TLR4 mutations are associated with endotoxin hyporesponsiveness in humans View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2000-06

AUTHORS

Nancy C. Arbour, Eva Lorenz, Brian C. Schutte, Joseph Zabner, Joel N. Kline, Michael Jones, Kathy Frees, Janet L. Watt, David A. Schwartz

ABSTRACT

There is much variability between individuals in the response to inhaled toxins, but it is not known why certain people develop disease when challenged with environmental agents and others remain healthy. To address this, we investigated whether TLR4 (encoding the toll-like receptor-4), which has been shown to affect lipopolysaccharide (LPS) responsiveness in mice, underlies the variability in airway responsiveness to inhaled LPS in humans. Here we show that common, co-segregating missense mutations (Asp299Gly and Thr399Ile) affecting the extracellular domain of the TLR4 receptor are associated with a blunted response to inhaled LPS in humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling. Moreover, the wild-type allele of TLR4 rescues the LPS hyporesponsive phenotype in either primary airway epithelial cells or alveolar macrophages obtained from individuals with the TLR4 mutations. Our findings provide the first genetic evidence that common mutations in TLR4 are associated with differences in LPS responsiveness in humans, and demonstrate that gene-sequence changes can alter the ability of the host to respond to environmental stress. More... »

PAGES

ng0600_187

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/76048

DOI

http://dx.doi.org/10.1038/76048

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1034294158

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/10835634


Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
Incoming Citations Browse incoming citations for this publication using opencitations.net

