title: 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 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.
authors: INSERM, U1160, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France.
authors: José
authors: J
authors: Oliveira
authors: INSERM, U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France; Fondation FondaMental, Créteil, France.
authors: Bruno
authors: B
authors: Etain
authors: INSERM, U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France.
authors: Mohamed
authors: M
authors: Lajnef
authors: INSERM, U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France; Fondation FondaMental, Créteil, France.
authors: Nora
authors: N
authors: Hamdani
authors: INSERM, U1160, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France.
authors: Meriem
authors: M
authors: Bennabi
authors: INSERM, U1160, Hôpital Saint Louis, Paris, France; Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France.
authors: Djaouida
authors: D
authors: Bengoufa
authors: INSERM, U1160, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France.
authors: Aparna
authors: A
authors: Sundaresh
authors: INSERM, U1160, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France.
authors: Arij Ben
authors: AB
authors: Chaabane
authors: INSERM, U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France; Fondation FondaMental, Créteil, France.
authors: Frank
authors: F
authors: Bellivier
authors: INSERM, U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France; Fondation FondaMental, Créteil, France.
authors: Chantal
authors: C
authors: Henry
authors: Service de Psychiatrie et Psychologie Clinique, CHU de Nancy, Hôpitaux de Brabois, Vandoeuvre Les Nancy, France; Fondation FondaMental, Créteil, France.
authors: Jean-Pierre
authors: JP
authors: Kahn
authors: INSERM, U1160, Hôpital Saint Louis, Paris, France; Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France; Université Paris Diderot, Sorbonne Paris-Cité, Paris, France.
authors: Dominique
authors: D
authors: Charron
authors: INSERM, U1160, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France.
authors: Rajagopal
authors: R
authors: Krishnamoorthy
authors: INSERM, U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France; Fondation FondaMental, Créteil, France.
authors: Marion
authors: M
authors: Leboyer
authors: INSERM, U1160, Hôpital Saint Louis, Paris, France; Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France; Université Paris Diderot, Sorbonne Paris-Cité, Paris, France.
authors: Ryad
authors: R
authors: Tamouza
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D002648:Child; D002650:Child Abuse, Sexual; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013315:Stress, Psychological; D011795:Surveys and Questionnaires; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4