A comparative study of the depth, breadth, and perception of pharmacogenomics instruction in a subgroup of US pharmacy curricula.

Curr Pharm Teach Learn. 2019 May;11(5):476-484

Authors: Shatnawi A, Khanfar NM, Latif DA, Shear M

Abstract
INTRODUCTION: This study was designed to assess the depth, breadth, and perception of pharmacogenomics education in pharmacy curricula in the United States (US).
METHODS: A modified, online questionnaire from previous studies was sent to all accredited US schools and colleges of pharmacy. The survey covered three distinct areas related to the schools' educational environments, the depth and the extent of pharmacogenomics core competencies and topics taught, and the institutions' perceptions of the importance of pharmacogenomics in the curriculum and future plans for expanded pharmacogenomics education. Multiple approaches were used to increase the response rate, and results were analyzed using descriptive statistics.
RESULTS: Of the 133 eligible programs, 32 participated in the survey. Six invalid surveys were excluded from our study, resulting in a 19.6% response rate. Results revealed that all responding schools included pharmacogenomics in the curriculum. Interestingly, 76.9% of the respondents believed pharmacists do not have the appropriate knowledge of pharmacogenomics. However, only 30.7% indicated that their programs planned to expand pharmacogenomics in their curriculum.
CONCLUSIONS: The responding schools all included some pharmacogenomics in their curriculum. However, the depth and the extent of pharmacogenomics topics covered varied. Respondents perceived that pharmacists today do not possess the appropriate level of pharmacogenomics knowledge. Despite this, there is limited emphasis on expanding pharmacogenomics instruction in the responding schools' curriculums.

PMID: 31171249 [PubMed - in process]

Tumor suppressor gene glycine N-methyltransferase and its potential in liver disorders and hepatocellular carcinoma.

Toxicol Appl Pharmacol. 2019 Jun 03;:114607

Authors: Chen M, Yang MH, Chang MM, Tyan YC, Chen YA

Abstract
Glycine N-methyltransferase is a protein with many functions. In addition to catalyzing the production of sarcosine in the one carbon metabolism pathway, it plays a role in the detoxification of environmental carcinogens such as benzo[a]pyrene, aflatoxin B1, and aristocholic acid. There is also increasing evidence suggesting a role of GNMT deficiency in liver carcinogenesis. In this review, we discuss the role of GNMT in the detoxification of xenobiotics and the mechanism of GNMT suppression during liver tumorigenesis. The protective role of GNMT in the liver allows GNMT to not only serve as a marker of liver disease, but also potentially be applied in the treatment of liver disorders and hepatocellular carcinoma. We describe the potential use of GNMT in gene therapy and we introduce the development of a GNMT promoter reporter assay that can be used to screen medicinal drugs and herbal libraries for natural compounds with anti-cancer properties.

PMID: 31170416 [PubMed - as supplied by publisher]

Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic Stellate Cells and Liver Fibrogenesis in Mice.

Gastroenterology. 2019 Jun 03;:

Authors: Yan J, Tung HC, Li S, Niu Y, Garbacz WG, Lu P, Bi Y, Li Y, He J, Xu M, Ren S, Monga SP, Schwabe RF, Yang D, Xie W

Abstract
BACKGROUND & AIMS: The role of aryl hydrocarbon receptor (AHR) in liver fibrosis is controversial, because loss and gain of AHR activity each lead to liver fibrosis. The goal of this study is to investigate how the expression of AHR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice.
METHODS: We studied the effects of AHR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-seq analysis. C57BL/6J mice were given the AHR agonists TCDD or ITE, or carbon tetrachloride (CCl4), or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting.
RESULTS: AHR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AHR-knockout mice was accelerated, compared to HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor beta (TGFB)-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis following administration of CCl4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl4-induced liver fibrosis, whereas mice without HSC AHR given ITE did develop CCl4-induced liver fibrosis. In studies of mouse and human HSCs, we found that AHR prevents TGFB-induced fibrogenesis by disrupting the interaction of SMAD3 with beta-catenin, which prevents the expression of genes that mediate fibrogenesis.
CONCLUSIONS: In studies of human and mouse HSCs, we found that AHR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of non-toxic AHR agonists or strategies to activate AHR signaling in HSCs might be developed to prevent or treat liver fibrosis.

