Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity.

Pharmacol Ther. 2019 Jan 21;:

Authors: Lauschke VM, Zhou Y, Ingelman-Sundberg M

Abstract
Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools. In this review we present an updated overview of current and emerging pharmacogenomic biomarkers in different therapeutic areas and critically discuss their potential to transform clinical care. Furthermore, we discuss opportunities of technological, methodological and institutional advances to improve biomarker discovery. We also summarize recent progress in our understanding of epigenetic effects on drug disposition and response, including a discussion of the only few pharmacogenomic biomarkers implemented into routine care. We anticipate, in part due to exciting rapid developments in Next Generation Sequencing technologies, machine learning methods and national biobanks, that the field will make great advances in the upcoming years towards unlocking the full potential of genomic data.

PMID: 30677473 [PubMed - as supplied by publisher]

Tamoxifen Pharmacogenetics and Metabolism: Results From the Prospective CYPTAM Study.

J Clin Oncol. 2019 Jan 24;:JCO1800307

Authors: Sanchez-Spitman A, Dezentjé V, Swen J, Moes DJAR, Böhringer S, Batman E, van Druten E, Smorenburg C, van Bochove A, Zeillemaker A, Jongen L, Los M, Neven P, Gelderblom H, Guchelaar HJ

Abstract
PURPOSE: Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM (The Netherlands National Trial Register: NTR1509) study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome in patients with early-stage breast cancer receiving tamoxifen.
PATIENTS AND METHODS: From February 2008 to December 2010, patients with breast cancer treated with adjuvant tamoxifen were included. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation. Blood samples were retrieved for CYP2D6 genotyping and endoxifen measurements by Amplichip (Roche Diagnostics, Indianapolis, IN) and high-performance liquid chromatography-tandem mass spectrometry, respectively. Endoxifen concentrations were analyzed as a continuous variable, classifying patients into quartiles and using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were associated with relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt) by Cox regression analysis.
RESULTS: A total of 667 pre- and postmenopausal patients were enrolled and had received tamoxifen for a median time of 0.37 years (range, 0.23 to 0.6 years) before study entry. No association was found between endoxifen concentrations and RFSt (adjusted hazard ratio, 0.991; 95% CI, 0.946 to 1.038; P = .691). Also, neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results. In addition, no association was found between CYP2D6 genotype and RFSt (adjusted hazard ratio, 0.929; 95% CI, 0.525 to 1.642; P = .799).
CONCLUSION: This prospective clinical study shows no association between endoxifen concentrations or CYP2D6 genotypes and clinical outcome in patients with early-stage breast cancer receiving adjuvant tamoxifen.

PMID: 30676859 [PubMed - as supplied by publisher]

Metastatic Tumor-In-A-Dish, A Novel Multi-Cellular Organoid to Study Lung Colonization and Predict Therapeutic Response.

Cancer Res. 2019 Jan 23;:

Authors: Ramamoorthy P, Thomas SM, Kaushik G, Subramaniam D, Chastain KM, Dhar A, Tawfik O, Kasi A, Sun W, Ramalingam S, Gunewardena S, Umar S, Mammen JMV, Padhye SB, Weir SJ, Jensen RA, Sittampalam GS, Anant S

Abstract
Metastasis is a major cause of cancer-related deaths. A dearth in preclinical models that recapitulates the metastatic microenvironment has impeded the development of therapeutic agents that are effective against metastatic disease. Since the majority of solid tumors metastasize to the lung, we developed a multi-cellular lung organoid that mimics the lung microenvironment with air sac like structures and production of lung surfactant protein. We used these cultures called primitive lung-in-a-dish (PLiD), to recreate metastatic disease using primary and established cancer cells. The metastatic tumor-in-a-dish (mTiD) cultures resemble the architecture of metastatic tumors in the lung including angiogenesis. Pretreating PLiD with tumor exosomes enhanced cancer cell colonization. We next tested the response of primary and established cancer cells to current chemotherapeutic agents and an anti-VEGF antibody in mTiD against cancer cells in 2-dimensional (2D) or 3D cultures. The response of primary patient-derived colon and ovarian tumor cells to therapy in mTiD cultures matched the response of the patient in the clinic, but not 2D or single cell type 3D cultures. The sensitive mTiD cultures also produced significantly lower circulating markers for cancer similar to that seen in patients that responded to therapy. Thus, we have developed a novel method for tumor colonization in vitro, a final stage in tumor metastasis. Moreover, the technique has significant utility in precision/personalized medicine, wherein this phenotypic screen can be coupled with current DNA pharmacogenetics to identify the ideal therapeutic agent, thereby increasing the probability of response to treatment while reducing unnecessary side effects.

