 [PubMed - as supplied by publisher]

Correction to: Similarities and differences between variants called with human reference genome HG19 or HG38.

BMC Bioinformatics. 2019 May 15;20(1):252

Authors: Pan B, Kusko R, Xiao W, Zheng Y, Liu Z, Xiao C, Sakkiah S, Guo W, Gong P, Zhang C, Ge W, Shi L, Tong W, Hong H

Abstract
After publication of this supplement article.

PMID: 31092200 [PubMed - in process]

Uridine diphosphate glucuronosyltransferase 1A1.

Xenobiotica. 2019 May 16;:1-47

Authors: Steventon G

Abstract
1. The role that the phase II reaction, glucuronidation, plays in the biotransformation of endo and xenobiotics is discussed with particular emphasis given to the UGT1A1 isoenzyme. This individual isoenzyme is responsible for both the mono and di-glucuronidation of bilirubin together with the glucuronidation of a number of xenobiotics of clinical interest (irinotecan, belinostat, atazanavir, pegvisomant). 2. The review than discusses the roles that the various allelic variants of the UGT1A1 gene play in bilirubin metabolism are and in particular how these allelic variants are involved in the clinical manifestation of the diseases of GS, CN1 and CN2 . 3. The review concludes with the roles that the UGT1A1*28 and UGT1A1*6 alleles play in adverse drug reactions (decreased glucuronidation of irinotecan, belinostat, atazanavir, pegvisomant) leading to increased exposure, reduced clearance and neutropenia (irinotecan, belinostat), increased risk for jaundice and hyperbilirubinaemia (atazanavir) and liver toxicity (pegvisomant) before discussing the future role of UGT1A1 in personalised medicine.

PMID: 31092094 [PubMed - as supplied by publisher]

Relevance of MTHFR polymorphisms with response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer: a meta-analysis.

BMJ Open. 2018 05 26;8(5):e020767

Authors: Zhong L, Fu Q, Zhou S, Chen L, Peng Q

Abstract
OBJECTIVE: To evaluate the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer.
DESIGN: Meta-analysis.
METHODS: We searched PubMed, Embase and Web of Science databases from inception up to October 2017 for relevant studies. The statistical analysis was performed using STATA V.12.0 software. The pooled ORs and 95% CIs were used to assess the strength of the association under the allele, dominant and recessive models. We also conducted subgroup analysis stratified by cancer type, ethnicity and study design. Additionally, the sensitivity analysis was performed by sequential omission of individual studies, and the publication bias was detected using both Begg's test and Egger's test.
RESULTS: A total of 2020 patients from 12 studies were included in this meta-analysis. The results showed that there was no significant association between MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms and the clinical response to fluoropyrimidine-based chemotherapy under all of the three genetic models (T vs C: OR 0.93, 95% CI 0.76 to 1.15; C vs A: OR 0.88, 95% CI 0.56 to 1.40. CT+TT vs CC: OR 0.94, 95% CI 0.72 to 1.23; AC+CC vs AA: OR 0.80, 95% CI 0.47 to 1.35. TT vs CC+CT: OR 1.02, 95% CI 0.74 to 1.39; CC vs AA+AC: OR 1.15, 95% CI 0.50 to 2.67). When stratified by cancer type, ethnicity or study design, the association was still not significant in all subgroups.
CONCLUSIONS: This meta-analysis suggested that MTHFR polymorphisms could not be considered as reliable factors for predicting the response to fluoropyrimidine-based chemotherapy in oesophagogastric cancer.

PMID: 29804062 [PubMed - indexed for MEDLINE]

Sex differences in behavior and neuropharmacology of zebrafish.

Eur J Neurosci. 2019 May 15;:

Authors: Genario R, de Abreu MS, Giacomini ACVV, Demin KA, Kalueff AV

Abstract
Sex is an important variable in biomedical research. The zebrafish (Danio rerio) is increasingly utilized as a powerful new model organism in translational neuroscience and pharmacology. Mounting evidence indicates important sex differences in zebrafish behavioral and neuropharmacological responses. Here, we discuss the role of sex in zebrafish central nervous system (CNS) models, their molecular mechanisms, recent findings and the existing challenges in this field. We also emphasize the growing utility of zebrafish models in translational neuropharmacological research of sex differences, fostering future CNS drug discovery and the search for novel sex-specific therapies. Finally, we highlight the interplay between sex and environment in zebrafish models of sex-environment correlations as an important strategy of CNS disease modeling using this aquatic organism. This article is protected by copyright. All rights reserved.

PMID: 31090957 [PubMed - as supplied by publisher]

β2 -Adrenergic Receptor Gene Affects the Heart Rate Response of β-Blockers: Evidence From 3 Clinical Studies.

