Oliveira José, Etain Bruno, Lajnef Mohamed, Hamdani Nora, Bennabi Meriem, Bengoufa Djaouida, Sundaresh Aparna, Chaabane Arij Ben, Bellivier Frank, Henry Chantal, Kahn Jean-Pierre, Charron Dominique, Krishnamoorthy Rajagopal, Leboyer Marion, Tamouza Ryad
INSERM, U1160, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France.
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.
PLoS One. 2015 Mar 19;10(3):e0119702. doi: 10.1371/journal.pone.0119702. eCollection 2015.
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.
基因-环境相互作用可能在调节早期应激事件对双相情感障碍（BD）临床病程的影响中发挥重要作用，尤其是与早发相关。免疫功能障碍被认为是将童年创伤与早发性BD联系起来的重要机制，因此免疫相关基因座的遗传多样性可能是个体对这种严重亚型易感性的重要组成部分。在此，我们研究了Toll样受体2（TLR2）和4（TLR4）的基因变异（对病原体的主要先天性免疫反应分子）与童年创伤问卷（CTQ）在BD发病年龄方面的潜在相互作用。我们招募了531名BD患者（I型和II型或未另行指定），对TLR2的rs4696480和rs3804099以及TLR4的rs1927914和rs11536891单核苷酸多态性进行基因分型，并使用CTQ记录童年创伤史。根据首次躁狂或抑郁发作的年龄定义，评估TLR2和TLR4风险基因型携带者状态以及童年情感、身体和性虐待史与发病年龄的关系。通过Kaplan-Meier生存曲线，我们观察到TLR2 rs3804099 TT基因型与报告的性虐待对确定BD发病较早年龄的联合作用（p = 0.002；校正p = 0.02）。然而，TLR2-CTQ性虐待相互作用项的回归分析无统计学意义。童年性虐待对BD发病年龄的负面影响可能通过免疫介导途径在TLR2 rs3804099风险基因型携带者中放大。未来涉及大量患者队列的研究应纳入疾病严重程度的临床特征、免疫表型和早期生活感染性损伤史。
