Association between toll-like receptor 2 gene diversity and early-onset bipolar disorder

Oliveira, J.; Hamdani, Nora; Busson, Marc; Étain, Bruno; Bennabi, Mériem; Amokrane, Kahina; Boukouaci, Wahid; Fortier, Catherine; Marzais, François; Bengoufa, Djaouïda; Bellivier, Frank; Henry, Chantal; Kahn, Jean‐Pierre; Charron, Dominique; Krishnamoorthy, Rajagopal; Corvoisier, Philippe Le; Leboyer, Marion; Tamouza, Ryad

doi:10.1016/j.jad.2014.04.059

Cited by 31 publications

(27 citation statements)

References 64 publications

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“…Finally, another recent gene-environment interaction study investigated the possible effect of interactions between serologically documented exposure to T. gondii , CMV, HSV-1 or HSV-2 and polymorphisms of TLR2 , TLR4 and NOD2 genes, which encode for pivotal pattern-recognition receptors, in a sample of 138 BD patients [130]. The genetic associations between TLR2 , TLR4 and NOD2 polymorphisms with susceptibility to infections, on the one hand, and BD, on the other, have been previously reported in the literature [131,132,133,134,135,136]. Oliveira et al [130], besides confirming the association between BD and T. gondii , first described a trend for an interaction between a TLR2 polymorphism and T. gondii seropositivity in conferring BD risk, suggesting that exposure to infection may modulate the immunogenetic background on BD.…”

Section: The Association Between Autoimmune/inflammatory Dysregulamentioning

confidence: 92%

Is Toxoplasma gondii a Trigger of Bipolar Disorder?

et al. 2017

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Toxoplasma gondii, a ubiquitous intracellular parasite, has a strong tropism for the brain tissue, where it forms intracellular cysts within the neurons and glial cells, establishing a chronic infection. Although latent toxoplasmosis is generally assumed to be asymptomatic in immunocompetent individuals, it is now clear that it can induce behavioral manipulations in mice and infected humans. Moreover, a strong relation has emerged in recent years between toxoplasmosis and psychiatric disorders. The link between T. gondii and schizophrenia has been the most widely documented; however, a significant association with bipolar disorder (BD) and suicidal/aggressive behaviors has also been detected. T. gondii may play a role in the etiopathogenesis of psychiatric disorders affecting neurotransmitters, especially dopamine, that are implicated in the emergence of psychosis and behavioral Toxoplasma-induced abnormalities, and inducing brain inflammation by the direct stimulation of inflammatory cytokines in the central nervous system. Besides this, there is increasing evidence for a prominent role of immune dysregulation in psychosis and BD. The aim of this review is to describe recent evidence suggesting a link between Toxoplasma gondii and BD, focusing on the interaction between immune responses and this infectious agent in the etiopathogenesis of psychiatric symptoms.

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Section: The Association Between Autoimmune/inflammatory Dysregulamentioning

confidence: 92%

Is Toxoplasma gondii a Trigger of Bipolar Disorder?

et al. 2017

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“…These patients were sampled from one large ongoing study that explored genetic and environmental risk factors of BD. Data regarding the association between TLR2/TLR4 genetic variations and BD have been previously published [22,23] and this was the same for the data regarding the association between AAO and childhood trauma [8]. To be included in this analysis, all cases had to have both a retrospective assessment of the AAO of BD, defined by the age of the first manic or depressive episode, as well as available genotypes for TLR2 or TLR4 genetic variations.…”

Section: Subjectsmentioning

confidence: 99%

“…Four functionally-relevant TLR2 and TLR4 single-nucleotide polymorphisms (SNPs) (rs4696480, rs3804099 and rs1927914, rs11536891 respectively) were selected based on previous genetic association studies of BD [22,23]. Genomic DNA was extracted from EDTA-treated peripheral blood samples or B-lymphoblastoid cell lines using the Nucleon BACC3 kit (GE HealthCare, Chalfont St Giles, UK).…”

Section: Tlr2 and Tlr4 Genetic Polymorphism Studiesmentioning

confidence: 99%

“…One of the proposed mechanisms is that acute stressor-mediated events may induce chronic alterations in immune/inflammatory processes in genetically predisposed individuals [12,13]. Exploring the control of innate immune responses in BD, we recently described associations between genetic variants of Toll-like receptor 2 (TLR2) and TLR4 loci and early-onset BD [22,23].…”

Section: Introductionmentioning

confidence: 99%

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Combined Effect of TLR2 Gene Polymorphism and Early Life Stress On the Age at Onset of Bipolar Disorders

Oliveira

Étain

Lajnef

et al. 2015

European Psychiatry

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Gene-environment interactions may play an important role in modulating the impact of earlylife stressful events on the clinical course of bipolar disorder (BD), particularly associated to early age at onset. Immune dysfunction is thought to be an important mechanism linking childhood trauma with early-onset BD, thus the genetic diversity of immune-related loci may account for an important part of the interindividual susceptibility to this severe subform. Here we investigated the potential interaction between genetic variants of Toll-like receptors 2 (TLR2) and 4 (TLR4), major innate immune response molecules to pathogens, and the childhood trauma questionnaire (CTQ) in age at onset of BD. We recruited 531 BD patients (type I and II or not otherwise specified), genotyped for the TLR2 rs4696480 and rs3804099 and TLR4 rs1927914 and rs11536891 single-nucleotide polymorphisms and recorded for history of childhood trauma using the CTQ. TLR2 and TLR4 risk genotype carrier state and history of childhood emotional, physical and sexual abuses were evaluated in relation to age at onset as defined by the age at first manic or depressive episode. We observed a combined effect of TLR2 rs3804099 TT genotype and reported sexual abuse on determining an earlier age at onset of BD by means of a Kaplan-Meier survival curve (p = 0.002; corrected p = 0.02). Regression analysis, however, was non-significant for the TLR2-CTQ sexual abuse interaction term. The negative effects of childhood sexual abuse on age at onset of BD may be amplified in TLR2 rs3804099 risk genotype carriers through immune-mediated pathways. Clinical characteristics of illness severity, immune phenotypes and history of early life infectious insults should be included in future studies involving large patient cohorts.

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“…By stratifying genetic data according to more homogeneous phenotypes based on clinical presentation, several studies revealed specific associations, namely with early-onset BD (73). Regarding immunogenetics, the genetic diversity of TLR2, considered to be the most pleiotropic TLR (sensing Gram-positive bacteria, viruses and T. gondii among others), has been explored (74).…”

Section: Modulators Of Clinical Presentationmentioning

confidence: 99%