Wong ML, Dong C, Maestre-Mesa J, Licinio J. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 13: 800-812

Department of Psychiatry and Behavioral Sciences, Center on Pharmacogenomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Molecular Psychiatry (Impact Factor: 14.5). 09/2008; 13(8):800-12. DOI: 10.1038/mp.2008.59
Source: PubMed


There are clinical parallels between the nature and course of depressive symptoms in major depressive disorder (MDD) and those of inflammatory disorders. However, the characterization of a possible immune system dysregulation in MDD has been challenging. Emerging data support the role of T-cell dysfunction. Here we report the association of MDD and antidepressant response to genes important in the modulation of the hypothalamic-pituitary-adrenal axis and immune functions in Mexican Americans with major depression. Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome beta4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation. Our analyses revealed a significant combined allele dose-effect: individuals who had one, two and three risk alleles were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We found associations of several SNPs and antidepressant response; those genes support the role of T cell (CD3E, PRKCH, PSMD9 and STAT3) and hypothalamic-pituitary-adrenal axis (UCN3) functions in treatment response. We also describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. This further suggests predominance of type 1 T-cell activity in MDD. T-cell function variations that we describe here may account for 47.8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups.

Download full-text


Available from: Chuanhui Dong, Jun 29, 2014
8 Reads
  • Source
    • "r suggested to induce GR resistance and trigger the inflammatory cascade ( Miller et al . , 2002 ; Raison et al . , 2006 ; Cohen et al . , 2012 ) . From the genetic perspective , polymorphisms in the genes PSMB4 ( proteasome β4 subunit ) and TBX21 ( T bet ) that result in T - cell dysfunction , were reported to contribute to the pathology of MDD ( Wong et al . , 2008 ; Berk et al . , 2013 ) . A recent meta - analysis of 28 studies identified significant associations between depression and infections in Borna disease virus ( BDV ) , herpes simplex virus - 1 , varicella zoster virus , Epstein - Bar virus ( EBV ) , and Chlamydophila trachomatis . Results indicated that patients with depression are 3 . 2"
    [Show abstract] [Hide abstract]
    ABSTRACT: Major depressive disorder (MDD) is a mood disorder of multifactorial origin affecting millions of people worldwide. The alarming estimated rates of prevalence and relapse make it a global public health concern. Moreover, the current setback of available antidepressants in the clinical setting is discouraging. Therefore, efforts to eradicate depression should be directed towards understanding the pathomechanisms involved in the hope of finding cost-effective treatment alternatives. The pathophysiology of MDD comprises the breakdown of different pathways, including the hypothalamus-pituitary-adrenal (HPA) axis, the glutamatergic system, and monoaminergic neurotransmission, affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. In addition, evidence from different studies suggests that impairment of glial functions appears to be a major contributor as well. Thus, the intricate role between glia, namely microglia and astrocytes, and the central nervous system's (CNSs) immune response is briefly discussed, highlighting the kynurenine pathway as a pivotal player. Moreover, evaluations of different treatment strategies targeting the inflammatory response are considered. The immuno-modulatory properties of vitamin D receptor (VDR) suggest that vitamin D is an attractive and plausible candidate in spite of controversial findings. Further research investigating the role of VDR in mood disorders is warranted.
    Frontiers in Cellular Neuroscience 07/2015; 9:268. DOI:10.3389/fncel.2015.00268 · 4.29 Impact Factor
  • Source
    • "Neuropsychiatric disorders, such as depression and schizophrenia, are debilitating diseases with a high prevalence (Kessler et al., 2003). Among other factors, inflammation has emerged as a critical player in the pathophysiology of depression and many other neuropsychiatric disorders (Wong et al., 2008; Maes et al., 2009; Farooq et al., 2012). In the clinic, medical conditions involving systemic and/or central inflammatory events are closely correlated with clinical manifestations of mental illnesses (Dantzer et al., 2008, 2011; Kumar et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammatory disturbances have been closely associated with depression and many other neuropsychiatric diseases. Although targeting neuroinflammatory mediators with centrally-acting drugs has shown certain promise, its translation is faced with several challenges especially drug delivery and safety concerns. Here, we report that neuroinflammation-induced behavioral abnormality could be effectively attenuated with immunomodulatory agents that need not to gain brain penetration. In a rat model with intracerebral lipopolysaccharide (LPS) challenge, we validated that ginsenoside Rg1 (Rg1), a well-established anti-inflammatory agent, was unable to produce a direct action in the brain. Interestingly, peripherally-restricted Rg1 could effectively attenuate the weight loss, anorexic- and depressive-like behavior as well as neurochemical disturbances associated with central LPS challenge. Biochemical assay of neuroimmune mediators in the periphery revealed that Rg1 could mitigate the deregulation of the hypothalamic-pituitary-adrenal (HPA) axis and selectively blunt the increase in circulating interleukin (IL)-6 levels. Furthermore, these peripheral regulatory effects were accompanied by dampened microglial activation, mitigated expression of pro-inflammatory mediators and neurotoxic species in the central compartment. Taken together, our work suggested that targeting the peripheral immune system may serve as a novel therapeutic approach to neuroinflammation-induced neuropsychiatric disorders. Moreover, our findings provided the rationale for employing peripherally-active agents like Rg1 to combat mental disturbances.
    Neuroscience 10/2013; 256. DOI:10.1016/j.neuroscience.2013.10.023 · 3.36 Impact Factor
  • Source
    • "From this set of six SNPs, an SNP in the gene CXCL10 was associated with both CXCL10 expression and treatment response. This is of interest due to the associations being found between immune response and neuropsychiatric disorders [28, 68] and the association of CXCL10 with antidepressant treatment response in MDD [28, 75, 76]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mood disorders and schizophrenia are common and complex disorders with consistent evidence of genetic and environmental influences on predisposition. It is generally believed that the consequences of disease, gene expression, and allelic heterogeneity may be partly the explanation for the variability observed in treatment response. Correspondingly, while effective treatments are available for some patients, approximately half of the patients fail to respond to current neuropsychiatric treatments. A number of peripheral gene expression studies have been conducted to understand these brain-based disorders and mechanisms of treatment response with the aim of identifying suitable biomarkers and perhaps subgroups of patients based upon molecular fingerprint. In this review, we summarize the results from blood-derived gene expression studies implemented with the aim of discovering biomarkers for treatment response and classification of disorders. We include data from a biomarker study conducted in first-episode subjects with schizophrenia, where the results provide insight into possible individual biological differences that predict antipsychotic response. It is concluded that, while peripheral studies of expression are generating valuable results in pathways involving immune regulation and response, larger studies are required which hopefully will lead to robust biomarkers for treatment response and perhaps underlying variations relevant to these complex disorders.
    Disease markers 07/2013; 35(1):11-21. DOI:10.1155/2013/748095 · 1.56 Impact Factor
Show more