PMID: 31170413 [PubMed - as supplied by publisher]

Association of endothelin genetic variants and hospitalized infection complications in end-stage renal disease (ESRD) patients.

BMC Nephrol. 2019 Jun 05;20(1):203

Authors: Kao CC, Cheng SY, Wang YJ, Chien SC, Hsu YW, Wu MY, Lu HF, Nam S, Sun T, Wu MS, Chang WC

Abstract
BACKGROUND: Infection is the second most common cause of mortality for patients with end-stage renal disease (ESRD), accompanying with immune dysfunction. Endothelin (EDN) is known to be related to inflammation; however, it is unknown whether genetic variants of the EDN gene family are associated with increased risk of hospitalized infection events.
METHODS: Nineteen tagging single-nucleotide polymorphisms (tSNPs) of the EDN gene family were selected for genotyping a cohort of 190 ESRD patients. Patient demographics were recorded, the subtypes of infection events were identified, and association analysis between the EDN genetic variants and hospitalized infection events was performed.
RESULTS: In this study, 106 patients were hospitalized for infection events. The leading events were pneumonia, bacteremia, and cellulitis. The minor allele of rs260741, rs197173, and rs926632 SNPs of EDN3 were found to be associated with reduced risk of hospitalized bacteremia events.
CONCLUSIONS: The minor allele of rs260741, rs197173, and rs926632 in EDN3 were associated with reduced risk of hospitalized bacteremia events in ESRD patients.

PMID: 31167651 [PubMed - in process]

Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines.

Front Pharmacol. 2019;10:542

Authors: Dawood M, Ooko E, Efferth T

Abstract
Parthenolide (PT) is a sesquiterpene lactone isolated from Tanacetum parthenium. In this study, PT showed varying cytotoxic effects against different solid tumor cell lines. HCT116 (p53+/+) colon carcinoma cells and their parental HCT116 knockout p53 (p53-/-) cell lines showed a resistance degree of 2.36. On the other hand, wild-type U87.MG cells or cells transfected with a deletion-activated EGFR cDNA (U87.MGΔEGFR) exhibited slight sensitivity toward PT. Multidrug-resistant MDA-MB-231-BCRP cells were even more sensitive toward PT than sensitive MDA-MB-231-pcDNA cells with a resistance degree of 0.07 (collateral sensitivity). To the best of our knowledge, hypersensitivity (collateral sensitivity) in MDA-MB-231-BCRP cell line is reported in this study for the first time. We attempted to identify the mechanism of collateral sensitivity. Firstly, we found that PT bound to IKK preventing IκBα degradation and eventually inhibition of the nuclear factor kappa B (NF-κB) pathway. Down-regulation of hypoxia inducing factor 1-alpha (HIF-1α) in MDA-MB-231-BCRP resistant cells may be a second mechanism, since it is a target gene of NF-κB. Moreover, PT also showed epigenetic effect by inhibition of HDAC activity as shown using both molecular docking and HDAC activity assay. Based on COMPARE and hierarchical cluster analyses, we found gene expression profiles that predicted sensitivity or resistance of 47 tumor cell lines toward PT. Interestingly, pathway analyses of gene expression profiles revealed NF-κB and HIF signaling as top networks of these genes, cellular functions and canonical pathways influencing the activity of PT against tumor cells. In conclusion, PT exerted profound cytotoxic activity against various cancer cell lines mainly against BCRP-overexpressing tumor cells, suggesting PT as novel candidate for cancer treatment.

PMID: 31164821 [PubMed]

Differential lung tissue gene expression in males and females: implications for the susceptibility to develop COPD.

Eur Respir J. 2019 Jun 04;:

Authors: van den Berge M, Brandsma CA, Faiz A, de Vries M, Rathnayake SNH, Paré PD, Sin DD, Bossé Y, Laviolette M, Nickle DC, Hao K, Obeidat M, Dragani TA, Colombo F, Timens W, Postma DS

PMID: 31164434 [PubMed - as supplied by publisher]

Pharmacogenomics: A Practical Primer for Senior Care Pharmacists.

