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

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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

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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.

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Risk of ischemic vascular disease in 52 000 individuals

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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.
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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

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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

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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

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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.

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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.