Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls

Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls

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J Psychiatry Neurosci 2012;37(1):53-7

Maria Holtze, MSc; Peter Saetre, PhD; Göran Engberg, PhD; Lilly Schwieler, PhD; Thomas Werge, PhD; Ole A. Andreassen, MD, PhD; Håkan Hall, PhD; Lars Terenius, PhD; Ingrid Agartz, MD, PhD; Erik G. Jönsson, MD, PhD; Martin Schalling, MD, PhD; Sophie Erhardt, PhD

Holtze, Engberg, Schwieler, Erhardt — Department of Physiology and Pharmacology, Karolinska Institutet; Saetre, Hall, Terenius, Agartz, Jönsson — Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and University Hospital, Stockholm, Sweden; Werge — Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark; Andreassen — TOP project, Division of Psychiatry, Ullevål University Hospital & Institute of Psychiatry, University of Oslo; Agartz — Institute of Psychiatry, University of Oslo, Psykiatrisk institutt, Vinderen, and the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway; Schalling — Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden

Abstract

Background: Patients with schizophrenia show increased brain and cerebrospinal fluid (CSF) concentrations of the endogenous N-methyl-D-aspartate receptor antagonist kynurenic acid (KYNA). This compound is an end-metabolite of the kynurenine pathway, and its formation indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine.
Methods: We analyzed the association between KMO gene polymorphisms and CSF concentrations of KYNA in patients with schizophrenia and healthy controls. Fifteen single nucleotide polymorphisms (SNPs) were selected covering KMO and were analyzed in UNPHASED.
Results: We included 17 patients with schizophrenia and 33 controls in our study. We found an association between a KMO SNP (rs1053230), encoding an amino acid change of potential importance for substrate interaction, and CSF concentrations of KYNA.
Limitations: Given the limited sample size, the results are tentative until replication.
Conclusion: Our results suggest that the nonsynonymous KMO SNP rs1053230 influences CSF concentrations of KYNA.


Submitted Dec. 8, 2010; Revised Mar. 14, Apr. 13, 2011; Accepted Apr. 15, 2011.

Acknowledgments: We thank patients and controls for their participation and express our gratitude toward health professionals who facilitated our work. We thank Frank Dudbridge for advice on UNPHASED, and Agneta Gunnar, Alexandra Tylec, Monica Hellberg and Kjerstin Lind for technical assistance. We also thank Kristina Larsson, Per Lundmark, Tomas Axelsson and Ann-Christine Syvänen at the SNP Technology Platform for performing the genotyping. The SNP Technology Platform is supported by Uppsala University, Uppsala University Hospital, and by the Knut and Alice Wallenberg Foundation.

Funding: This study was financed by grants from the Hållstens Forskningsstiftelse, Swedish Brain Foundation, Svenska Läkaresällskapet, Karolinska Institutet, Torsten och Ragnar Söderbergs stiftelse, Swedish Medical Research Council, Söderström-Königskastiftelsen, the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Copenhagen Hospital Corporation Research Fund, the Danish National Psychiatric Research Foundation, the Danish Agency for Science, Technology and Innovation (Centre for Pharmacogenetics) to T. Werge, the Research Council of Norway (147787, 167153), the Eastern Norway Health Authority (Helse ØstRHF 123/2004), Ullevål University Hospital, and University of Osloto the TOP study (O.A. Andreassen), the Swedish Research Council (No. 2009-4046 and 2009-7053 [S. Erhardt], K2009-62X-07484-24-3 [G. Engberg], K2007-62X-15077-04-1 [Ingrid Agartz], K2007- 62X-15078-04-3 [E.G. Jönsson], K2008-62P-20597-01-3 [E.G. Jönsson], 10909 [M. Schalling]), the Knut and Alice Wallenberg Foundation (L. Terenius) and the HUBIN project. The funding sources had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Competing interests: None declared for M. Holtze and P. Saetre, L. Schwieler, H. Hall, M. Schalling and S. Erhardt. As above for G. Engberg, T. Werge, O.A. Andreassen, L. Terenius, I. Agartz and E.G. Jönsson. T. Werge also declares having received consultancy and lecture fees from Lundbeck A/S.

Contributors: M. Holtze coordinated the preparation of the manuscript and wrote the initial draft. P. Saetre performed and drafted the statistical analyses. G. Engberg participated in the study design and supervised the KYNA analyses. L. Schwieler, T. Werge and O.A. Andreassen participated in the study design and performed the KYNA analyses. H. Hall, L. Terenius and I. Agartz participated in the study design and contributed to data collection. E.G. Jönsson participated in the study design, clinical characterization and contributed to data collection. M. Schalling participated in the study design. S. Erhardt participated in the study design, performed the KYNA analyses and helped write the paper. All authors contributed article review and approved the publication of the final manuscript.

DOI: 10.1503/jpn.100175

Correspondence to: Dr. E.G. Jönsson, Department of Clinical Neuroscience, HUBIN, Project, Karolinska Institutet and University Hospital, R5:00, SE-171 76 Stockholm, Sweden; erik.jonsson@ki.se