PMID: 30674533 [PubMed - as supplied by publisher]

Influence of Vitamin D in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab.

Cancers (Basel). 2019 Jan 21;11(1):

Authors: Cusato J, Genova C, Tomasello C, Carrega P, Ottonello S, Pietra G, Mingari MC, Cossu I, Rijavec E, Leggieri A, Perri GD, Bello MGD, Coco S, Boccardo S, Ferlazzo G, Grossi F, D'Avolio A

Abstract
Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug metabolism and elimination. Immune system regulation and immunodeficiency is frequent in non-small cell lung cancer patients. To date, no data have been reported about the relationship between nivolumab and VD. The aim of this study was to quantify plasma 25-hydroxyVD (25-VD) and 1,25-VD, nivolumab, and its anti-antibody before starting treatment (baseline) and at 15, 45 and 60 days of therapy. VD-pathway-associated gene single nucleotide polymorphisms (SNPs) were also evaluated. Molecules were quantified through enzyme-linked immunosorbent assay, and SNPs through real-time PCR. Forty-five patients were enrolled. Median nivolumab concentrations were 12.5 ug/mL, 22.3 ug/mL and 27.1 ug/mL at 15, 45 and 60 days respectively. No anti-nivolumab antibodies were found. Correlations were observed between nivolumab concentrations and 25-VD levels. Nivolumab concentrations were affected by VD-pathway-related gene SNPs. VDBP AC/CC genotype and baseline 25-VD < 10 ng/mL predicted a nivolumab concentration cut-off value of <18.7ug/mL at 15 days, which was associated with tumor progression. This is the first study showing VD marker predictors of nivolumab concentrations in a real-life context of non-small cell lung cancer treatment.

PMID: 30669662 [PubMed]

Towards pharmacogenetic-based treatment in psychiatry.

J Neural Transm (Vienna). 2019 Jan 23;:

Authors: Bousman CA, Menke A, Müller DJ

Abstract

PMID: 30673860 [PubMed - as supplied by publisher]

Germline BRCA2 K3326X and CHEK2 I157T Mutations Increase Risk for Sporadic Pancreatic Ductal Adenocarcinoma.

Int J Cancer. 2019 Jan 23;:

Authors: Obazee O, Archibugi L, Andriulli A, Soucek P, Małecka-Panas E, Ivanauskas A, Johnson T, Gazouli M, Pausch T, Lawlor RT, Cavestro GM, Milanetto AC, Di Leo M, Pasquali C, Hegyi P, Szentesi A, Radu CE, Gheorghe C, Theodoropoulos GE, Bergmann F, Brenner H, Vodickova L, Katzke V, Campa D, Strobel O, Kaiser J, Pezzilli R, Federici F, Mohelnikova-Duchonova B, Boggi U, Lemstrova R, Johansen JS, Bojesen SE, Chen I, Jensen BV, Capurso G, Pazienza V, Dervenis C, Sperti C, Mambrini A, Hackert T, Kaaks R, Basso D, Talar-Wojnarowska R, Maiello E, Izbicki JR, Cuk K, Saum KU, Cantore M, Kupcinskas J, Palmieri O, Fave GD, Landi S, Salvia R, Fogar P, Vashist YK, Scarpa A, Vodicka P, Tjaden C, Iskierka-Jazdzewska E, Canzian F

Abstract
Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with P values < 0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26 - 2.52, P = 1.19 x 10-3 and ORdom = 1.74, 95% CI = 1.15 - 2.63, P = 8.57 x 10-3 respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history. This article is protected by copyright. All rights reserved.

PMID: 30672594 [PubMed - as supplied by publisher]

Association of endothelin receptor type A rs5333 gene polymorphism with steroid response in Egyptian children with idiopathic nephrotic syndrome.

