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

Abstract

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.

Oxidative and nitrosative stress markers in obsessive–compulsive disorder: a systematic review and meta‐analysis

“…Regarding pre‐morbid environmental factors, OCD patients have been proposed to be exposed more frequently to stressors, such as perinatal events, psychological stressors, and other traumatic events, all thought to induce inflammation and oxidative stress, which may induce neurochemical modifications in several neurotransmitter pathways, including glutamate . Schiavone and collaborators hypothesized that oxidative stress could initially be adaptive, through enhancement of neurotransmission, but that chronic generation of ROS could lead to exaggerated neurophysiological responses, with disruption of physiological neurotransmission and increase of blood–brain barrier permeability, ultimately promoting neuroinflammation and neuronal death .…”

HLA genetics in bipolar disorder

“…In accordance with other common immune disorders, BD may be understood within the framework of gene‐environment interactions , with host immunogenetics having a significant role in BD risk or in BD‐associated clinical manifestations or both. This is supported by recent data showing associations of functionally relevant Toll‐like receptor 4 ( TLR ‐4 and TLR ‐2) polymorphisms with early onset BD , autoimmune comorbidities .…”

A Toll‐like receptor 2 genetic variant modulates occurrence of bacterial infections in patients with sickle cell disease

“…TLRs are glycoproteins that recognize a wide range of PAMPs and DAMPs, with the consequent induction of inflammatory responses via nuclear factor (NF)‐κB family members (Akira et al , ; Oliveira et al , ; Ntoufa et al , ). Currently, 13 TLRs are known.…”

“…Seven SNPs in TLR1 (rs4833095) , TLR2 (rs4308099, rs4696480, rs4308100) , TLR6 (rs5743810) and TLR10 (rs11466653, rs11096957), all located in chromosome 4, were genotyped by mean of TaqMan 5′ nuclease assay (Applied Biosystems, Foster City, CA, USA) using pre‐designed allele‐specific fluorogenic oligonucleotide probes. The polymerase chain reaction (PCR) technique employed was described elsewhere (Oliveira et al , ). Prior to PCR reaction, DNA was pre‐amplified, using the following protocol: primers 40× were diluted with Trizol to 0·2×; for each sample, we added 1·3 μl of DNA at 20 ng/μl, 1 μl of pre‐amplification master mix (Fluidigm, San Francisco, CA, USA), 1·25 μl of pooling assay with primers and 1·45 μl of pure water.…”

“…In this context, Toll‐like receptors (TLRs) are a family of transmembrane and intra‐cellular proteins expressed on immune cells that sense pathogen‐associated molecular patterns (PAMPs) and endogenous damage‐associated molecular patterns (DAMPs). TLRs bind specific related ligands and, by activating downstream signalling cascades, promote transcription of inflammatory cytokines and chemokines (Akira et al , ; Oliveira et al , ; Ntoufa et al , ). TLRs are part of the innate immune system and are at the forefront response against several types of pathogens, including bacteria.…”