Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Original Article - click here for text.

The Pharmacogenomics Journal advance online publication 17 November 2009; doi: 10.1038/tpj.2009.49

A K Maiti¹

¹A&I, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

Correspondence: Dr AK Maiti, A&I, Oklahoma Medical Research Foundation, 825 NE13th, Oklahoma City, OK 73104, USA. E-mails: amit-maiti@omrf.org, Akmit123@yahoo.com

Received 23 March 2009; Revised 21 August 2009; Accepted 24 September 2009; Published online 17 November 2009.

Drug resistance in cancer cells involves complex molecular mechanisms and ovarian carcinoma cells become resistant to chlorambucil (Cbl) after continuous treatment. This drug- and ionizing radiation-resistant cells have lower level of endogenous ROS (reactive oxygen species) compared with sensitive cells. Elevation of the cellular ROS level by exogenous ROS generation increases the sensitivity of Cbl to resistant cells. In contrast, antioxidants prevent the sensitization of resistant cells to Cbl by H₂O₂, COS (chronic oxidative stress) or NOO^-. The molecular mechanism of drug sensitivity with COS has been investigated by microarray gene expressions followed by gene network analysis and it reveals that a cdc42/rac1 guanine exchange factor, ARHGEF6, with p53 and DNA-Pkc (PRKDC) is central to induce apoptosis in Cbl^cos (Cbl with COS) cells. mRNA and protein levels of major gene network pathway differ significantly in Cbl^cos cells than in Cbl-treated cells. Moreover, DNA-PKc physically interacts with ARHGEF6 and p53 mostly in the nucleus of Cbl-treated cells, whereas in Cbl^cos-treated cells, its interactions are mostly in the cytoplasm. These results suggest that low doses of Cbl and very low doses of COS together kill Cbl-resistant ovarian carcinoma cells and ARHGEF6 signaling may have an instrumental role in induction of apoptosis in Cbl^cos cells.

Human Genome Sequencing Using Unchained Base Reads on Self-Assembling DNA Nanoarrays

SCIENCE - Published Online November 5, 2009 Science DOI: 10.1126/science.1181498

Reports - Click here for article.

Submitted on September 3, 2009
Accepted on October 23, 2009

Radoje Drmanac ^1*, Andrew B. Sparks ¹, Matthew J. Callow ¹, Aaron L. Halpern ¹, Norman L. Burns ¹, Bahram G. Kermani ¹, Paolo Carnevali ¹, Igor Nazarenko ¹, Geoffrey B. Nilsen ¹, George Yeung ¹, Fredrik Dahl ², Andres Fernandez ¹, Bryan Staker ¹, Krishna P. Pant ¹, Jonathan Baccash ¹, Adam P. Borcherding ¹, Anushka Brownley ¹, Ryan Cedeno ¹, Linsu Chen ¹, Dan Chernikoff ¹, Alex Cheung ¹, Razvan Chirita ¹, Benjamin Curson ¹, Jessica C. Ebert ¹, Coleen R. Hacker ¹, Robert Hartlage ¹, Brian Hauser ¹, Steve Huang ¹, Yuan Jiang ¹, Vitali Karpinchyk ¹, Mark Koenig ¹, Calvin Kong ¹, Tom Landers ¹, Catherine Le ¹, Jia Liu ¹, Celeste E. McBride ¹, Matt Morenzoni ¹, Robert E. Morey ³, Karl Mutch ¹, Helena Perazich ¹, Kimberly Perry ¹, Brock A. Peters ¹, Joe Peterson ¹, Charit L. Pethiyagoda ¹, Kaliprasad Pothuraju ¹, Claudia Richter ¹, Abraham M. Rosenbaum ⁴, Shaunak Roy ¹, Jay Shafto ¹, Uladzislau Sharanhovich ¹, Karen W. Shannon ⁵, Conrad G. Sheppy ¹, Michel Sun ¹, Joseph V. Thakuria ⁴, Anne Tran ¹, Dylan Vu ¹, Alexander Wait Zaranek ⁴, Xiaodi Wu ⁶, Snezana Drmanac ¹, Arnold R. Oliphant ¹, William C. Banyai ¹, Bruce Martin ¹, Dennis G. Ballinger ^1*, George M. Church ⁴, Clifford A. Reid ¹