Pharmacogenomics. 2019 Jan 23;:

Authors: Ezzat GM, Ali AB, Mohamed NA, Hetta HF

Abstract
AIM: To investigate ENDRA rs5333 gene polymorphism distribution in idiopathic nephrotic syndrome (INS) and to analyze their association with response to steroid therapy, and biochemical markers of INS.
SUBJECTS & METHODS: The PCR-restriction fragment length polymorphism was used to analyze ENDRA rs5333 polymorphism in 100 children with idiopathic nephrotic syndrom (INS) and 100 healthy children. Plasma endothelin-1 were measured by ELISA.
RESULTS: The ENDRA rs5333 gene polymorphism was not associated with risk of INS. The frequency of minor allele (C) was significantly higher in the steroid resistant nephrotic syndrome group than the steroid sensitive group. The CC and TC mutant variants were associated with higher plasma levels of cholesterol, albumin, urea and 24-h urinary protein, but were not associated with risk of hypertension. The endothelin-1 plasma level was higher in INS than control and in steroid resistant nephrotic syndrome group when compared with steroid sensitive group cases.
CONCLUSION: The ENDRA rs5333 gene polymorphism may be associated with genetic predisposition to steroid resistance in INS Egyptian children.

PMID: 30672385 [PubMed - as supplied by publisher]

Polymorphisms in IGF2/H19 gene locus are associated with platinum-based chemotherapeutic response in Chinese patients with epithelial ovarian cancer.

Pharmacogenomics. 2019 Jan 23;:

Authors: Zeng Y, Li TL, Zhang HB, Deng JL, Zhang R, Sun H, Wan ZR, Liu YZ, Zhu YS, Wang G

Abstract
AIM: The present study aimed to assess the association between IGF2/H19 genetic variants and susceptibility to platinum-based chemotherapy in epithelial ovarian cancer (EOC).
METHODS: A total of 43 platinum-resistant (PR) and 138 platinum-sensitive (PS) EOC patients were recruited in our study. Twenty-one polymorphisms in IGF2/H19 locus were genotyped by Sequenom MassARRAY assay.
RESULTS: The frequencies of GG genotype in both rs3842761(C/G) and rs4244809(A/G) were significantly lower in PR group compared with those in PS group (9.76 vs 23.36%, p = 0.049; 9.76 vs 26.09%, p = 0.045; respectively). Compared with the AA genotype, rs4244809 GG genotype was associated with significantly reduced risk of platinum resistance (adjusted OR: 0.30; 95% CI: 0.10-0.91; p = 0.033). Further stratified analyses revealed that the SNPs of rs3842761 and rs4244809 were greatly related to PR risk in FIGO stage III-IV (rs3842761GG/CC+CG: adjusted OR: 0.15; 95% CI: 0.02-1.21; rs4244809 GG/AA+AG: adjusted OR: 0.24; 95% CI: 0.07-0.84; respectively) and serous adenocarcinoma subgroups (rs3842761 GG/CC+CG: adjusted OR: 0.21; 95% CI: 0.05-0.94; rs4244809 GG/AA+AG: adjusted OR: 0.19; 95% CI: 0.04-0.5; respectively), while rs7924316 polymorphism was associated with reduced risk of PR in serous adenocarcinoma subgroup as analyzed by a recessive model (rs7924316 GG/TT+TG: adjusted OR: 0.22; 95% CI: 0.05-0.98). In addition, both TCT haplotypes of rs3741206/rs3842761/rs7924316 and TC haplotype of rs3741206/rs3842761 were associated with elevated risk of PR (for the TCT haplotype of rs3741206/rs3842761/rs7924316: p = 0.049; OR: 1.69; 95% CI: 1.00-2.87; for the TC haplotype of rs3741206/rs3842761: p = 0.044; OR: 1.71; 95% CI: 1.01-2.88).
CONCLUSION: These results suggest that polymorphisms in IGF2/H19 gene locus are associated with PR risk in EOC.

PMID: 30672383 [PubMed - as supplied by publisher]

Association between genetic polymorphisms and angiotensin-converting enzyme inhibitor-induced cough: a systematic review and meta-analysis.

Pharmacogenomics. 2019 Jan 23;:

Authors: Mu G, Xiang Q, Zhou S, Xie Q, Liu Z, Zhang Z, Cui Y

Abstract
AIM: Genetic polymorphisms may influence the incidence of angiotensin-converting enzyme (ACE) inhibitor-induced cough. This study aims to investigate this association.
METHODS: Ten electronic databases and PharmGKB were systematically searched. Pooled odds ratio values and their 95% CI were used to assess the association, using the random-effects model.
RESULTS: A total of 26 studies were included in the review, 17 of them were included from two separated meta-analysis (ACE I/D or BDKRB2-58T/C). Significant association was found between ACE I/D I carriers (ACE gene insertion) and ACE inhibitor-induced cough, showing racial and age differences.
CONCLUSION: This study demonstrated that ACE I/D but not BDKRB2-58T/C polymorphism could be a predictor for the risk of ACE inhibitor-induced cough, especially in east Asians and the aged.