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/0604", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Genetics", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/06", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Biological Sciences", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Administration, Inhalation", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Adolescent", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Adult", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Alleles", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Amino Acid Sequence", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Base Sequence", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Cells, Cultured", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "DNA Mutational Analysis", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Drosophila Proteins", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Female", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Forced Expiratory Volume", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Humans", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Lipopolysaccharides", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Macrophages, Alveolar", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Male", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Membrane Glycoproteins", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Middle Aged", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Molecular Sequence Data", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mutation, Missense", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Receptors, Cell Surface", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Respiratory Hypersensitivity", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Respiratory Mucosa", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Signal Transduction", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Toll-Like Receptor 4", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Toll-Like Receptors", 
        "type": "DefinedTerm"
      }
    ], 
    "author": [
      {
        "affiliation": {
          "alternateName": "University of Iowa", 
          "id": "https://www.grid.ac/institutes/grid.214572.7", 
          "name": [
            "Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Arbour", 
        "givenName": "Nancy C.", 
        "id": "sg:person.0756173755.72", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0756173755.72"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Iowa", 
          "id": "https://www.grid.ac/institutes/grid.214572.7", 
          "name": [
            "Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Lorenz", 
        "givenName": "Eva", 
        "id": "sg:person.01221371403.67", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01221371403.67"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Iowa", 
          "id": "https://www.grid.ac/institutes/grid.214572.7", 
          "name": [
            "Department of Pediatrics, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Schutte", 
        "givenName": "Brian C.", 
        "id": "sg:person.01354006524.80", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01354006524.80"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Iowa", 
          "id": "https://www.grid.ac/institutes/grid.214572.7", 
          "name": [
            "Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Zabner", 
        "givenName": "Joseph", 
        "id": "sg:person.0715343137.38", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0715343137.38"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Iowa", 
          "id": "https://www.grid.ac/institutes/grid.214572.7", 
          "name": [
            "Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Kline", 
        "givenName": "Joel N.", 
        "id": "sg:person.0634304176.73", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0634304176.73"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Iowa", 
          "id": "https://www.grid.ac/institutes/grid.214572.7", 
          "name": [
            "Department of Biostatistics, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Jones", 
        "givenName": "Michael", 
        "id": "sg:person.01254764155.51", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01254764155.51"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Iowa", 
          "id": "https://www.grid.ac/institutes/grid.214572.7", 
          "name": [
            "Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Frees", 
        "givenName": "Kathy", 
        "id": "sg:person.01133350735.39", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01133350735.39"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Iowa", 
          "id": "https://www.grid.ac/institutes/grid.214572.7", 
          "name": [
            "Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Watt", 
        "givenName": "Janet L.", 
        "id": "sg:person.013175314377.51", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.013175314377.51"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Iowa", 
          "id": "https://www.grid.ac/institutes/grid.214572.7", 
          "name": [
            "Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Schwartz", 
        "givenName": "David A.", 
        "id": "sg:person.0637453473.51", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0637453473.51"
        ], 
        "type": "Person"
      }
    ], 
    "citation": [
      {
        "id": "https://doi.org/10.1165/ajrcmb.19.4.3176", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1000846240"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1172/jci2732", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1009096766"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/0022-2836(87)90292-0", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1014427071"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.282.5396.2085", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1016546809"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1164/ajrccm.151.1.7812571", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1017503885"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1164/ajrccm.154.6.8970348", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1017738562"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1006/exnr.1994.1028", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1018892097"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1164/ajrccm.152.2.7633714", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1019110746"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1002/0471142905.hg0704s15", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1027383377"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1074/jbc.274.16.10689", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1028648474"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/287440a0", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1030742343", 
          "https://doi.org/10.1038/287440a0"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1136/oem.46.6.412", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1034339178"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1136/oem.46.6.412", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1034339178"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1164/ajrccm.160.4.9901062", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1037951693"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1086/301956", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1046389040"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1164/ajrccm.160.1.9808144", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1047100992"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/41131", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1048300852", 
          "https://doi.org/10.1038/41131"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/41131", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1048300852", 
          "https://doi.org/10.1038/41131"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1084/jem.189.11.1777", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1052892932"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1073/pnas.95.2.588", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1053189019"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.1439770", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1062482219"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1074357839", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1079358096", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1079547684", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1082957603", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1083072552", 
        "type": "CreativeWork"
      }
    ], 
    "datePublished": "2000-06", 
    "datePublishedReg": "2000-06-01", 
    "description": "There is much variability between individuals in the response to inhaled toxins, but it is not known why certain people develop disease when challenged with environmental agents and others remain healthy. To address this, we investigated whether TLR4 (encoding the toll-like receptor-4), which has been shown to affect lipopolysaccharide (LPS) responsiveness in mice, underlies the variability in airway responsiveness to inhaled LPS in humans. Here we show that common, co-segregating missense mutations (Asp299Gly and Thr399Ile) affecting the extracellular domain of the TLR4 receptor are associated with a blunted response to inhaled LPS in humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling. Moreover, the wild-type allele of TLR4 rescues the LPS hyporesponsive phenotype in either primary airway epithelial cells or alveolar macrophages obtained from individuals with the TLR4 mutations. Our findings provide the first genetic evidence that common mutations in TLR4 are associated with differences in LPS responsiveness in humans, and demonstrate that gene-sequence changes can alter the ability of the host to respond to environmental stress.", 
    "genre": "research_article", 
    "id": "sg:pub.10.1038/76048", 
    "inLanguage": [
      "en"
    ], 
    "isAccessibleForFree": false, 
    "isFundedItemOf": [
      {
        "id": "sg:grant.2502968", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2436260", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2423976", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2536905", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2503086", 
        "type": "MonetaryGrant"
      }
    ], 
    "isPartOf": [
      {
        "id": "sg:journal.1103138", 
        "issn": [
          "1061-4036", 
          "1546-1718"
        ], 
        "name": "Nature Genetics", 
        "type": "Periodical"
      }, 
      {
        "issueNumber": "2", 
        "type": "PublicationIssue"
      }, 
      {
        "type": "PublicationVolume", 
        "volumeNumber": "25"
      }
    ], 
    "name": "TLR4 mutations are associated with endotoxin hyporesponsiveness in humans", 
    "pagination": "ng0600_187", 
    "productId": [
      {
        "name": "readcube_id", 
        "type": "PropertyValue", 
        "value": [
          "a35d1109ceac8f1431e65de8c353b17e918d96443d6a4929f6185b0b44004cbf"
        ]
      }, 
      {
        "name": "pubmed_id", 
        "type": "PropertyValue", 
        "value": [
          "10835634"
        ]
      }, 
      {
        "name": "nlm_unique_id", 
        "type": "PropertyValue", 
        "value": [
          "9216904"
        ]
      }, 
      {
        "name": "doi", 
        "type": "PropertyValue", 
        "value": [
          "10.1038/76048"
        ]
      }, 
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "pub.1034294158"
        ]
      }
    ], 
    "sameAs": [
      "https://doi.org/10.1038/76048", 
      "https://app.dimensions.ai/details/publication/pub.1034294158"
    ], 
    "sdDataset": "articles", 
    "sdDatePublished": "2019-04-11T12:22", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com-uberresearch-data-dimensions-target-20181106-alternative/cleanup/v134/2549eaecd7973599484d7c17b260dba0a4ecb94b/merge/v9/a6c9fde33151104705d4d7ff012ea9563521a3ce/jats-lookup/v90/0000000362_0000000362/records_87088_00000001.jsonl", 
    "type": "ScholarlyArticle", 
    "url": "http://www.nature.com/articles/ng0600_187"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/76048'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/76048'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/76048'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/76048'


 

This table displays all metadata directly associated to this object as RDF triples.