¹ Complete Genomics, Inc., 2071 Stierlin Court, Mountain View, CA 94043, USA.
² Complete Genomics, Inc., 2071 Stierlin Court, Mountain View, CA 94043, USA.; Present address: Ion Torrent Systems, San Francisco, CA, USA.
³ Complete Genomics, Inc., 2071 Stierlin Court, Mountain View, CA 94043, USA.; Present address: San Diego State University, San Diego, CA, USA.
⁴ Department of Genetics, Harvard Medical School, Cambridge, MA, USA.
⁵ Complete Genomics, Inc., 2071 Stierlin Court, Mountain View, CA 94043, USA.; Present address: Life Technologies, Carlsbad, CA, USA.
⁶ School of Medicine, Washington University, St. Louis, St. Louis, MO, USA.

^* To whom correspondence should be addressed.
Radoje Drmanac , E-mail: rdrmanac@completegenomics.com
Dennis G. Ballinger , E-mail: dballinger@completegenomics.com

Genome sequencing of large numbers of individuals promises to advance the understanding, treatment, and prevention of human diseases, among other applications. We describe a genome sequencing platform that achieves efficient imaging and low reagent consumption with combinatorial probe anchor ligation (cPAL) chemistry to independently assay each base from patterned nanoarrays of self-assembling DNA nanoballs (DNBs). We sequenced three human genomes with this platform, generating an average of 45- to 87-fold coverage per genome and identifying 3.2 to 4.5 million sequence variants per genome. Validation of one genome data set demonstrates a sequence accuracy of about 1 false variant per 100 kilobases. The high-accuracy, affordable cost of $4,400 for sequencing consumables and scalability of this platform enable complete human genome sequencing for the detection of rare variants in large-scale genetic studies.

ADRA1A gene is associated with BMI in chronic schizophrenia patients exposed to antipsychotics

Original Article - click here to go to article.

The Pharmacogenomics Journal advance online publication 17 November 2009; doi: 10.1038/tpj.2009.55

Y-R Liu^1,2,11, E-W Loh^1,11, T-H Lan^1,3,4, S-F Chen⁵, Y-H Yu⁶, Y-H Chang^1,7, C-J Huang⁸, T-M Hu⁹, K-M Lin¹, Y-T Yao² and H-J Chiu¹⁰

1. Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan
2. Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
3. Faculty of Medicine, National Yang Ming University, Taipei, Taiwan
4. Department of Psychiatry, Taichung Veterans General Hospital, Taichung, Taiwan
5. Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan
6. Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei, Taiwan
7. Institute of Public Health and Department of Public Health, National Yang Ming University, Taipei, Taiwan
8. Department of Industrial Engineering and Engineering Management, College of Engineering, National Tsing-Hua University, HsinChu, Taiwan
9. Department of Psychiatry, Yu-Li Veterans Hospital, Hualian County, Taiwan
10. Jianan Mental Hospital, Tainan County, Taiwan

Correspondence: Dr H-J Chiu, Department of Health, Jianan Mental Hospital, #80, Lane 870, Jhung-Shan Road, Rende Township, Tainan 717, Taiwan. E-mail: chiu8@mail2000.com.tw

¹¹These authors contributed equally to this study.

Received 28 April 2009; Revised 28 July 2009; Accepted 23 September 2009; Published online 17 November 2009.

