Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2003-5-14
pubmed:abstractText
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.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-10087992, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-10199352, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-10359581, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-10435584, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-10549626, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-10681462, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-10835634, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-11022119, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-11022120, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-11067888, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-11178226, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-11267672, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-11276206, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-11494169, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-11514453, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-11996613, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-12055629, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-16562068, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-1698311, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-202651, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-325138, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-3347221, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-3397181, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-6389367, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-6985638, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-7829975, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-8524927, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-8612135, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-8861035, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-9154025, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-9374167, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-9374458, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-9521923, http://linkedlifedata.com/resource/pubmed/commentcorrection/12730365-9851930
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0027-8424
pubmed:author
pubmed:issnType
Print
pubmed:day
13
pubmed:volume
100
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6075-80
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed-meshheading:12730365-Alleles, pubmed-meshheading:12730365-Amino Acid Substitution, pubmed-meshheading:12730365-Chromosome Mapping, pubmed-meshheading:12730365-Codon, Nonsense, pubmed-meshheading:12730365-England, pubmed-meshheading:12730365-Ethnic Groups, pubmed-meshheading:12730365-Gene Frequency, pubmed-meshheading:12730365-Genetic Predisposition to Disease, pubmed-meshheading:12730365-Humans, pubmed-meshheading:12730365-Membrane Glycoproteins, pubmed-meshheading:12730365-Meningococcal Infections, pubmed-meshheading:12730365-Mutation, pubmed-meshheading:12730365-Mutation, Missense, pubmed-meshheading:12730365-Odds Ratio, pubmed-meshheading:12730365-Receptors, Cell Surface, pubmed-meshheading:12730365-Reference Values, pubmed-meshheading:12730365-Toll-Like Receptor 2, pubmed-meshheading:12730365-Toll-Like Receptor 4, pubmed-meshheading:12730365-Toll-Like Receptors
pubmed:year
2003
pubmed:articleTitle
Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility.
pubmed:affiliation
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S.