Association between polymorphisms of TLR2-1-6 and bipolar disorder in a tunisian population

Background Bipolar disorder (BD) is a complex neuropsychiatric disease that has been strongly linked to immune dysregulation. In particular, an abnormal inflammatory response mediated by toll-like receptor 2-1/6 (TLR2-1/6) was described in BD. Nevertheless, genetic factors' contribution is still unknown. Thus, we suggested that functional polymorphisms of TLR2, 1 and 6 could be involved in BD predisposition. Methods and results TLR2, 1 and 6 polymorphisms were genotyped by PCR-RFLP in 292 controls and 131 patients from a Tunisian population. Polymorphisms and haplotype associations were explored in BD and binary logistic regression analysis was performed for more powerful associations. In dominant model, we found a significantly higher genotype and minor allele frequencies in healthy females compared to patients for TLR2-196-174Ins/Del (p=0.04; OR=0.3, p=0.04; OR=0.3, respectively) and for TLR6-S249P only with minor allele (p=0.03; OR=0.2). In contrast, TLR2-R677W CT+TT and T allele frequencies were significantly higher in BD (p(adjusted)< 10(-4); ORadjusted =46.6, p < 10(-4); OR=6.3, respectively), specifically in females (CT+TT: 100%). Similarly, TLR1-R80T showed significantly increased GC+CC and C allele frequencies in patients compared to controls (p(adjusted)=0.04; ORadjusted=4, p=0.009; OR=4.3, respectively). Moreover, haplotype investigation demonstrated that InsGTCGT (p < 10(-4), OR=275) and delGCCGT (p=0.03, OR=18.5) were significantly overrepresented in BD patients compared to controls. Conclusions We suggest that TLR2-196-174Ins/Del and TLR6-S249P could be protective factors of females against BD. However, TLR2-R677W and TLR1-R80T could be strongly associated with higher risk of BD. Interestingly, TLR2-R677W could be a genetic marker for BD in females. However, further studies with larger groups are needed to confirm these findings.