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A Discriminating Messenger RNA Signature for Bipolar Disorder Formed by an Aberrant Expression of Inflammatory Genes in Monocytes
Roos C. Padmos, MD;
Manon H. J. Hillegers, MD, PhD;
Esther M. Knijff, MD, PhD;
Ronald Vonk, MD;
Anne Bouvy, MSc;
Frank J. T. Staal, PhD;
Dick de Ridder, PhD;
Ralph W. Kupka, MD, PhD;
Willem A. Nolen, MD, PhD;
Hemmo A. Drexhage, MD, PhD
Arch Gen Psychiatry. 2008;65(4):395-407.
Context Mood disturbances are associated with an activated inflammatory response system.
Objective To identify a discriminating and coherent expression pattern of proinflammatory genes in monocytes of patients with bipolar disorder.
Design A quantitative polymerase chain reaction (Q-PCR) case-control gene expression study on purified monocytes of bipolar patients, the offspring of bipolar patients, and healthy control participants after having selected 22 discriminating inflammatory genes using whole genome analyses.
Setting Academic research setting in the Netherlands.
Patients Forty-two bipolar patients with 25 healthy controls, 54 offspring of a bipolar parent (13 had a mood disorder and 3 developed one during follow-up), and 70 healthy children underwent Q-PCR.
Main Outcome Measure Inflammatory gene expression levels in monocytes.
Results We detected in the monocytes of bipolar patients a coherent mutually correlating set (signature) of 19 aberrantly expressed (P < .01) messenger RNAs of inflammatory (PDE4B, IL1B, IL6, TNF, TNFAIP3, PTGS2, and PTX3), trafficking (CCL2, CCL7, CCL20, CXCL2, CCR2, and CDC42), survival (BCL2A1 and EMP1), and mitogen-activated protein kinase pathway (MAPK6, DUSP2, NAB2, and ATF3) genes. Twenty-three of 42 bipolar patients (55%) had a positive signature test result vs 7 of 38 healthy controls (18%) (positive test result: positivity for PDE4B, ie, a messenger RNA 1 SD higher than the mean level found in healthy controls, plus 25% of the other genes with similar positive findings). Positive signature test results were also present in 11 of 13 offspring with a mood disorder (85%), 3 of 3 offspring developing a mood disorder (100%), and 17 of 38 euthymic offspring (45%) vs 13 of 70 healthy children (19%). Lithium carbonate and antipsychotic treatment downregulated the gene expression of most inflammatory genes.
Conclusions The monocytes of a large proportion of bipolar patients and offspring of bipolar parents showed an inflammatory gene expression signature. This coherent set of genes opens new avenues for biomarker development with possibilities for disease prediction in individuals genetically at risk and for the subclassification of bipolar patients who could possibly benefit from anti-inflammatory treatment.
Author Affiliations: Department of Immunology, Erasmus Medical Center, Rotterdam (Drs Padmos, Knijff, Staal, and Drexhage and Ms Bouvy); Department of Child and Adolescent Psychiatry, University Medical Center Utrecht (Dr Hillegers), and Altrecht Institute for Mental Health Care (Dr Kupka), Utrecht; Reinier van Arkel group, ’s-Hertogenbosch (Dr Vonk); Department of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft (Dr de Ridder); and Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen (Dr Nolen), the Netherlands.
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