Abstract

Noradrenaline and adrenaline are neurotransmitters of the sympathetic nervous system that interact with various adrenergic receptor (ADR) subtypes, and this regulates the basal metabolic rate, thermogenesis and efficiency of energy utilization. We examined a possible role of the gene coding for ADRA1A receptor in weight gain in schizophrenia subjects exposed to antipsychotics. A total of 401 schizophrenia in-patients treated with antipsychotics for >2 years were recruited and a final 394 DNA samples were genotyped. Their body mass indexes (BMIs) were recorded for 12 months and parameterized to be correlated in regression. Among the 58 single-nucleotide polymorphisms (SNPs) genotyped, 44 valid SNPs, which had minor allele frequency 0.03, were analyzed in statistics. Linear regression model with age, gender, diabetes, use of typical antipsychotics and use of atypical antipsychotics as covariates, with or without gender interaction, showed evidence of associations between the ADRA1A gene and BMI. Most of the SNPs associated with BMI are located in the promoter and intron regions, and being female appeared to enhance the gene effect. Our study suggests that the ADRA1A gene is involved in weight gain among schizophrenia patients treated with antipsychotics. Further molecular dissection of the ADRA1A gene warrants better understanding on weight gain mechanisms in schizophrenia.

The modulating effect of the androgen receptor on craving in alcohol withdrawal of men is partially mediated by leptin

For article, click here.

Original Article

The Pharmacogenomics Journal advance online publication 3 November 2009; doi: 10.1038/tpj.2009.56

B Lenz 1,
H Frieling 1,2,
C Jacob 1,
A Heberlein 1,2,
J Kornhuber 1,
S Bleich 1,2 and
T Hillemacher 1,2

1. Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany
2. Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany

Correspondence: Dr B Lenz, Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6-10, D-91054 Erlangen, Germany. E-mail: bernd.lenz@uk-erlangen.de

Received 3 August 2009; Revised 2 October 2009; Accepted 6 October 2009; Published online 3 November 2009.
Abstract

We reported recently that a functional relevant CAG trinucleotide repeat of the androgen receptor influences craving of men in alcohol withdrawal. It is known to modulate serum concentrations of leptin, which affects hypothalamic appetite regulation. Its plasma levels are elevated during chronic alcohol consumption, normalize within periods of abstinence and are associated with craving. The aim of this study was to further elucidate the role of leptin in mediating the effects of the mentioned polymorphism on craving in men undergoing alcohol withdrawal. We included 110 male in-patients who were admitted for detoxification treatment. Each one had an established diagnosis of alcohol dependence according to the DSM-IV. Our results show on the one hand negative associations between the number of CAG repeats and (i) leptin serum levels (P<0.01)>P<0.05),>P<0.001).>r=-0.144) accounting for 60% and indirect, leptin-mediated effects (r=-0.096) accounting for 40% of the total effect. Dysregulation of sexual hormones influences human metabolism and seems to affect leptin homeostasis. This report suggests that the investigated polymorphism mediates its effect on craving of men in alcohol withdrawal mostly through the regulation of leptin. Nevertheless future studies are needed to further explore the functionality of the androgen receptor gene in terms of craving.

Featured Review: The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

Click here for article.

The Pharmacogenomics Journal advance online publication 3 November 2009; doi: 10.1038/tpj.2009.54

S P R Romaine¹, K M Bailey¹, A S Hall² and A J Balmforth¹

1. Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK
2. Multidisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK

Correspondence: SPR Romaine, Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, The LIGHT Laboratories, University of Leeds, Leeds LS2 9JT, UK. E-mail: S.Romaine04@leeds.ac.uk

Received 23 April 2009; Revised 15 September 2009; Accepted 28 September 2009; Published online 3 November 2009.

Abstract

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are well established in the treatment of hypercholesterolaemia and the prevention of coronary artery disease. Despite this, there is wide inter-individual variability in response to statin therapy, in terms of both lipid-lowering and adverse drug reactions. The major site of statin action is within hepatocytes and recent interest has focussed on genetic variation in hepatic influx and efflux transporters for their potential to explain these differences. In this review we explore current literature regarding the pharmacokinetic and pharmacodynamic influence of the common c.388A>G and c.521T>C single-nucleotide polymorphisms (SNPs) within the solute carrier organic anion transporter 1B1 (SLCO1B1) gene, encoding the organic anion transporter polypeptide 1B1 (OATP1B1) influx transporter. We discuss their potential to predict the efficacy of statin therapy and the likelihood that patients will experience adverse effects.

Very interesting new article on pharmacogenomics

By Jeffrey Perkel.

Click here to read it.