Sr Care Pharm. 2019 Jun 01;34(6):363-369

Authors: Hilden MP, Bright DR, Kisor DF, Christensen H

Abstract
Pharmacogenomics (PGx), the study of how an individual's genetic makeup affects his or her response to drugs, is a fast-growing field that gives health care providers a valuable tool to help safely and effectively manage medication. However, few providers have experience in applying the results of PGx tests to their practices, and this can lead to disregarding the data or unnecessarily modifying medication regimens. Pharmacists are uniquely positioned to become wellversed in the interpretation of PGx data, critically evaluating the "green-yellow-red" result categories that seemingly signal "go, caution, stop" regarding the use of a particular medication. Pharmacists also can evaluate genotype and phenotype information, commonly included in PGx laboratory reports, to optimize therapy. Using a case-based approach, this primer is intended to provide consultant pharmacists with practical direction to aid in PGx interpretation that will provide contextappropriate recommendations that contributes to positive patient outcomes.

PMID: 31164183 [PubMed - in process]

Pharmacogenetics of alcohol use disorder treatments: an update.

Expert Opin Drug Metab Toxicol. 2019 Jun 04;:

Authors: Hartwell EE, Kranzler HR

Abstract
INTRODUCTION: Alcohol use disorder (AUD) is a highly prevalent; costly economically, socially, and interpersonally; and grossly undertreated disorder. The low rate of utilization of pharmacological treatments with demonstrated efficacy is particularly noteworthy. This is due, in part, to the modest efficacy of the medications approved to treat the disorder. One approach to increasing the utility and safety of these medications is to use precision medicine, which seeks to identify patients for whom specific medications are likely to have the most robust therapeutic effects and the fewest adverse effects. Areas Covered: Here we review the current literature on the pharmacogenetics of AUD treatment. We cover both laboratory studies and clinical trials that have provided valuable insights into the mechanisms and value of precision-based care for AUD. We discuss studies of genetic moderators for personalizing pharmacotherapy with medications approved by regulatory agencies in the United States and Europe and those that are used off-label to treat AUD. Expert Opinion: Pharmacotherapy can be a useful component of AUD treatment. Currently, the evidence regarding genetic predictors of medication efficacy is very limited. Thus, precision medicine is not yet ready for widespread clinical implementation. Further research is needed to identify candidate genetic variants that moderate the response to both established and novel medications in development for this goal to be achieved. The growing availability of large-scale, longitudinal datasets that enable the synthesis of genetic and electronic health record data could provide important opportunities to develop this area of research.

PMID: 31162983 [PubMed - as supplied by publisher]

Complicated disease and response to initial therapy predicts early surgery in paediatric Crohn's disease: results from the Porto Group GROWTH study.

J Crohns Colitis. 2019 Jun 03;:

Authors: Levine A, Chanchlani N, Ziv-Baran T, Escher JC, Amil Dias J, Veres G, Koletzko S, Turner D, Kolho KL, Paerregaard A, Staiano A, Lionetti P, Nuti F, Sladek M, Shaoul R, Lazowska-Prezeorek I, de Carpi JM, Sigall Boneh R, Pfeffer Gik T, Cohen-Dolev N, Russell RK, Porto Group of ESPGHAN

