DRD4 polymosphisms and tardive dyskinesia

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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

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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.

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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

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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

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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.

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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.