PMID: 30672376 [PubMed - as supplied by publisher]

CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial.

Genet Med. 2019 Jan 23;:

Authors: Smith DM, Weitzel KW, Elsey AR, Langaee T, Gong Y, Wake DT, Duong BQ, Hagen M, Harle CA, Mercado E, Nagoshi Y, Newsom K, Wright A, Rosenberg EI, Starostik P, Clare-Salzler MJ, Schmidt SO, Fillingim RB, Johnson JA, Cavallari LH

Abstract
PURPOSE: CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of CYP2D6-guided opioid prescribing on pain control.
METHODS: Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (n = 235) or usual care (n = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS® measures.
RESULTS: On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (n = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P = 0.540).
CONCLUSION: These data support the potential benefits of CYP2D6-guided pain management.

PMID: 30670877 [PubMed - as supplied by publisher]

Publisher Correction: Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles.

Nat Nanotechnol. 2019 Jan 22;:

Authors: Vu VP, Gifford GB, Chen F, Benasutti H, Wang G, Groman EV, Scheinman R, Saba L, Moghimi SM, Simberg D

Abstract
In the version of this Article originally published, a technical error led to Fig. 1a containing '!!!!!!!!' above the scale bar. This has now been corrected in all versions of the Article.

PMID: 30670872 [PubMed - as supplied by publisher]

PharmGKB summary: clobazam pathway, pharmacokinetics.

Pharmacogenet Genomics. 2018 04;28(4):110-115

Authors: Huddart R, Leeder JS, Altman RB, Klein TE

PMID: 29517622 [PubMed - indexed for MEDLINE]

Aucubin Alleviates Seizures Activity in Li-Pilocarpine-Induced Epileptic Mice: Involvement of Inhibition of Neuroinflammation and Regulation of Neurotransmission.

Neurochem Res. 2019 Jan 21;:

Authors: Chen S, Zeng X, Zong W, Wang X, Chen L, Zhou L, Li C, Huang Q, Huang X, Zeng G, Hu K, Ouyang DS

Abstract
Neuroinflammation and imbalance of neurotransmitters play pivotal roles in seizures and epileptogenesis. Aucubin (AU) is an iridoid glycoside derived from Eucommia ulmoides that possesses anti-inflammatory and neuroprotective effects. However, the anti-seizure effects of AU have not been reported so far. The present study was designed to investigate the effects of AU on pilocarpine (PILO) induced seizures and its role in the regulation of neuroinflammation and neurotransmission. We found that AU reduced seizure intensity and prolonged the latency of seizures. AU significantly attenuated the activation of astrocytes and microglia and reduced the levels of interleukine-1 beta (IL-1β), high mobility group box 1 (HMGB1), tumor necrosis factor-α (TNF-α). Furthermore, the contents of γ-aminobutyric acid (GABA) were increased while the levels of glutamate were decreased in the hippocampus with AU treatment. The expression of γ-aminobutyric acid type A receptor subunit α1 (GABAARα1) and glutamate transporter-1 (GLT-1) protein were up-regulated in AU treatment group. However, AU had no significant effect on N-methyl-d-aspartate receptor subunit 2B (NR2B) expression in status epilepticus (SE). In conclusion, our findings provide the first evidence that AU can exert anti-seizure effects by attenuating gliosis and regulating neurotransmission. The results suggest that AU may be developed as a drug candidate for the treatment of epilepsy.

PMID: 30666488 [PubMed - as supplied by publisher]

Transformation of ALK expression and PD-L1 0% to PD-L1 90% only after surgery: the need for rebiopsy in lung cancer patients.

Int Med Case Rep J. 2019;12:15-20

Authors: Kosmidis C, Koimtzis G, Giannakidis D, Tteralli N, Mantalovas S, Tsakalidis A, Tsopouridou K, Atmatzidis S, Liavas L, Zarogoulidis P

Abstract
Lung cancer is still diagnosed at a late stage although novel diagnostic techniques are in use. However, as pharmacogenomics have evolved novel targeted therapies either with tyrosine kinase inhibitors or immunotherapy can be currently used as daily treatment. We present the case of a woman with anaplastic lymphoma-positive expression and programmed death-ligand 1 (PD-L1) 0% score upon diagnosis who underwent therapeutic surgery and represented PD-L1 90% expression, however, without anaplastic lymphoma kinase expression. Transformation of the tumor or new tumor is a question to be answered for this patient and possibly we should try and direct rebiopsies for this group of targeted therapy patients.