Abstract
INTRODUCTION: The ability to predict risk for poor outcomes in Crohn's disease (CD) would enable early treatment intensification. We aimed to identify children with CD with complications at baseline and throughout the study period who are at risk for surgery two years from diagnosis.
MATERIAL AND METHODS: Newly diagnosed children with CD were enrolled into a prospective, multicentre inception cohort. Disease characteristics and serological markers were obtained at baseline and week 12 thereafter. Outcome data including disease activity, therapies, complications, and need for surgery were collected through 104 weeks. Chi-square automatic interaction detection (CHAID) algorithm was used to develop a prediction model for early surgery.
RESULTS: Of 285 children enrolled, 31(10.9%) required surgery within two years. Multivariate analysis identified stricturing disease at baseline (OR 5.26, 95% CI 2.02 - 13.67 (p=0.001)), and Paediatric Crohn's Disease Activity Index (PCDAI) >10 at week 12 (OR 1.06, 95% CI 1.02 - 1.10 (p=0.005) as key predictors for early surgery. CHAID demonstrated that absence of strictures at diagnosis (7.6%), corticosteroid-free remission at week 12 (4.1%), and early immunomodulator therapy (0.8%) were associated with the lowest risk of surgery, while stricturing disease at diagnosis (27.1%, P<0.001) or elevated PCDAI at week 12 (16.7%, p=0.014) had an increased risk of surgery at follow-up. Anti-OmpC status further stratified high-risk patients.
DISCUSSION: A risk algorithm using clinical and serological variables at diagnosis and week 12 can categorise patients into high- and low- risk groups from diagnosis.
FUNDING: A.L Thrasher foundation, Catherine McEwan foundation, and the Porto group of ESPGHAN.

PMID: 31162532 [PubMed - as supplied by publisher]

Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Nat Genet. 2019 Jun 03;:

Authors: Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, den Hoed M, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CLM, Tanislav C, Tatlisumak T, Taylor KD, Thijs VNS, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, AFGen Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, International Genomics of Blood Pressure (iGEN-BP) Consortium, INVENT Consortium, STARNET, Bis JC, Pastinen T, Ruusalepp A, Schadt EE, Koplev S, Björkegren JLM, Codoni V, Civelek M, Smith NL, Trégouët DA, Christophersen IE, Roselli C, Lubitz SA, Ellinor PT, Tai ES, Kooner JS, Kato N, He J, van der Harst P, Elliott P, Chambers JC, Takeuchi F, Johnson AD, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium (ISGC), METASTROKE Consortium, Neurology Working Group of the CHARGE Consortium, NINDS Stroke Genetics Network (SiGN), UK Young Lacunar DNA Study, MEGASTROKE Consortium, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JMM, Kamatani Y, Debette S, Dichgans M

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 31160810 [PubMed - as supplied by publisher]

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet. 2019 Jun 03;:

