Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy

  • 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
Article

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 < 0.001, additive model). Similarly, the 1196CC, CT and TT genotypes were found in 98.1, 1.9 and 0% of leprosy cases versus 91.8, 7.7 and 0.5% of controls, respectively (OR = 0.16, 95% CI 0.06-–.40, P < 0.001, dominant model). We found that 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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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • P.-Y. Bochud
    • 1
    • 7
  • D. Sinsimer
    • 3
    • 6
  • A. Aderem
    • 1
    • 2
  • M. R. Siddiqui
    • 3
    • 8
  • P. Saunderson
    • 4
    • 9
  • S. Britton
    • 5
    • 10
  • I. Abraham
    • 5
  • A. Tadesse Argaw
    • 5
    • 11
  • M. Janer
    • 1
  • T. R. Hawn
    • 1
    • 2
  • G. Kaplan
    • 3
  1. 1.Institute for Systems BiologySeattleUSA
  2. 2.Department of MedicineUniversity of WashingtonSeattleUSA
  3. 3.Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center at the University of Medicine and Dentistry of New JerseyNewarkUSA
  4. 4.All Africa Leprosy Rehabilitation and TrainingAddis AbabaEthiopia
  5. 5.Armauer Hansen Research InstituteAddis AbabaEthiopia
  6. 6.Graduate School of Biomedical SciencesUniversity of Medicine and Dentistry of New JerseyNewarkUSA
  7. 7.Service of Infectious Diseases, Department of Medicine, Institute of MicrobiologyUniversity Hospital and University of LausanneLausanneSwitzerland
  8. 8.Centre for Infections, Health Protection AgencyLondonUK
  9. 9.American Leprosy MissionsGreenvilleUSA
  10. 10.Department of MedicineKarolinska InstituteStockholmSweden
  11. 11.Mount Sinai School of MedicineNew YorkUSA

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