PMID: 30666169 [PubMed]

Racial and ethnic differences in knowledge and attitudes about genetic testing in the US: Systematic review.

J Genet Couns. 2019 Jan 21;:

Authors: Canedo JR, Miller ST, Myers HF, Sanderson M

Abstract
Precision medicine has grown over the past 20 years with the availability of genetic tests and has changed the one-size-fits-all paradigm in medicine. Precision medicine innovations, such as newly available genetic tests, could potentially widen racial and ethnic disparities if access to them is unequal and if interest to use them differs across groups. The objective of this systematic review was to synthesize existing evidence on racial and ethnic differences in knowledge of and attitudes toward genetic testing among adult patients and the general public in the US, focusing on research about the use of genetic testing in general, not disease-specific tests. Twelve articles published in 1997-2017 met inclusion and exclusion criteria, with 10 including knowledge variables and seven including attitude variables. Studies found consistent patterns of lower awareness of genetic testing in general among non-Whites compared to Whites, lower factual knowledge scores among Blacks and Hispanics/Latinos, and mixed findings of differences in awareness of direct-to-consumer (DTC) genetic testing or the term precision medicine. Blacks, Hispanics/Latinos, and non-Whites generally had more concerns about genetic testing than Whites. The findings suggest that patients and the general public need access to culturally appropriate educational material about the use of genetic testing in precision medicine.

PMID: 30663831 [PubMed - as supplied by publisher]

High-throughput Nitrobenzoxadiazole-labeled Cholesterol Efflux Assay.

J Vis Exp. 2019 Jan 07;(143):

Authors: Pastor-Ibáñez R, Arnedo M, Tort O

Abstract
Atherosclerosis leads to cardiovascular disease (CVD). It is still unclear whether cholesterol-HDL (cHDL) concentration plays a causal role in atherosclerosis development. However, an important factor in early stages of atheroma plaque formation is cholesterol efflux capacity to HDL (the ability of HDL particles to accept cholesterol from macrophages) in order to avoid foam cell formation. This is a key step in avoiding the accumulation of cholesterol in the endothelium and a part of reverse cholesterol transport (RCT) to eliminate cholesterol through the liver. Cholesterol efflux capacity to serum or plasma in macrophage cell models is a promising tool that can be used as biomarker for atherosclerosis. Traditionally, [3H]-cholesterol has been used in cholesterol efflux assays. In this study, we aim to develop a safer and faster strategy using fluorescent labelled-cholesterol (NBD-cholesterol) in a cellular assay to trace the cholesterol uptake and efflux process in THP-1-derived macrophages. Finally, we optimize and standardize the NBD-cholesterol efflux method and develop a high-throughput analysis using 96-well plates.

PMID: 30663699 [PubMed - in process]

Introducing "Precision Addiction Management (PAM®)" as an Adjunctive Genetic Guided Therapy for Abusable Drugs in America.

Open Access J Behav Sci Psychol. 2018 Nov 20;1(2):1-4

Authors: Blum K, Modestino EJ, Lott L, Siwicki D, Baron D, Howeedy A, Badgaiyan RD

PMID: 30662982 [PubMed]

A Functional 5'-UTR Polymorphism of MYC Contributes to Nasopharyngeal Carcinoma Susceptibility and Chemoradiotherapy Induced Toxicities.

J Cancer. 2019;10(1):147-155

Authors: Guo Z, Wang Y, Zhao Y, Jin Y, An L, Xu H, Liu Z, Chen X, Zhou H, Wang H, Zhang W

