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Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy |
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| Authors: | P.-Y. Bochud D. Sinsimer A. Aderem M. R. Siddiqui P. Saunderson S. Britton I. Abraham A. Tadesse Argaw M. Janer T. R. Hawn G. Kaplan |
| Affiliation: | 1. Institute for Systems Biology, Seattle, WA, USA 7. Service of Infectious Diseases, Department of Medicine, Institute of Microbiology, University Hospital and University of Lausanne, 1011, Lausanne, Switzerland 3. Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center at the University of Medicine and Dentistry of New Jersey, Newark, NJ, USA 6. Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA 2. Department of Medicine, University of Washington, Seattle, WA, USA 8. Centre for Infections, Health Protection Agency, London, UK 4. All Africa Leprosy Rehabilitation and Training, Addis Ababa, Ethiopia 9. American Leprosy Missions, Greenville, SC, USA 10. Department of Medicine, Karolinska Institute, Stockholm, Sweden 5. Armauer Hansen Research Institute, Addis Ababa, Ethiopia 11. Mount Sinai School of Medicine, New York, NY, USA |
| Abstract: | Accumulating evidence suggests that polymorphisms in Toll-like receptors (TLRs) influence the pathogenesis of mycobacterial infections, including leprosy, a disease whose manifestations depend on host immune responses. Polymorphisms in TLR2 are associated with an increased risk of reversal reaction, but not susceptibility to leprosy itself. We examined whether polymorphisms in TLR4 are associated with susceptibility to leprosy in a cohort of 441 Ethiopian leprosy patients and 197 healthy controls. We found that two single nucleotide polymorphisms (SNPs) in TLR4 (896G>A [D299G] and 1196C>T [T399I]) were associated with a protective effect against the disease. The 896GG, GA and AA genotypes were found in 91.7, 7.8 and 0.5% of leprosy cases versus 79.9, 19.1 and 1.0% of controls, respectively (odds ratio [OR]?=?0.34, 95% confidence interval [CI] 0.20–0.57, P?P?Mycobacterium leprae stimulation of monocytes partially inhibited their subsequent response to lipopolysaccharide (LPS) stimulation. Our data suggest that TLR4 polymorphisms are associated with susceptibility to leprosy and that this effect may be mediated at the cellular level by the modulation of TLR4 signalling by M. leprae. |
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