306 TRIPLES      21 PREDICATES      78 URIs      46 LITERALS      34 BLANK NODES

Subject Predicate Object
1 sg:pub.10.1038/76048 schema:about N1990ddd6f570446fae3229a6263b0f32
2 N1fe27ba866e0453f906f53aa3285c3d3
3 N2101718d4e1240798f56a7f0cf26b099
4 N3106b0709920498886cded0099b97dfc
5 N3b62e634903443f0a9554ac59cdd69fa
6 N404da6a3595a449095736c07efaf88a2
7 N424d5eb2c9c34a549b4f84a33c3a12e2
8 N4261fb29d21e4f01ae9f5c10ab200b3c
9 N46131267c0344dbbbf36b13076a383d1
10 N559aaed13f454676ad2ff18e175ece2f
11 N5b66f4ea07e541d3aa12fb2ac8072a93
12 N74d42146e785468c83cf7c6813736f45
13 N761978f546e846e4aa96ae9920601831
14 N78291511a1ad4688ae81945d8f13f2a2
15 N7c61caabba4c48448cae14e963df4402
16 N881abd13eba74e4d93c8e0237d3a2980
17 N958f12da55324cec83b751efa3a61b59
18 N9d15de5d20994f5088ea6a86642ba5a4
19 Nb225ceb4b5e04ebab0a9d89a58624249
20 Nb8c982d743ad47c799397c5f60ad0ff3
21 Nbbec34eab8694836b39557369d2bbd40
22 Ndddf24815cb74b15ab96196923da17c1
23 Ne325ac4937154d588f4a8fd78dc5d8e6
24 Nea86e07d3a4544079e8f40b9af3bb9ad
25 Nf90257d6fd9440099ac45009b69b3055
26 anzsrc-for:06
27 anzsrc-for:0604
28 schema:author N13211192cd8a4f0bad9f69e9e73b1782
29 schema:citation sg:pub.10.1038/287440a0
30 sg:pub.10.1038/41131
31 https://app.dimensions.ai/details/publication/pub.1074357839
32 https://app.dimensions.ai/details/publication/pub.1079358096
33 https://app.dimensions.ai/details/publication/pub.1079547684
34 https://app.dimensions.ai/details/publication/pub.1082957603
35 https://app.dimensions.ai/details/publication/pub.1083072552
36 https://doi.org/10.1002/0471142905.hg0704s15
37 https://doi.org/10.1006/exnr.1994.1028
38 https://doi.org/10.1016/0022-2836(87)90292-0
39 https://doi.org/10.1073/pnas.95.2.588
40 https://doi.org/10.1074/jbc.274.16.10689
41 https://doi.org/10.1084/jem.189.11.1777
42 https://doi.org/10.1086/301956
43 https://doi.org/10.1126/science.1439770
44 https://doi.org/10.1126/science.282.5396.2085
45 https://doi.org/10.1136/oem.46.6.412
46 https://doi.org/10.1164/ajrccm.151.1.7812571
47 https://doi.org/10.1164/ajrccm.152.2.7633714
48 https://doi.org/10.1164/ajrccm.154.6.8970348
49 https://doi.org/10.1164/ajrccm.160.1.9808144
50 https://doi.org/10.1164/ajrccm.160.4.9901062
51 https://doi.org/10.1165/ajrcmb.19.4.3176
52 https://doi.org/10.1172/jci2732
53 schema:datePublished 2000-06
54 schema:datePublishedReg 2000-06-01
55 schema:description There is much variability between individuals in the response to inhaled toxins, but it is not known why certain people develop disease when challenged with environmental agents and others remain healthy. To address this, we investigated whether TLR4 (encoding the toll-like receptor-4), which has been shown to affect lipopolysaccharide (LPS) responsiveness in mice, underlies the variability in airway responsiveness to inhaled LPS in humans. Here we show that common, co-segregating missense mutations (Asp299Gly and Thr399Ile) affecting the extracellular domain of the TLR4 receptor are associated with a blunted response to inhaled LPS in humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling. Moreover, the wild-type allele of TLR4 rescues the LPS hyporesponsive phenotype in either primary airway epithelial cells or alveolar macrophages obtained from individuals with the TLR4 mutations. Our findings provide the first genetic evidence that common mutations in TLR4 are associated with differences in LPS responsiveness in humans, and demonstrate that gene-sequence changes can alter the ability of the host to respond to environmental stress.
56 schema:genre research_article