Abstract
MYC is a transcription factor acting as a pivotal regulator of genes involved in cell cycle progression, apoptosis, differentiation and metabolism. In this study, we evaluated the association of MYC polymorphisms with nasopharyngeal carcinoma (NPC) risk and chemoradiotherapy induced toxicities among Chinese population. By using bioinformatic tools, five potential functional single nucleotide polymorphisms of MYC were genotyped in a case-control study with 684 NPC patients and 823 healthy controls. We found two SNPs rs4645948 (C>T) and rs2071346 (G>T) were significantly associated with increased risk of developing NPC (TT+CT vs CC, OR=1.557, P=3.34×10-4; TT+GT vs GG, OR=1.361, P=0.007, respectively). In addition, rs4645948 (C>T) was conferred with increased risk of anemia (CT vs CC, OR=2.152, P=0.001) and severe leukopenia (CT vs CC, OR=1.893, P=0.034) for NPC patients receiving chemoradiotherapy. We also found rs2071346 (G>T) variant genotype carriers were subjected to higher risk of anemia (GT vs GG, OR=1.665, P=0.022) and thrombocytopenia (GT vs GG, OR=1.685, P=0.035). Our results demonstrated that the relative expression of MYC was dramatically higher in NPC tissues compared to rhinitis tissues. Over-expression of MYC was positively correlated with advanced T stage, N stage, and late clinical stage. Notably, the expression of MYC in rs4645948 CT and TT genotypes carriers were significantly higher than CC genotype carriers. Luciferase reporter assay indicated that the T allele of rs4645948 led to significantly higher transcription activity of MYC compared to the C allele. These findings suggested that individual carrying the rs4645948 T allele may be at greater risk for NPC due to an increase of MYC transcriptional activity and an augment of MYC expression.

PMID: 30662535 [PubMed]

Analysis of Lithuanian CYP2D6 polymorphism and its relevance to psychiatric care of the local population.

Nord J Psychiatry. 2019 Jan 19;:1-5

Authors: Dlugauskas E, Strumila R, Lengvenyte A, Ambrozaityte L, Dagyte E, Molyte A, Navickas A, Utkus A

Abstract
BACKGROUND: CYP450 system gene CYP2D6 polymorphisms have been associated with an altered response to psychotropic drugs. While there exists interindividual and interethnic differences of clinical significance, there is no data concerning the Lithuanian population.
AIMS: To determine the distribution of CYP2D6 alleles and predicted phenotype in the Lithuanian population, compare it to other Europeans and find the differences between patients with affective disorders and the healthy population.
METHODS: Our study sample consisted of 179 subjects that included 104 healthy volunteers and 75 patients with clinical diagnosis of affective disorders according to ICD-10AM classification, treated in hospital settings. DNA samples were taken from the blood and alleles of the CYP2D6 gene were determined for each participant. Frequencies were compared to other Europeans.
RESULTS: The frequency of the most common alleles *1 and *2 was 45.0% and 28.8% accordingly. Dysfunctional *5 (1 vs. 30, p < .002) allele was less frequent in Lithuania inhabitants than previously established in other Europeans. There were no polymorphisms of the CYP2D6 gene that could be associated with changes in drug metabolism in the patients. The functional CYP2D6 *2 allele was more prevalent in the control group, while the non functional CYP2D6 *4 allele was more prevalent in the patient group (p < .05 for both cases).
CONCLUSION: The genetic makeup of Lithuanians was generally comparable to other Europeans, but fewer Lithuanians had non-functional *5 allele. More patients had non-functional alleles. Study findings contradict previous results from other countries, where CYP2D6 gene polymorphism was associated with treatment outcomes.

PMID: 30661435 [PubMed - as supplied by publisher]

Pharmacoepigenomic Interventions as Novel Potential Treatments for Alzheimer's and Parkinson's Diseases.

Int J Mol Sci. 2018 Oct 16;19(10):

Authors: Teijido O, Cacabelos R

Abstract
Cerebrovascular and neurodegenerative disorders affect one billion people around the world and result from a combination of genomic, epigenomic, metabolic, and environmental factors. Diagnosis at late stages of disease progression, limited knowledge of gene biomarkers and molecular mechanisms of the pathology, and conventional compounds based on symptomatic rather than mechanistic features, determine the lack of success of current treatments, including current FDA-approved conventional drugs. The epigenetic approach opens new avenues for the detection of early presymptomatic pathological events that would allow the implementation of novel strategies in order to stop or delay the pathological process. The reversibility and potential restoring of epigenetic aberrations along with their potential use as targets for pharmacological and dietary interventions sited the use of epidrugs as potential novel candidates for successful treatments of multifactorial disorders involving neurodegeneration. This manuscript includes a description of the most relevant epigenetic mechanisms involved in the most prevalent neurodegenerative disorders worldwide, as well as the main potential epigenetic-based compounds under investigation for treatment of those disorders and their limitations.

PMID: 30332838 [PubMed - indexed for MEDLINE]