Authors: Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, Guo X, Hendricks AE, Karaderi T, Lempradl A, Locke AE, Mahajan A, Marouli E, Sivapalaratnam S, Young KL, Alfred T, Feitosa MF, Masca NGD, Manning AK, Medina-Gomez C, Mudgal P, Ng MCY, Reiner AP, Vedantam S, Willems SM, Winkler TW, Abecasis G, Aben KK, Alam DS, Alharthi SE, Allison M, Amouyel P, Asselbergs FW, Auer PL, Balkau B, Bang LE, Barroso I, Bastarache L, Benn M, Bergmann S, Bielak LF, Blüher M, Boehnke M, Boeing H, Boerwinkle E, Böger CA, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Brumat M, Burt AA, Butterworth AS, Campbell PT, Cappellani S, Carey DJ, Catamo E, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Galbany JC, Cox AJ, Crosslin DS, Cuellar-Partida G, D'Eustacchio A, Danesh J, Davies G, Bakker PIW, Groot MCH, Mutsert R, Deary IJ, Dedoussis G, Demerath EW, Heijer M, Hollander AI, Ruijter HM, Dennis JG, Denny JC, Di Angelantonio E, Drenos F, Du M, Dubé MP, Dunning AM, Easton DF, Edwards TL, Ellinghaus D, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Farooqi IS, Faul JD, Fauser S, Feng S, Ferrannini E, Ferrieres J, Florez JC, Ford I, Fornage M, Franco OH, Franke A, Franks PW, Friedrich N, Frikke-Schmidt R, Galesloot TE, Gan W, Gandin I, Gasparini P, Gibson J, Giedraitis V, Gjesing AP, Gordon-Larsen P, Gorski M, Grabe HJ, Grant SFA, Grarup N, Griffiths HL, Grove ML, Gudnason V, Gustafsson S, Haessler J, Hakonarson H, Hammerschlag AR, Hansen T, Harris KM, Harris TB, Hattersley AT, Have CT, Hayward C, He L, Heard-Costa NL, Heath AC, Heid IM, Helgeland Ø, Hernesniemi J, Hewitt AW, Holmen OL, Hovingh GK, Howson JMM, Hu Y, Huang PL, Huffman JE, Ikram MA, Ingelsson E, Jackson AU, Jansson JH, Jarvik GP, Jensen GB, Jia Y, Johansson S, Jørgensen ME, Jørgensen T, Jukema JW, Kahali B, Kahn RS, Kähönen M, Kamstrup PR, Kanoni S, Kaprio J, Karaleftheri M, Kardia SLR, Karpe F, Kathiresan S, Kee F, Kiemeney LA, Kim E, Kitajima H, Komulainen P, Kooner JS, Kooperberg C, Korhonen T, Kovacs P, Kuivaniemi H, Kutalik Z, Kuulasmaa K, Kuusisto J, Laakso M, Lakka TA, Lamparter D, Lange EM, Lange LA, Langenberg C, Larson EB, Lee NR, Lehtimäki T, Lewis CE, Li H, Li J, Li-Gao R, Lin H, Lin KH, Lin LA, Lin X, Lind L, Lindström J, Linneberg A, Liu CT, Liu DJ, Liu Y, Lo KS, Lophatananon A, Lotery AJ, Loukola A, Luan J, Lubitz SA, Lyytikäinen LP, Männistö S, Marenne G, Mazul AL, McCarthy MI, McKean-Cowdin R, Medland SE, Meidtner K, Milani L, Mistry V, Mitchell P, Mohlke KL, Moilanen L, Moitry M, Montgomery GW, Mook-Kanamori DO, Moore C, Mori TA, Morris AD, Morris AP, Müller-Nurasyid M, Munroe PB, Nalls MA, Narisu N, Nelson CP, Neville M, Nielsen SF, Nikus K, Njølstad PR, Nordestgaard BG, Nyholt DR, O'Connel JR, O'Donoghue ML, Loohuis LMO, Ophoff RA, Owen KR, Packard CJ, Padmanabhan S, Palmer CNA, Palmer ND, Pasterkamp G, Patel AP, Pattie A, Pedersen O, Peissig PL, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JRB, Pers TH, Person TN, Peters A, Petersen ERB, Peyser PA, Pirie A, Polasek O, Polderman TJ, Puolijoki H, Raitakari OT, Rasheed A, Rauramaa R, Reilly DF, Renström F, Rheinberger M, Ridker PM, Rioux JD, Rivas MA, Roberts DJ, Robertson NR, Robino A, Rolandsson O, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Sapkota Y, Sattar N, Schoen RE, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe MP, Shah SH, Sheu WH, Sim X, Slater AJ, Small KS, Smith AV, Southam L, Spector TD, Speliotes EK, Starr JM, Stefansson K, Steinthorsdottir V, Stirrups KE, Strauch K, Stringham HM, Stumvoll M, Sun L, Surendran P, Swift AJ, Tada H, Tansey KE, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorleifsson G, Thorsteinsdottir U, Thuesen BH, Tönjes A, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer JP, Uher R, Uitterlinden AG, Uusitupa M, Laan SW, Duijn CM, Leeuwen N, van Setten J, Vanhala M, Varbo A, Varga TV, Varma R, Edwards DRV, Vermeulen SH, Veronesi G, Vestergaard H, Vitart V, Vogt TF, Völker U, Vuckovic D, Wagenknecht LE, Walker M, Wallentin L, Wang F, Wang CA, Wang S, Wang Y, Ware EB, Wareham NJ, Warren HR, Waterworth DM, Wessel J, White HD, Willer CJ, Wilson JG, Witte DR, Wood AR, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong LM, Young R, Zeggini E, Zhan X, Zhang W, Zhao JH, Zhao W, Zhao W, Zhou W, Zondervan KT, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Rotter JI, Pospisilik JA, Rivadeneira F, Borecki IB, Deloukas P, Frayling TM, Lettre G, North KE, Lindgren CM, Hirschhorn JN, Loos RJF

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 31160809 [PubMed - as supplied by publisher]

The Prevalence of DPYD*9A(c.85T>C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines: Updated Analysis.

