Functional consequences of toll-like receptor 4 polymorphisms. Mol Med

Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Molecular Medicine (Impact Factor: 4.51). 05/2008; 14(5-6):346-52. DOI: 10.2119/2007-00135.Ferwerda
Source: PubMed


Toll-like receptor 4 (TLR4) is an important pathogen recognition receptor that recognizes mainly lipopolysaccharide (LPS) of Gram-negative bacteria, but also structures from fungal and mycobacterial pathogens, as well as endogenous ligands. Two nonsynonymous polymorphisms of TLR4, Asp299Gly and Thr399Ile, have been suggested to alter the function of the receptor. Some, but not all, studies have proposed that these polymorphisms lead to reduced cytokine response and increased susceptibility to Gram-negative infections. In this review, we compare studies that assessed the effect of the Asp299Gly and Thr399Ile polymorphisms on susceptibility to Gram-negative infections and examine the phenotypic consequences of these polymorphisms. In addition, we review the geographical distribution of TLR4 polymorphisms and present a model for evolutionary pressures on the TLR4 genetic make-up.

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    • "Thus, of the two variant of TLR4, we included only TLR4 D299G variant in our study. The TLR4 D299G variant has been experimentally shown to cause altered binding of PfGPI, reduced surface expression of TLR4 and altered cytokine response to LPS (Arbour et al., 2000; Lorenz et al., 2002; Ferwerda et al., 2008). In Ghana, the minor allele has been associated with maternal anemia, low birth weight in infants and severe malaria in children (Mockenhaupt et al., 2006a,b). "
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    ABSTRACT: Background: In malaria, the toll-like receptors (TLRs) have recently emerged as major player of innate immunity. However, implication of TLR variants on clinical manifestations of malaria is conflicting. The present study aims to provide relevant information of growing interest in understanding the role of TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms on clinical outcomes of malaria. Methods: We genotyped TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms by PCR-RFLP methods and subsequently analysed in 200 uncomplicated patients and 200 severe patients. Further, the severe malaria was categorised into sub-clinical groups such as cerebral malaria (CM), non-cerebral severe malaria (NCSM), single organ dysfunction (SOD) and multi-organ dysfunctions (MODS) and analysed. Result: The TLR9-1237CC genotype was observed at significantly low frequency in MODS (p=0.0008), while in heterozygous state (TC) it was proportionately more frequent in SOD (p=0.087) as compared to mild malaria. The TLR9T-1486C heterozygote was more common in all categories of severe malaria. However, pair wise LD analysis revealed significant linkage between T-1237C and T-1486C, whereas haplotype analysis showed significantly low frequency of C-T haplotype in CM (P=0.005, Pc=0.02) and high frequency of T-C haplotype in NCSM as compared to mild malaria. Conclusion: Although TLR9-1237C could be a risk factor for severe malaria in heterozygous state, negative association of CC genotype with MODS warrants caution of segregating severe malaria into its sub-clinical groups while interpreting data. Further, clinical outcome in malaria was observed to be apparently modulated by LD between TLR9 promoter variants.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 10/2015; 36. DOI:10.1016/j.meegid.2015.10.008 · 3.02 Impact Factor
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    • "TLRs identify these PAMPs and activate innate cells for humoral complement activation during infection that opsonise and kill pathogens (Mogensen, 2009). TLR4 mainly recognize lipopolysaccharides (LPS) of gram-negative bacteria (Ferwerda et al., 2008) and are expressed on many innate cells and mastocytes which activate immune and inflammatory responses against invaders (Baines et al., 2011; Qing et al., 2013). TLR family is characterized by leucinerich repeats (LRR) and a cytoplasmic toll/interleukin-1 receptor domain, which initiates common signalling pathways (Carvalho et al., 2008; Coscia et al., 2011; Roach et al., 2013) such as MyD88-dependent pathway (Krishnan et al., 2007) which activates transcription factors like NF-jB (nuclear factor kappalight-chain-enhancer of activated B cells) and interferon regulatory factors (IRF3) (Davoodi et al., 2012) that regulate the expression of interferons, inflammatory cytokines and chemokines or increase the production of IL12 (Romagnani, 2004) which differentiate naive T cells into Th1 cells and disturb the Th1/Th2 balance in asthma and allergic rhinitis (Neill & Bowie, 2007). "
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    ABSTRACT: Toll-like receptor 4 (TLR4) is the most important TLR among the pattern recognition receptors which recognizes lipopolysaccharide of gram-negative bacteria. They identify a highly conserved structure of microbes called pathogen-associated molecular patterns and activate immune and inflammatory responses that have been shown to be involved in the pathogenesis of asthma. The role of TLR4 gene polymorphisms in asthma was detected in a total of 964 individuals, including 483 healthy controls and 481 asthma patients from a North Indian population. The genotyping was carried out using polymerase chain reaction–restriction fragment length polymorphism method. Statistical analysis revealed that the heterozygous genotype as well as the mutant (T) allele of the TLR4 C>1196T (Thr399Ile) polymorphism shows resistance towards asthma with OR = 0.70, 95% CI (0.49–0.99), P corrected value = 0.046 and OR = 0.72, 95% CI (0.52–0.98), P corrected value = 0.039, respectively. However, no association was found between the TLR4 A>896G (Asp299Gly) polymorphism and asthma patients (P > 0.05). This is the first study conducted in India conferring TLR4 (Thr399Ile) polymorphism resistance towards asthma, while lack of association was found between TLR4 (Asp299Gly) polymorphism and asthma in the studied North Indian population.
    International Journal of Immunogenetics 10/2014; 41(6). DOI:10.1111/iji.12115 · 1.25 Impact Factor
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    • "This observation suggests that TLR4-MyD88 signaling pathway plays a role in the development of liver tumor [42]. Although the main ligand for TLR4 is the bacteria endotoxin lipopolysaccharides (LPS) [12], it was also found that several HCV proteins, such as nonstructural protein 5A (NS5A), core, and NS3, stimulate TLR4 pathway [21]. Due to the importance of TLR4 in innate immunity, several studies have examined the role of TLR4 polymorphism in human diseases. "
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    ABSTRACT: Hepatitis C virus (HCV) is a single stranded RNA virus. It affects millions of people worldwide and is considered as a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. A recent study reported that TLR4 gene polymorphisms are good prognostic predictors and are associated with protection from liver fibrosis among Caucasians. This study aims to investigate the implication of genetic polymorphisms of TLR4 gene on the HCV infection in Saudi Arabian patients. Two SNPs in the TLR4 gene, rs4986790 (A/G) and rs4986791 (C/T), were genotyped in 450 HCV patients and 600 uninfected controls. The association analysis confirmed that both SNPs showed a significant difference in their distribution between HCV-infected patients and uninfected control subjects (P < 0.0001; OR = 0.404, 95% CI = 0.281-0.581) and (P < 0.0001; OR = 0.298, 95% CI = 0.201-0.443), respectively. More importantly, haplotype analysis revealed that four haplotypes, AC, GT, GC, and AT (rs4986790, rs4986791), were significantly associated with HCV infection when compared with control subjects. One haplotype AC was more prominently found when chronic HCV-infected patients were compared with cirrhosis/HCC patients (frequency = 94.7% and P = 0.04). Both TLR4 SNPs under investigation were found to be significantly implicated with HCV-infection among Saudi Arabian population.
    BioMed Research International 08/2014; 2014:357062. DOI:10.1155/2014/357062 · 1.58 Impact Factor
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