57 schema:inLanguage en
58 schema:isAccessibleForFree false
59 schema:isPartOf Nba42c57de81d482197c0c84fc15ef47b
60 Nc15bffaba6f644128aa8837f3ebfcc50
61 sg:journal.1103138
62 schema:name TLR4 mutations are associated with endotoxin hyporesponsiveness in humans
63 schema:pagination ng0600_187
64 schema:productId N233e9d6b9f844831b9784b1c22c5a09b
65 N2dd69a145fd246d69c4bbbc9fe3b783b
66 N4e5be262b61f441f90930ae99c56cf19
67 Na09e08cb21b24996b8cb50f5d06bc76c
68 Ne23845e89fa9406dad85d7c1dcf1d75e
69 schema:sameAs https://app.dimensions.ai/details/publication/pub.1034294158
70 https://doi.org/10.1038/76048
71 schema:sdDatePublished 2019-04-11T12:22
72 schema:sdLicense https://scigraph.springernature.com/explorer/license/
73 schema:sdPublisher Na638340f2b724bf3b2a8f6bcb2e544f7
74 schema:url http://www.nature.com/articles/ng0600_187
75 sgo:license sg:explorer/license/
76 sgo:sdDataset articles
77 rdf:type schema:ScholarlyArticle
78 N0e15accdf0314a5492a9188888dd7361 rdf:first sg:person.0637453473.51
79 rdf:rest rdf:nil
80 N13211192cd8a4f0bad9f69e9e73b1782 rdf:first sg:person.0756173755.72
81 rdf:rest N41dda7e5a0b84825b2d1484541b30177
82 N1990ddd6f570446fae3229a6263b0f32 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
83 schema:name Adolescent
84 rdf:type schema:DefinedTerm
85 N1d59ad2548ff4b989e750bb9369d30d5 rdf:first sg:person.013175314377.51
86 rdf:rest N0e15accdf0314a5492a9188888dd7361
87 N1fe27ba866e0453f906f53aa3285c3d3 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
88 schema:name Lipopolysaccharides
89 rdf:type schema:DefinedTerm
90 N2101718d4e1240798f56a7f0cf26b099 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
91 schema:name Mutation, Missense
92 rdf:type schema:DefinedTerm
93 N233e9d6b9f844831b9784b1c22c5a09b schema:name readcube_id
94 schema:value a35d1109ceac8f1431e65de8c353b17e918d96443d6a4929f6185b0b44004cbf
95 rdf:type schema:PropertyValue
96 N2dd69a145fd246d69c4bbbc9fe3b783b schema:name dimensions_id
97 schema:value pub.1034294158
98 rdf:type schema:PropertyValue
99 N3106b0709920498886cded0099b97dfc schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
100 schema:name Cells, Cultured
101 rdf:type schema:DefinedTerm
102 N3ad3c67a455a4e8e8e870e8c02ad829e rdf:first sg:person.0634304176.73
103 rdf:rest N98d7bf22a7ba4559ac7690b1bd700ecc
104 N3b62e634903443f0a9554ac59cdd69fa schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
105 schema:name Male
106 rdf:type schema:DefinedTerm
107 N404da6a3595a449095736c07efaf88a2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
108 schema:name Adult
109 rdf:type schema:DefinedTerm
110 N41dda7e5a0b84825b2d1484541b30177 rdf:first sg:person.01221371403.67
111 rdf:rest Nc67abd7393c848c2a5e836e79b13bbf3
112 N424d5eb2c9c34a549b4f84a33c3a12e2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
113 schema:name Middle Aged
114 rdf:type schema:DefinedTerm
115 N4261fb29d21e4f01ae9f5c10ab200b3c schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
116 schema:name Forced Expiratory Volume
117 rdf:type schema:DefinedTerm
118 N46131267c0344dbbbf36b13076a383d1 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
119 schema:name Macrophages, Alveolar
120 rdf:type schema:DefinedTerm
121 N4e5be262b61f441f90930ae99c56cf19 schema:name nlm_unique_id
122 schema:value 9216904
123 rdf:type schema:PropertyValue
124 N559aaed13f454676ad2ff18e175ece2f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
125 schema:name Toll-Like Receptors
126 rdf:type schema:DefinedTerm
127 N5b66f4ea07e541d3aa12fb2ac8072a93 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