Risk of ischemic vascular disease in 52 000 individuals

For the article, click here.

Original Article

The Pharmacogenomics Journal advance online publication 4 August 2009; doi: 10.1038/tpj.2009.34

Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52 000 individuals

D Kaur-Knudsen1,2,4, S E Bojesen1,2,3,4 and B G Nordestgaard1,2,3,4

1. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
2. The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
3. The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
4. Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

Correspondence: Professor BG Nordestgaard, Department of Clinical Biochemistry, 54M1, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail: brno@heh.regionh.dk

Received 3 April 2009; Accepted 25 June 2009; Published online 4 August 2009.
Top of page
Abstract

Cytochrome P450 2C9 (CYP2C9) enzymes metabolize warfarin and arachidonic acid. We hypothesized that the CYP2C9*2 (rs.1799853) and CYP2C9*3 (rs.1057910) polymorphisms with decreased enzyme activity affect risk of subclinical atherosclerosis (reduced ankle brachial index and increased C-reactive protein), ischemic vascular diseases (ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease and ischemic stroke) and death after an ischemic heart disease diagnosis. We genotyped the Copenhagen City Heart Study, a prospective study including 10 398 participants with 30–32 years of follow-up; the Copenhagen General Population Study, a cross-sectional study including 21 629 participants; and the Copenhagen Ischemic Heart Disease Study, a case–control study including 5082 cases and 14 904 controls. CYP2C9 carriers versus noncarriers did not associate with subclinical atherosclerosis. Furthermore, the odds/hazard ratios for ischemic vascular disease did not differ from 1.0 for CYP2C9 carriers versus noncarriers. Finally, we found no altered risk of early death after a diagnosis of ischemic heart disease. For all end points, we could exclude even minor changes in risk of disease with 90% power. In conclusion, in three independent studies totaling more than 52 000 individuals, we found no association between CYP2C9*2 and CYP2C9*3 polymorphisms and risk of subclinical atherosclerosis, ischemic vascular disease or death after ischemic heart disease.

Adrenomedullin gene (ADM) and response to paroxetine

For a link to the article, click here.

Original Article

The Pharmacogenomics Journal advance online publication 28 July 2009; doi: 10.1038/tpj.2009.33

Association of a functional polymorphism in the adrenomedullin gene (ADM) with response to paroxetine

D M Glubb 1, P C McHugh 1, X Deng 1, P R Joyce 2 and M A Kennedy 1

1 Gene Structure & Function Laboratory, Department of Pathology, University of Otago, Christchurch, New Zealand

2 Department of Psychological Medicine, University of Otago, Christchurch, New Zealand

Correspondence: Dr DM Glubb, Department of Pathology, Gene Structure & Function Laboratory, University of Otago, Christchurch P.O. Box 4345, Christchurch 8140, New Zealand. E-mail: dylan.glubb@otago.ac.nz

Received 17 February 2009; Revised 8 May 2009; Accepted 25 June 2009; Published online 28 July 2009.

Abstract

To identify genes that may be relevant to the molecular action of antidepressants, we investigated transcriptional changes induced by the selective serotonin reuptake inhibitor paroxetine in a serotonergic cell line. We examined gene expression changes after acute treatment with paroxetine and sought to validate microarray results by quantitative PCR (qPCR). Concordant transcriptional changes were confirmed for 14 genes by qPCR and five of these, including the adrenomedullin gene (Adm), either approached or reached statistical significance. Reporter gene assays showed that a SNP (rs11042725) in the upstream flanking region of ADMsignificantly altered expression. Association analysis demonstrated rs11042725 to be significantly associated with response to paroxetine (odds ratio=0.075, P<0.001)>ADM is involved with the therapeutic efficacy of paroxetine, which may have pharmacogenetic utility.