Clin Colorectal Cancer. 2019 May 03;:

Authors: Maharjan AS, McMillin GA, Patel GK, Awan S, Taylor WR, Pai S, Frankel AE, Nelson C, Wang B, Hosein PJ, Singh AP, Khushman M

Abstract
INTRODUCTION: The dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (13 patients [46%]) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD*9A variant and to confirm the genotype-phenotype correlation.
PATIENTS AND METHODS: Between 2011 and 2018, in addition to genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies treated with fluoropyrimidines. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Fisher exact test was used for statistical analysis.
RESULTS: Heterozygous and homozygous DPYD*9A genotypes were identified in 46 (41%) and 11 (10%) patients, respectively. Among patients with DPYD*9A genotypes (n = 57), men and women represented 30 (53%) and 27 (47%) patients, respectively. Caucasian, African American, and other ethnicities represented 29 (50.9%), 26 (45.6%), and 2 (3.5%) patients, respectively. Grade 3/4 toxicities were experienced in 26 patients with DPYD*9A genotype (3 patients had homozygous status) and in 20 patients with wild type DPYD*9A (P = .4405). In patients who received full-dose fluoropyrimidines (n = 85), Grade 3/4 toxicities were experienced in 22 patients with DPYD*9A genotype (2 patients had homozygous status), and in 17 patients with wild type DPYD (P = .8275).
CONCLUSION: In our updated analysis, the prevalence of heterozygous and homozygous DPYD*9A genotypes were 41% and 10%, respectively. The correlation between DPYD*9A genotype and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias.

PMID: 31160238 [PubMed - as supplied by publisher]

Neuroimaging findings from an experimental pharmacology trial of naltrexone in heavy drinkers of East Asian descent.

Drug Alcohol Depend. 2019 May 09;:

Authors: Lim AC, Ghahremani DG, Grodin EN, Green R, Bujarski S, Hartwell EE, Courtney KE, Hutchison K, Miotto K, Ray LA

Abstract
BACKGROUND: Despite known genetic variation across races, studies examining pharmacogenetics of a single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1) on clinical response to naltrexone have been conducted in predominantly Caucasian samples. Evidence is mixed for pharmacogenetic OPRM1 and naltrexone effects on neural responses to alcohol cues. The current study tests the pharmacogenetic effects of naltrexone and OPRM1 on neural responses to alcohol taste cues in heavy drinkers of East Asian descent.
METHODS: Participants (N = 41) completed two double-blinded and counterbalanced functional magnetic resonance imaging (fMRI) sessions: one after taking naltrexone (50 mg/day) for four days and one after taking placebo for four days. Following titration, participants completed an fMRI alcohol taste-cues task. Analyses tested effects of naltrexone, OPRM1, and their interaction in whole-brain and region of interest (ROI) analyses of functional activation and functional connectivity in response to alcohol versus water taste cues.
RESULTS: We found no effects of naltrexone orOPRM1 on neural activation in whole-brain and ROI analyses, which included left and right ventral striatum (VS), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). Naltrexone increased functional connectivity between left VS and clusters in medial prefrontal cortex, posterior cingulate gyrus, as well as right VS and occipital cortex, compared to placebo.
CONCLUSIONS: Naltrexone treatment enhanced functional connectivity in a key reinforcement-related pathway during alcohol versus water taste cues, corroborating neuroimaging work with other substances. Null medication and pharmacogenetics effects on functional activation add to a mixed naltrexone literature and may underscore the modest size of these effects in East Asians.

PMID: 31160146 [PubMed - as supplied by publisher]

Targeted next generation sequencing as a tool for precision medicine.

BMC Med Genomics. 2019 Jun 03;12(1):81

Authors: Gulilat M, Lamb T, Teft WA, Wang J, Dron JS, Robinson JF, Tirona RG, Hegele RA, Kim RB, Schwarz UI

Abstract
BACKGROUND: Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response.
METHODS: A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms.
RESULTS: Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy.
CONCLUSIONS: PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.

