Association between toll-like receptor 2 gene diversity and early-onset bipolar disorder

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.