Transgenic primates as research tools: now a reality

To see the article, click here

Article

Nature 459, 523-527 (28 May 2009) | doi:10.1038/nature08090; Received 27 September 2008; Accepted 30 April 2009

Generation of transgenic non-human primates with germline transmission

Erika Sasaki¹, Hiroshi Suemizu¹, Akiko Shimada¹, Kisaburo Hanazawa², Ryo Oiwa¹, Michiko Kamioka¹, Ikuo Tomioka^1,3, Yusuke Sotomaru⁵, Reiko Hirakawa^1,3, Tomoo Eto¹, Seiji Shiozawa^1,4, Takuji Maeda^1,4, Mamoru Ito¹, Ryoji Ito¹, Chika Kito¹, Chie Yagihashi¹, Kenji Kawai¹, Hiroyuki Miyoshi⁶, Yoshikuni Tanioka¹, Norikazu Tamaoki¹, Sonoko Habu⁷, Hideyuki Okano⁴ & Tatsuji Nomura¹

1. Central Institute for Experimental Animals, 1430 Nogawa, Miyamae-ku, Kawasaki, Kanagawa 216-0001, Japan
2. Department of Urology, Juntendo University Nerima Hospital 3-1-10 Takanodai, Nerima-ku, Tokyo 177-8521, Japan
3. Center for Integrated Medical Research,
4. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
5. Natural Science Centre for Basic Research and Development, Hiroshima University 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan
6. Subteam for Manipulation of Cell Fate, RIKEN BioResource Centre, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
7. Department of Immunology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan

Correspondence to: Erika Sasaki¹Hideyuki Okano⁴ Correspondence and requests for materials should be addressed to E.S. (Email: esasaki@ciea.or.jp) or H.O. (Email: hidokano@sc.itc.keio.ac.jp).

Abstract

The common marmoset (Callithrix jacchus) is increasingly attractive for use as a non-human primate animal model in biomedical research. It has a relatively high reproduction rate for a primate, making it potentially suitable for transgenic modification. Although several attempts have been made to produce non-human transgenic primates, transgene expression in the somatic tissues of live infants has not been demonstrated by objective analyses such as polymerase chain reaction with reverse transcription or western blots. Here we show that the injection of a self-inactivating lentiviral vector in sucrose solution into marmoset embryos results in transgenic common marmosets that expressed the transgene in several organs. Notably, we achieved germline transmission of the transgene, and the transgenic offspring developed normally. The successful creation of transgenic marmosets provides a new animal model for human disease that has the great advantage of a close genetic relationship with humans. This model will be valuable to many fields of biomedical research.

Nicotinic acetylcholine receptor variants are associated with cigarette smoking

To go to the article's website click here.

Original Article

The Pharmacogenomics Journal advance online publication 17 March 2009; doi: 10.1038/tpj.2009.6

Association of nicotinic acetylcholine receptor subunit 4 polymorphisms with nicotine dependence in 5500 Germans

L P Breitling¹, N Dahmen², K Mittelstra³, D Rujescu⁴, J Gallinat⁵, C Fehr², I Giegling⁴, C Lamina^3,6, T Illig^3,7, H Müller¹, E Raum¹, D Rothenbacher¹, H-E Wichmann³, H Brenner¹ and G Winterer⁸

1. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
2. Department of Psychiatry, University of Mainz, Mainz, Germany
3. Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
4. Department of Psychiatry, Ludwig Maximilians University, Munich, Germany
5. Department of Psychiatry, Charité University Medicine Berlin, Campus Mitte, Berlin, Germany
6. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbrnuck, Austria
7. Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany
8. Department of Psychiatry, Heinrich Heine University, Düsseldorf, Germany

Correspondence: Dr LP Breitling, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Bergheimer Street 20, D-69115 Heidelberg, Germany. Email: L.Breitling@dkfz.de

Received 12 November 2008; Revised 6 February 2009; Accepted 9 February 2009; Published online 17 March 2009.