PMID: 31159795 [PubMed - in process]

Systematic review and meta-analysis of genetic risk factors for neuropathic pain.

Pain. 2018 May;159(5):825-848

Authors: Veluchamy A, Hébert HL, Meng W, Palmer CNA, Smith BH

Abstract
Neuropathic pain (NP) is an increasingly common chronic pain state and a major health burden, affecting approximately 7% to 10% of the general population. Emerging evidence suggests that genetic factors could partially explain individual susceptibility to NP and the estimated heritability in twins is 37%. The aim of this study was to systematically review and summarize the studies in humans that have investigated the influence of genetic factors associated with NP. We conducted a comprehensive literature search and performed meta-analyses of all the potential genetic variants associated with NP. We reviewed 29 full-text articles and identified 28 genes that were significantly associated with NP, mainly involved in neurotransmission, immune response, and metabolism. Genetic variants in HLA genes, COMT, OPRM1, TNFA, IL6, and GCH1, were found to have an association with NP in more than one study. In the meta-analysis, polymorphisms in HLA-DRB1*13 (odds ratio [OR], 2.96; confidence interval [CI], 1.93-4.56), HLA-DRB1*04 (OR, 1.40; CI, 1.02-1.93), HLA-DQB1*03 (OR, 2.86; CI, 1.57-5.21), HLA-A*33 (OR, 2.32; CI, 1.42-3.80), and HLA-B*44 (OR, 3.17; CI, 2.22-4.55) were associated with significantly increased risk of developing NP, whereas HLA-A*02 (OR, 0.64; CI, 0.47-0.87) conferred reduced risk and neither rs1799971 in OPRM1 (OR, 0.55; CI, 0.27-1.11) nor rs4680 in COMT (OR, 0.95; CI, 0.81-1.13) were significantly associated with NP. These findings demonstrate an important and specific contribution of genetic factors to the risk of developing NP. However, large-scale replication studies are required to validate these candidate genes. Our review also highlights the need for genome-wide association studies with consistent case definition to elucidate the genetic architecture underpinning NP.

PMID: 29351172 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Validation of in vitro methods for human cytochrome P450 enzyme induction: Outcome of a multi-laboratory study.

Toxicol In Vitro. 2019 May 31;:

Authors: Bernasconi C, Pelkonen O, Andersson TB, Strickland J, Wilk-Zasadna I, Asturiol D, Cole T, Liska R, Worth A, Müller-Vieira U, Richert L, Chesne C, Coecke S

Abstract
CYP enzyme induction is a sensitive biomarker for phenotypic metabolic competence of in vitro test systems; it is a key event associated with thyroid disruption, and a biomarker for toxicologically relevant nuclear receptor-mediated pathways. This paper summarises the results of a multi-laboratory validation study of two in vitro methods that assess the potential of chemicals to induce cytochrome P450 (CYP) enzyme activity, in particular CYP1A2, CYP2B6, and CYP3A4. The methods are based on the use of cryopreserved primary human hepatocytes (PHH) and human HepaRG cells. The validation study was coordinated by the European Union Reference Laboratory for Alternatives to Animal Testing of the European Commission's Joint Research Centre and involved a ring trial among six laboratories. The reproducibility was assessed within and between laboratories using a validation set of 13 selected chemicals (known human inducers and non-inducers) tested under blind conditions. The ability of the two methods to predict human CYP induction potential was assessed. Chemical space analysis confirmed that the selected chemicals are broadly representative of a diverse range of chemicals. The two methods were found to be reliable and relevant in vitro tools for the assessment of human CYP induction, with the HepaRG method being better suited for routine testing. Recommendations for the practical application of the two methods are proposed.

PMID: 31158489 [PubMed - as supplied by publisher]

Placenta growth factor and sFlt-1 as biomarkers in ischemic heart disease and heart failure: a review.

