A study identified five low-frequency missense mutations (Ser73Arg, Ala97Val, Tyr98Cys, Thr175Ala and Thr399Ile) in the ectoplasmic LRR domain [69], which are
common variants in the Caucasian population [70]. The amino acid substitutions may alter protein structure and function, but it is still not known whether Tyr98Cys and Thr175Ala alter the function of TLR4. Ser73Arg showed a slightly higher frequency in typhoid cases [69]. Asp299Gly and Thr399Ile SNPs were not found in Korean, Taiwan Chinese and Japanese populations [71, 72]. Thr399Ile occurred in a low frequency in the Vietnamese population. Asp299Gly variant is associated with TB susceptibility in HIV-infected patients in Tanzania [73], and there is no association between TLR4 ICG-001 Asp299Gly and TB susceptibility in Gambian [74] and Mexican population [75]. The two cosegregated mutations Thr399Ile and Asp299Gly, which lies in the ectoplasmic LRR domain, are significantly associated with a decreased cytokine response to LPS [76] stimulation and increased susceptibility to a variety of infections [77-80] by affecting
the extracellular domain of the TLR4 receptor [70]. These LRR region mutations may potentially disturb phosphorylation of TLR4 altering downstream signalling of inflammatory mediator activation, ultimately contributing to disease susceptibility [69]. Thus, individuals who have these variations in TLR4 may prone to develop PD0325901 price TB (Table 1). Toll-like receptor 6 consists of 796 amino acid polypeptide containing only one exon [81]. It is expressed in the spleen and peripheral blood leucocytes and is a coreceptor for TLR2. TLR-6 activated through MYD88 and TRAF6, leading to NF-kB activation, cytokine secretion and inflammatory response. It recognizes lipid-containing ligands like Chloroambucil lipoteichoic acid, diacylated lipopeptides like PAM2 (PAM2CSKKKK, S-[2,3-bis(palmitoyloxy)-propyl]-(R)-cysteinyl-(lysyl)3-lysine) [82], and it also recognizes soluble tuberculosis factor (STF), Borrelia burgdorferi outer surface
protein A lipoprotein (OspA-L) and phenol-soluble modulin (PSM) with TLR2[83]. Polymorphisms in the coding region of TLR-6 gene were investigated in Chinese Cantonese population, a total of seven SNPs were detected, five of them with amino acid substitution, (Met59Thr (+176T/C), Ile120Thr (+359T/C), Val327Met (+979G/A), Val465Ile (+1393G/A) and Val470Leu (+1408G/T). Remaining two are (+1083C/G and +1263A/G) without amino acid substitution. An nSNP, +745T/C (Ser249Pro) was significantly associated with protection from asthma in African Americans and European Americans. In African Americans, homozygote for the common variant TLR6 249S had a significantly increased risk for TB disease [47].