Top of page

Abstract

Polymorphisms in the CHRNA4 gene coding the nicotinic acetylcholine receptor subunit 4 have recently been suggested to play a role in the determination of smoking-related phenotypes. To examine this hypothesis, we conducted a genetic association study in three large samples from the German general population (N₁=1412; N₂=1855; N₃=2294). Five single-nucleotide polymorphisms in CHRNA4 were genotyped in 5561 participants, including 2707 heavily smoking cases (regularly smoking at least 20 cigarettes per day) and 2399 never-smoking controls (100 cigarettes over lifetime). We examined associations of the polymorphisms with smoking case–control status and with the extent of nicotine dependence as measured by the Fagerstrom test of nicotine dependence (FTND) score (N=1030). The most significant association was observed between rs2236196 and FTND (P=0.0023), whereas the closely linked rs1044396 had most statistical support in the case–control models (P=0.0080). The consistent effect estimates across three independent cohorts elaborate on recently published functional studies of rs2236196 from the CHRNA4 3'-untranslated region and seem to converge with accumulating evidence to firmly implicate the variant G allele of this polymorphism in the intensification of nicotine dependence.

DRD4 polymosphisms and tardive dyskinesia

Click here for a link to this article.

The Pharmacogenomics Journal advance online publication 24 February 2009; doi: 10.1038/tpj.2009.2

Association study of tardive dyskinesia and five DRD4 polymorphisms in schizophrenia patients

C C Zai¹, A K Tiwari¹, V Basile¹, V De Luca¹, D J Müller¹, N King¹, A N Voineskos¹, G Remington¹, H Y Meltzer², J A Lieberman³, S G Potkin⁴ and J L Kennedy¹

1. Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
2. Psychiatric Hospital, Vanderbilt University, Nashville, TN, USA
3. Columbia University Medical Centre, New York State Psychiatric Institute, New York City, NY, USA
4. Brain Imaging Center, University of California, Irvine, CA, USA

Correspondence: Dr JL Kennedy, Neurogenetics, Centre for Addiction and Mental Health, 250, College Street, R-30, Toronto, Ontario, Canada M5T 1R8. E-mail: James_Kennedy@camh.net

Received 23 September 2008; Revised 11 November 2008; Accepted 8 January 2009; Published online 24 February 2009.

Abstract

Tardive dyskinesia (TD) is a side effect of chronic antipsychotic medication exposure. Abnormalities in dopaminergic activity in the nigro-striatal system have been most often suggested to be involved because the agents that cause TD share in common potent antagonism of dopamine D₂ receptors (DRD2). Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD, with the most consistent findings being an association between TD and the Ser9Gly polymorphism of the DRD3 gene and the TaqIA site 3' of the DRD2 gene. The DRD4 gene codes for the third member of the D₂-like dopamine receptor family, and the variable number tandem-repeat polymorphism in exon 3 of DRD4 has been associated with TD. However, other polymorphisms have not been thoroughly examined. In this study, we investigated five polymorphisms spanning the DRD4 gene and their association with TD in our European Caucasian sample (N=171). Although the exon 3 variable number tandem repeat was not associated with TD, haplotypes consisting of four tag polymorphisms were associated with TD in males. This study suggests that DRD4 may be involved in TD in the Caucasian population, although further replication studies are needed.

Pharmacogenetics of esophageal cancer

Click here for a link to the article.

The Pharmacogenomics Journal advance online publication 10 March 2009; doi: 10.1038/tpj.2009.5

GNAS1 T393C polymorphism is associated with histopathological response to neoadjuvant radiochemotherapy in esophageal cancer

H Alakus¹, U Warnecke-Eberz¹, E Bollschweiler¹, S P Mönig¹, D Vallböhmer¹, J Brabender¹, U Drebber², S E Baldus³, K Riemann⁴, W Siffert⁴, A H Hölscher¹ and R Metzger¹

1. Department of General, Visceral and Cancer Surgery, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany
2. Institute of Pathology, University of Cologne, Cologne, Germany
3. Institute of Pathology, University of Düsseldorf, Düsseldorf, Germany
4. Institute of Pharmacogenetics, University Hospital Essen, Essen, Germany

Correspondence: Dr R Metzger, Department of General, Visceral and Cancer Surgery, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Kerpener Str. 62, Cologne D-50937, Germany. E-mail: ralf.metzger@uk-koeln.de

Received 14 October 2008; Revised 6 February 2009; Accepted 9 February 2009; Published online 10 March 2009.

