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      Absence of the toll-like receptor 4 gene polymorphisms Asp299Gly and Thr399Ile in Singaporean Chinese

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          Abstract

          Toll-like receptor 4 (TLR4) is the transuding subunit of lipopolysaccharide receptor and an important intracellular signal pathway of the innate immune response. Published data about the relationship between TLR4 mutations and atopy/asthma are not consistent. This study was performed to detect two commonly reported Asp299Gly and Thr399Ile polymorphisms in TLR4 gene in Singaporean Chinese and their possible association with atopy-related phenotypes. A total of 117 unrelated Singapore residents were randomly selected for this study. Among them, atopy was evident in 66 subjects while 61 had allergic rhinitis. Twenty-one patients had concomitant asthma and 17 were atopic. In all subjects, neither the Asp299Gly nor Thr399Ile polymorphism was found by DNA sequencing. This discrepant result could be due to the ethnic variation of allelic distribution in TLR4 gene. Although it is still debatable whether there is any role of TLR4 polymorphisms on atopy-related phenotypes, one needs to develop an appropriate model to investigate the interactions between genetic variations and environmental factors that contribute to the complex traits in allergic diseases.

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          Most cited references 18

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          Family size, infection and atopy: the first decade of the 'hygiene hypothesis'

           D. Strachan (2000)
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            Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide.

            Lipopolysaccharide (LPS) is the main inducer of shock and death in Gram-negative sepsis. Recent evidence suggests that LPS-induced signal transduction begins with CD14-mediated activation of 1 or more Toll-like receptors (TLRs). The lipid A analogues lipid IVa and Rhodobacter sphaeroides lipid A (RSLA) exhibit an uncommon species-specific pharmacology. Both compounds inhibit the effects of LPS in human cells but display LPS-mimetic activity in hamster cells. We transfected human TLR4 or human TLR2 into hamster fibroblasts to determine if either of these LPS signal transducers is responsible for the species-specific pharmacology. RSLA and lipid IVa strongly induced NF-kappaB activity and IL-6 release in Chinese hamster ovary fibroblasts expressing CD14 (CHO/CD14), but these compounds antagonized LPS antagonists in CHO/CD14 fibroblasts that overexpressed human TLR4. No such antagonism occurred in cells overexpressing human TLR2. We cloned TLR4 from hamster macrophages and found that human THP-1 cells expressing the hamster TLR4 responded to lipid IVa as an LPS mimetic, as if they were hamster in origin. Hence, cells heterologously overexpressing TLR4 from different species acquired a pharmacological phenotype with respect to recognition of lipid A substructures that corresponded to the species from which the TLR4 transgene originated. These data suggest that TLR4 is the central lipid A-recognition protein in the LPS receptor complex.
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              Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock.

              Septic shock remains a significant health concern worldwide, and despite progress in understanding the physiological and molecular basis of septic shock, the high mortality rate of patients with septic shock remains unchanged. We recently identified a common polymorphism in toll-like receptor 4 (TLR4) that is associated with hyporesponsiveness to inhaled endotoxin or lipopolysaccharide in humans. Since TLR4 is a major receptor for lipopolysaccharide in mammals and gram-negative bacteria are the prevalent pathogen associated with septic shock, we investigated whether these specific TLR4 alleles are associated with a predisposition to a more severe disease outcome for patients with septic shock. We genotyped 91 patients with septic shock as well as 73 healthy blood donor controls for the presence of the TLR4 Asp299Gly and TLR4 Thr399Ile mutations. We found the TLR4 Asp299Gly allele exclusively in patients with septic shock (P =.05). Furthermore, patients with septic shock with the TLR4 Asp299Gly/Thr399Ile alleles had a higher prevalence of gram-negative infections. Mutations in the TLR4 receptor may predispose people to develop septic shock with gram-negative microorganisms.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                September 2005
                September 2005
                : 1
                : 3
                : 243-246
                Affiliations
                [1 ]Department of Otolaryngology, National University of Singapore Singapore
                [2 ]Department of Pediatrics, National University of Singapore Singapore
                [3 ]Department of Pediatrics, Oregon Health and Science University OR, USA
                Author notes
                Correspondence: De-Yun Wang Department of Otolaryngology, Faculty of Medicine, National University of Singapore, 5 Lower Kent Ridge Crescent, Singapore 119074 Tel +65 6772 5373 Fax +65 6775 3820 Email entwdy@ 123456nus.edu.sg
                Article
                1661622
                18360565
                © 2005 Dove Medical Press Limited. All rights reserved
                Categories
                Original Research

                Medicine

                singaporean chinese, atopy, tlr4 polymorphisms

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