Biomark Med. 2019 Jun 03;:

Authors: Draker N, Torry DS, Torry RJ

Abstract
Coronary heart disease (CHD) and heart failure (HF) produce significant morbidity/mortality but identifying new biomarkers could help in the management of each. In this article, we summarize the molecular regulation and biomarker potential of PIGF and sFlt-1 in CHD and HF. PlGF is elevated during ischemia and some studies have shown PlGF, sFlt-1 or PlGF:sFlt-1 ratio, when used in combination with standard biomarkers, strengthens predictions of outcomes. sFlt-1 and PlGF are elevated in HF with sFlt-1 as a stronger predictor of outcomes. Although promising, we discuss additional study criteria needed to confirm the clinical usefulness of PlGF or sFlt-1 in the detection and management of CHD or HF.

PMID: 31157982 [PubMed - as supplied by publisher]

The future of apolipoprotein E mimetic peptides in the prevention of cardiovascular disease.

Curr Opin Lipidol. 2019 May 30;:

Authors: Valanti EK, Chroni A, Sanoudou D

Abstract
PURPOSE OF REVIEW: This review aims to discuss the recent developments in the area of apolipoprotein E (apoE) mimetics and their therapeutic potential for treating cardiovascular disease, the leading cause of mortality worldwide.
RECENT FINDINGS: Ongoing research efforts target the development of novel therapies that would not only reduce circulating levels of atherogenic lipoproteins, but could also increase high density lipoprotein cholesterol (HDL-C) levels and/or improve HDL function. Among them, synthetic peptides that mimic the structure of natural human apoE, a component of triglyceride-rich lipoproteins and HDL, have been designed and proven to be functionally similar to apoE. In specific, apoE mimetic peptides mediate hepatic clearance of circulating atherogenic lipoproteins, dramatically reduce plasma cholesterol, and lead to attenuation of atherosclerosis development in vivo. These peptides also exhibit pleiotropic antiatherogenic properties, such as macrophage cholesterol efflux capacity, as well as anti-inflammatory and antioxidative functions.
SUMMARY: ApoE mimetics are undergoing preclinical and clinical evaluation with promising results to date that render them attractive candidates in cardiovascular disease prevention and treatment.

PMID: 31157629 [PubMed - as supplied by publisher]

Estimating the Effectiveness of DPYD Genotyping in Italian Individuals Suffering from Cancer Based on the Cost of Chemotherapy-Induced Toxicity.

Am J Hum Genet. 2019 May 18;:

Authors: Fragoulakis V, Roncato R, Fratte CD, Ecca F, Bartsakoulia M, Innocenti F, Toffoli G, Cecchin E, Patrinos GP, Mitropoulou C

Abstract
Fluoropyrimidines (FLs) have been widely used for more than 60 years against a range of solid tumors and still remains the cornerstone for the treatment of colorectal, gastric, and breast cancer. Here, we performed an economic analysis to estimate the cost of DPYD-guided toxicity management and the clinical benefit expressed as quality adjusted life years (QALYs) in a large group of 571 individuals of Italian origin suffering from cancer and treated with a fluoropyrimidines-based chemotherapy. Individuals suffering from cancer with a histologically confirmed diagnosis of cancer, who received a fluoropyrimidines-based treatment, were retrospectively genotyped in the DPYD gene. Effectiveness was measured as survival of individuals from chemotherapy, while study data on safety and efficacy as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups. DPYD extensive metabolizers (528 individuals) had greater effectiveness and lesser cost, representing a cost-saving option over DPYD intermediate and poor metabolizers (43 individuals) with mean QALYs of 4.18 (95%CI: 3.16-5.55) versus 3.02 (95%CI: 1.94-4.25), respectively. Our economic analysis showed that there are some indications for differences in survival between the two groups (p > 0.05), while the cost of DPYD extensive metabolizers was significantly lower (p < 0.01) compared with those belonging to the group of intermediate/poor metabolizers. These findings suggest that DPYD-guided fluoropyrimidines treatment represent a cost-saving choice for individuals suffering from cancer in the Italian healthcare setting.

PMID: 31155283 [PubMed - as supplied by publisher]