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Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility

Academic Article
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Overview

authors

  • Smirnova, I.
  • Mann, N.
  • Dols, A.
  • Derkx, H. H.
  • Hibberd, M. L.
  • Levin, M.
  • Beutler, Bruce

publication date

  • May 2003

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • As the central component of the human endotoxin sensor, Toll-like receptor 4 (TLR4) functions in the early detection and response to Gram-negative infection. We therefore examined a large collection of patients with meningococcal sepsis, comparing the frequency of rare TLR4 coding changes to those in an ethnically matched control population. TLR2 sequences were also acquired and compared. Total nucleotide variation at TLR4 and TLR2 loci was assayed by using a novel computational method. A total of 3.01 megabases of coding sequence was captured at these loci from white subjects with or without meningococcal disease. Authentic mutations were found and high-quality, bidirectional coverage was measured across the coding region by using mutationseeker, a program specifically designed to assay locus-specific genetic load. Using a method that obviates the confounding effect of linkage disequilibrium, we observed that rare heterozygous missense mutations of TLR4 contribute to the development of systemic meningococcal disease among white populations of the southern United Kingdom (P = 0.02; odds ratio 8.2). When results from all white populations were pooled, an overwhelmingly significant excess of such mutations was observed among individuals with disease (P = 2 x 10(-6); odds ratio 27.0). The common white TLR4 variant (TLR4B), synonymous TLR4 substitutions, and variant TLR2 alleles were not significantly over-represented among patients with systemic meningococcal infections. No single variant of TLR4 was significantly over-represented in the meningococcal population. Collectively, however, rare TLR4 coding variants were markedly over-represented. Sensing via TLR4 probably contributes to the early containment of meningococcal infection, and sensing defects create increased risk of disease.

subject areas

  • Alleles
  • Amino Acid Substitution
  • Chromosome Mapping
  • Codon, Nonsense
  • England
  • Ethnic Groups
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Membrane Glycoproteins
  • Meningococcal Infections
  • Mutation
  • Mutation, Missense
  • Odds Ratio
  • Receptors, Cell Surface
  • Reference Values
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
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Identity

PubMed Central ID

  • PMC156328

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1031605100

PubMed ID

  • 12730365
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Additional Document Info

start page

  • 6075

end page

  • 6080

volume

  • 100

issue

  • 10

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