J Clin Pharmacol. 2019 May 14;:

Authors: Shahin MH, Rouby NE, Conrado DJ, Gonzalez D, Gong Y, Lobmeyer MT, Beitelshees AL, Boerwinkle E, Gums JG, Chapman A, Turner ST, Pepine CJ, Cooper-DeHoff RM, Johnson JA

Abstract
β-Blockers' heart rate (HR)-lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β-blocker-treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β-blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single-nucleotide polymorphisms (SNPs) previously associated with the HR response to β-blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β-blocker used in the PEAR (n = 757), PEAR-2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR-2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β-blockers in whites (rs1042714 C-allele carriers, meta-analysis β = -0.95 beats per minute [bpm], meta-analysis P = 3×10-4 ; rs1042713 A-allele carriers, meta-analysis β = -1.15 bpm, meta-analysis P = 2×10-3 ). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β-blockade in hypertensive patient cohorts.

PMID: 31090079 [PubMed - as supplied by publisher]

Novel predictive epigenetic signature for temozolomide in non-G-CIMP glioblastomas.

Clin Epigenetics. 2019 May 14;11(1):76

Authors: Yin AA, He YL, Etcheverry A, Liu YH, Aubry M, Barnholtz-Sloan J, Liu BL, Mosser J, Lu ZF, Zhang X

Abstract
OBJECTIVE: To identify novel epigenetic signatures that could provide predictive information that is complementary to promoter methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) gene for predicting temozolomide (TMZ) response, among glioblastomas (GBMs) without glioma-CpGs island methylator phenotype (G-CIMP) METHODS: Different cohorts of primary non-G-CIMP GBMs with genome-wide DNA methylation microarray data were included for discovery and validation of a multimarker signature, combined using a RISK score model. Different statistical analyses and functional experiments were performed for clinical and biological validation.
RESULTS: By employing discovery cohorts with radiotherapy (RT) and TMZ versus RT alone and a strict multistep selection strategy, we identified seven CpGs, each of which was significantly correlated with overall survival (OS) of non-G-CIMP GBMs with RT/TMZ, independent of age, MGMT promoter methylation status, and other identified CpGs. A RISK score signature of the 7 CpGs was developed and validated to distinguish non-G-CIMP GBMs with differential survival outcomes to RT/TMZ, but not to RT alone. The interaction analyses also showed differential outcomes to RT/TMZ versus RT alone within the RISK score-based subgroups. The signature could also improve the risk classification by age and MGMT promoter methylation status. Functional experiments showed that HSBP2 appeared to be epigenetically regulated by one identified CpG and was associated with TMZ resistance, but it was not associated with cell proliferation or apoptosis in GBM cell lines. The predictive value of the single CpG methylation of HSBP2 by pyrosequencing was observed in a local cohort of isocitrate dehydrogenase 1 (IDH1) R132H wild-type GBMs.
CONCLUSIONS: This novel epigenetic signature might be a promising predictive (but not a general prognostic) biomarker and be helpful for refining the MGMT-based guiding approach to TMZ usage in non-G-CIMP GBMs.

PMID: 31088577 [PubMed - in process]

Decreased H3K9ac level of AT2R mediates the developmental origin of glomerulosclerosis induced by prenatal dexamethasone exposure in male offspring rats.

Toxicology. 2019 01 01;411:32-42

Authors: Li B, Zhu Y, Chen H, Gao H, He H, Zuo N, Pei L, Xie W, Chen L, Ao Y, Wang H

Abstract
This study aimed to demonstrate that prenatal dexamethasone exposure (PDE) can induce kidney dysplasia in utero and adult glomerulosclerosis in male offspring, and to explore the underlying intrauterine programming mechanisms. Pregnant rats were subcutaneously administered dexamethasone 0.2 mg/kg.d from gestational day (GD) 9 to GD20. The male fetus on GD20 and the adult offspring at age of postnatal week 28 were analyzed. The adult offspring kidneys in the PDE group displayed glomerulosclerosis, elevated levels of serum creatinine and urine protein, ultrastructural damage of podocytes, the reduced expression levels of podocyte marker genes, nephrin and podocin. The histone 3 lysine 9 acetylation (H3K9ac) level in the promoter of renal angiotensin II receptor type 2 (AT2R) and its expression were reduced, whereas the angiotensin II receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PDE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio, reduced the expression level of glial-cell-line derived neurotrophic factor/c-Ret tyrosine kinase receptor (GDNF/c-Ret) signal pathway and podocyte marker genes. Moreover, the H3K9ac and H3K27ac levels of AT2R as well as the gene and protein expression levels of AT2R in fetal kidneys were inhibited by PDE. In vitro, primary metanephric mesenchyme stem cells (MMSCs) were treated with dexamethasone. Overexpression of AT2R reversed the inhibited expression of GDNF/c-Ret and podocin/nephrin induced by dexamethasone, and glucocorticoids receptor antagonist abolished the decreased H3K9ac level and gene expression of AT2R. In conclusion, PDE induced the offspring's kidney dysplasia as well as adult glomerulosclerosis, which was mediated by a sustained decrease in renal AT2R expression via decreasing the H3 K9ac level.

PMID: 30359671 [PubMed - indexed for MEDLINE]