Oliveira José, Hamdani Nora, Busson Marc, Etain Bruno, Bennabi Meriem, Amokrane Kahina, Boukouaci Wahid, Fortier Catherine, Marzais François, Bengoufa Djaouida, Bellivier Frank, Henry Chantal, Kahn Jean-Pierre, Charron Dominique, Krishnamoorthy Rajagopal, Le Corvoisier Philippe, Leboyer Marion, Tamouza Ryad
INSERM, U1160, Hôpital Saint Louis, Paris F75010, France; Fondation FondaMental, Créteil F94000 France.
INSERM, U955, Psychiatrie Génétique, Créteil F94000, France; Université Paris-Est, Faculté de Médecine, Créteil F94000, France; AP-HP, Pôle de Psychiatrie, Hôpitaux Universitaires Henri Mondor, Créteil F94000, France; Fondation FondaMental, Créteil F94000 France.
J Affect Disord. 2014 Aug;165:135-41. doi: 10.1016/j.jad.2014.04.059. Epub 2014 May 4.
Toll-like receptor 2 (TLR2) molecules play a pivotal role in innate immune responses by their ability to recognize and sense a wide repertoire of infectious and endogenous cellular structural elements. Here we evaluated whether genetic variants in TLR2 influence the age of the disease onset in bipolar disorder (BD).
DNAs from 571 BD patients 229 early-onset (EO-BD) and 342 late-onset (LO-BD) and 199 healthy controls (HC) were analyzed for the following TLR2 polymorphisms: the 5'-UTR -196 to -174 insertion/deletion (ins/del), the intron 1 rs4696480 A/T, and the exon 3 rs3804099 C/T and rs3804100 C/T. PHASE software was used for haplotype reconstruction. Genetic associations were examined using a chi-square test.
We found that the TLR2 rs3804099 TT was significantly more prevalent in EO-BD than in LO-BD patients (corrected p (pc)=0.024). After excluding family history of psychiatric disorders, we also found that the TLR2 rs4696480 TT genotype was significantly more prevalent in EO-BD as compared to LO-BD and controls (pc=0.002 and 0.002). Homozygous state for the insTTT haplotype, carrying the above mentioned risk genotypes, was significantly more frequent in EO-BD than in LO-BD patients (pc=0.007) and in EO-BD without family history of psychiatric disorders as compared to (i) those with positive history (pc=0.03), (ii) with LO-BD without family history (pc=0.001) and (iii) with HC (pc=0.009).
Confirmation by replication in independent BD cohorts is warranted.
Our data suggest the potential role of TLR2 genetic variants in the pathogen-mediated susceptibility to BD.
Toll样受体2（TLR2）分子通过识别和感知多种传染性和内源性细胞结构元件的能力，在先天免疫反应中发挥关键作用。在此，我们评估了TLR2基因变异是否会影响双相情感障碍（BD）的发病年龄。
对571例BD患者（229例早发型（EO-BD）和342例晚发型（LO-BD））以及199例健康对照（HC）的DNA进行分析，检测以下TLR2多态性：5'-非翻译区-196至-174插入/缺失（ins/del）、内含子1 rs4696480 A/T以及外显子3 rs3804099 C/T和rs3804100 C/T。使用PHASE软件进行单倍型重建。采用卡方检验检测基因关联性。
我们发现，TLR2 rs3804099 TT在EO-BD患者中比在LO-BD患者中显著更常见（校正p值（pc）=0.024）。在排除精神疾病家族史后，我们还发现，与LO-BD和对照组相比，TLR2 rs4696480 TT基因型在EO-BD中显著更常见（pc=0.002和0.002）。携带上述风险基因型的insTTT单倍型纯合状态在EO-BD患者中比在LO-BD患者中显著更常见（pc=0.007），并且在无精神疾病家族史的EO-BD患者中，与（i）有阳性家族史者相比（pc=0.03），（ii）无家族史的LO-BD患者相比（pc=0.001）以及（iii）与HC相比（pc=0.009）也显著更常见。
有必要在独立的BD队列中进行重复验证。
我们的数据表明TLR2基因变异在病原体介导的BD易感性中可能发挥作用。
