Abstract
Gene-environment interactions may play an important role in modulating the impact of early-life 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.
Highlights
Viewed as a cyclical disease, bipolar disorder (BD) is seen as a multi-systemic, progressive chronic illness whose clinical manifestations can be underpinned by biological and environmental factors interacting in a complex manner [1,2]
We hypothesized that the genetic potential of innate immune/ inflammatory responses may variably modulate the impact of psychosocial stressors on the clinical expression of BD, assessed here by age at onset (AAO) used as a proxy of severity. In this cross-sectional study, we investigated potential interactions on AAO of BD between functionally-relevant Toll-like receptor 2 (TLR2)/TLR4 genetic variations and reported childhood trauma, both previously showed to be independently associated with early-onset BD
We found that the TLR2 rs3804099 TT genotype was marginally associated with an earlier AAO [p = 0.01; corrected p = 0.1] with mean AAO of 23.5±9.56 years for patients bearing the TT genotype and 25.5±9.93 years for those carrying the others (CT and CC)
Summary
Viewed as a cyclical disease, bipolar disorder (BD) is seen as a multi-systemic, progressive chronic illness whose clinical manifestations can be underpinned by biological and environmental factors interacting in a complex manner [1,2]. It is noteworthy that early-life psychosocial stressors, notably emotional and sexual abuses are associated to early AAO [8,9] Such stressful events are known to induce acute and chronic immune/inflammatory alterations [10,11,12,13] possibly leading to an increased vulnerability to diabetes, obesity, cardiovascular disorders, autoimmunity, cancer and neurodegeneration commonly observed in adults with history of childhood maltreatment [14,15,16,17,18]. Of interest is that elevated C-reactive-protein (CRP), as well as high prevalence of cardiovascular disorders, type 2 diabetes mellitus, hypertension and obesity, are observed in early onset BD [19,20] and that some of these conditions even precede the diagnosis of BD in pediatric patients [20] These epidemiological observations may reflect the immune/inflammatory dysfunctions possibly important in early-onset BD. 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]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