Top of page

Abstract

Recent studies have shown an association between the GNAS1 T393C polymorphism and clinical outcome for various solid tumors. In this study, we genotyped 51 patients from an observational trial on cisplatin/5-FU-based neoadjuvant radiochemotherapy of locally advanced esophageal cancer (cT2-4, Nx, M0) and genotyping was correlated with histomorphological tumor regression. The C-allele frequency in esophageal cancer patients was 0.49. Pearson's ²-test showed a significant (P<0.05)>

Control of CYP1A2 mRNA levels

Click here for a link to the article.

The Pharmacogenomics Journal advance online publication 10 March 2009; doi: 10.1038/tpj.2009.4

Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers

Roza Ghotbi¹, Alvin Gomez², Lili Milani³, Gunnel Tybring¹, Ann-Christine Syvänen³, Leif Bertilsson¹, Magnus Ingelman-Sundberg² and Eleni Aklillu¹

1. Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
2. Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
3. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

Correspondence: Dr E Aklillu, Division of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, C-168, SE-141 86 Stockholm, Sweden. E-mail: eleni.aklillu@ki.se

Received 7 October 2008; Revised 13 January 2009; Accepted 3 February 2009; Published online 10 March 2009.

Abstract

The basis for interindividual variation in the CYP1A2 gene expression is not fully understood and the known genetic polymorphisms in the gene provide no explanation. We investigated whether the CYP1A2 gene expression is regulated by DNA methylation and displays allele-specific expression (ASE) using 65 human livers. Forty-eight percent of the livers displayed ASE not associated to the CYP1A2 mRNA levels. The extent of DNA methylation of a CpG island including 17 CpG sites, close to the translation start site, inversely correlated with hepatic CYP1A2 mRNA levels (P=0.018). The methylation of two separate core CpG sites was strongly associated with the CYP1A2 mRNA levels (P=0.005) and ASE phenotype (P=0.01), respectively. The CYP1A2 expression in hepatoma B16A2 cells was strongly induced by treatment with 5-aza-2'-deoxycytidine. In conclusion, the CYP1A2 gene expression is influenced by the extent of DNA methylation and displays ASE, mechanisms contributing to the large interindividual differences in CYP1A2 gene expression.

Assessing the AmpliChip CYP450

Click here for a link to the article.

The Pharmacogenomics Journal (2009) 9, 34–41; doi:10.1038/tpj.2008.7; published online 1 July 2008

The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction

M C Rebsamen¹, J Desmeules², Y Daali², A Chiappe¹, A Diemand¹, C Rey¹, J Chabert², P Dayer², D Hochstrasser¹ and M F Rossier¹

1. Service of Laboratory Medicine, University Hospitals, Geneva, Switzerland
2. Service of Clinical Pharmacology and Toxicology, University Hospitals, Geneva, Switzerland

Correspondence: Dr MC Rebsamen, Services of Laboratory Medicine, University Hospitals of Geneva, 24 Rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. E-mail: michela.rebsamen@hcuge.ch

Received 14 December 2007; Revised 16 May 2008; Accepted 21 May 2008; Published online 1 July 2008.

Top of page

Abstract

Polymorphisms of the cytochrome P450 2D6 (CYP2D6) gene affecting enzyme activity are involved in interindividual variability in drug efficiency/toxicity. Four phenotypic groups are found in the general population: ultra rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. The AmpliChip CYP450 test is the first genotyping array allowing simultaneous analysis of 33 CYP2D6 alleles. The main aim of this study was to evaluate the performance of this test in CYP2D6 phenotype prediction. We first verified the AmpliChip CYP450 test genotyping accuracy for five CYP2D6 alleles routinely analysed in our laboratory (alleles 3,4,5,6, N; n=100). Results confirmed those obtained by real-time PCR. Major improvements using the array are the detection of CYP2D6 intermediate alleles and identification of the duplicated alleles. CYP2D6 phenotype was determined by assessing urinary elimination of dextromethorphan and its metabolite dextrorphan and compared to the array prediction (n=165). Although a low sensitivity of UM prediction by genotyping was observed, phenotype prediction was optimal for PM and satisfying for EM and IM.