Genetic predisposition of variants in TLR2 and its co-receptors to severe malaria in Odisha, India

Abstract

Although the role of TLRs signalling in malaria pathogenesis is well established, contribution of individual TLR to clinical outcome of malaria still remains inconclusive. Given the importance of TLR2 and its co-receptors in recognising distinct structural forms of key malaria toxins and mediating innate immune response, it is essential to delineate their genetic contribution. Variants in TLR1 (I602S) and TLR6 (P249S) were genotyped by PCR-RFLP methods, and TLR2 (I/D) was genotyped by PCR in 200 samples each from uncomplicated malaria (UM) and severe malaria (SM). Further, SM was categorised into its sub-clinical groups (CM and NCSM or SOD and MODS) and analysed. The results showed the PP genotype of TLR6 (P249S) to be significantly more common in UM (P < 0.0001), whereas the 'SS' genotype was the risk factor for SM including its sub-clinical categories. The TLR1 (602S) and TLR2 (D) variants were significantly high in patients with CM; however, negative LD was observed between TLR2 and TLR6 in NCSM and MODS. Haplotype analysis showed significantly high frequency of I-I-S haplotype in all forms of subclinical SM and was associated with low parasite load in SM (P = 0.013). The haplotypes I-D-S and S-I-P were significantly high in SOD and CM, respectively. The TLR6 '249S' variant appeared to be the dominant determinant for genetic predisposition to SM and that its association with either TLR2 'D' or TLR1 '602S' modulates for CM development. The present study opens up several new avenues for their exploration and validation in future studies in different global settings for malaria.

Susceptibility to HIV‐1 infection is influenced by toll like receptor‐2 (−196 to −174) polymorphism in a north Indian population

“…evaluated the role of TLR2 in periodontal disease in an HIV positive North American cohort and found it to be associated with bleeding on probing, an indicator of an subgingival inflammatory response to bacterial pathogens. The results of the present study are also consistent with previous studies conducted in Indian and other Asian population showing that the TLR2 Ins/Del polymorphism is associated with the risk of severe malaria, cervical cancer, gallbladder cancer, prostate cancer, Epstein–Barr virus associated gastric carcinoma in Chinese and tuberculosis …”

“…29 It was also found to be associated with tuberculosis in Caucasians and Africans, 30 colorectal cancer in Brazilians, 31 in breast cancer 32 and in Parkinson 0 s disease in a Greek population. 33 Asian population showing that the TLR2 Ins/Del polymorphism is associated with the risk of severe malaria, 35 cervical cancer, 36,37 gallbladder cancer, 38 prostate cancer, 17,39 Epstein-Barr virus associated gastric carcinoma in Chinese 40,41 and tuberculosis. 42 The three nonsynonymous polymorphisms in the TLR2 gene (Arg753Gyn, Arg677Trp and Pro631His) are associated with altered TLR2 signaling and have been reported to influence susceptibility to various infections.…”

“…galore Genei, India) The reaction mixture was subjected to an initial temperature of 94°C for 5 min followed by35 cycles of 30 s at 95°C, 40 s at 60°C for −194 to −174, 65°C for 2258 G/A, 65°C for 2029 C/T and 60°C for 1892 C/A; 55 s at 72°C and a final elongation at 72°C for 10 min. 18,192.6 | Statistical analysisAll the statistical analysis were performed using SPSS, version 20.0 (IBM Corp., Armonk, NY, USA).…”

Sambiloto (AS201-01) is better than standard antimalarial drug (DHP) in reducing Toll-Like Receptor 2 (TLR2) on placenta malaria model

“…However, the contribution of TLR2 in the pathogenesis of malaria still kontroversial. [9][10][11] Malaria morbidity and mortality can be reduced by means of appropriate and rapid treatment. In the past, malaria treated with chloroquine.…”

Polimorfismos genéticos em genes relacionados com imunidade inata em população de área de baixa endemicidade para malária

“…Esta frequência alélica é divergente da disponível no projeto 1000Genomes 40 79,89 , enquanto os outros dois 80,81 , assim como neste presente estudo, onde nenhuma associação foi encontrada, foram analisadas uma população positiva para malária e uma população controle, sem malária.…”