128 schema:name Drosophila Proteins
129 rdf:type schema:DefinedTerm
130 N74d42146e785468c83cf7c6813736f45 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
131 schema:name Administration, Inhalation
132 rdf:type schema:DefinedTerm
133 N761978f546e846e4aa96ae9920601831 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
134 schema:name Base Sequence
135 rdf:type schema:DefinedTerm
136 N78291511a1ad4688ae81945d8f13f2a2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
137 schema:name Humans
138 rdf:type schema:DefinedTerm
139 N7c61caabba4c48448cae14e963df4402 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
140 schema:name DNA Mutational Analysis
141 rdf:type schema:DefinedTerm
142 N881abd13eba74e4d93c8e0237d3a2980 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
143 schema:name Toll-Like Receptor 4
144 rdf:type schema:DefinedTerm
145 N958f12da55324cec83b751efa3a61b59 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
146 schema:name Respiratory Hypersensitivity
147 rdf:type schema:DefinedTerm
148 N98d7bf22a7ba4559ac7690b1bd700ecc rdf:first sg:person.01254764155.51
149 rdf:rest Nc44d8c0539be436dbd6e4b4f23a4534f
150 N9d15de5d20994f5088ea6a86642ba5a4 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
151 schema:name Molecular Sequence Data
152 rdf:type schema:DefinedTerm
153 Na09e08cb21b24996b8cb50f5d06bc76c schema:name pubmed_id
154 schema:value 10835634
155 rdf:type schema:PropertyValue
156 Na638340f2b724bf3b2a8f6bcb2e544f7 schema:name Springer Nature - SN SciGraph project
157 rdf:type schema:Organization
158 Naae4e1f0e103488eabb5fefe892cf6ef rdf:first sg:person.0715343137.38
159 rdf:rest N3ad3c67a455a4e8e8e870e8c02ad829e
160 Nb225ceb4b5e04ebab0a9d89a58624249 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
161 schema:name Amino Acid Sequence
162 rdf:type schema:DefinedTerm
163 Nb8c982d743ad47c799397c5f60ad0ff3 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
164 schema:name Receptors, Cell Surface
165 rdf:type schema:DefinedTerm
166 Nba42c57de81d482197c0c84fc15ef47b schema:volumeNumber 25
167 rdf:type schema:PublicationVolume
168 Nbbec34eab8694836b39557369d2bbd40 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
169 schema:name Female
170 rdf:type schema:DefinedTerm
171 Nc15bffaba6f644128aa8837f3ebfcc50 schema:issueNumber 2
172 rdf:type schema:PublicationIssue
173 Nc44d8c0539be436dbd6e4b4f23a4534f rdf:first sg:person.01133350735.39
174 rdf:rest N1d59ad2548ff4b989e750bb9369d30d5
175 Nc67abd7393c848c2a5e836e79b13bbf3 rdf:first sg:person.01354006524.80
176 rdf:rest Naae4e1f0e103488eabb5fefe892cf6ef
177 Ndddf24815cb74b15ab96196923da17c1 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
178 schema:name Signal Transduction
179 rdf:type schema:DefinedTerm
180 Ne23845e89fa9406dad85d7c1dcf1d75e schema:name doi
181 schema:value 10.1038/76048
182 rdf:type schema:PropertyValue
183 Ne325ac4937154d588f4a8fd78dc5d8e6 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
184 schema:name Membrane Glycoproteins
185 rdf:type schema:DefinedTerm
186 Nea86e07d3a4544079e8f40b9af3bb9ad schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
187 schema:name Respiratory Mucosa
188 rdf:type schema:DefinedTerm
189 Nf90257d6fd9440099ac45009b69b3055 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
190 schema:name Alleles
191 rdf:type schema:DefinedTerm
192 anzsrc-for:06 schema:inDefinedTermSet anzsrc-for:
193 schema:name Biological Sciences
194 rdf:type schema:DefinedTerm
195 anzsrc-for:0604 schema:inDefinedTermSet anzsrc-for:
196 schema:name Genetics
197 rdf:type schema:DefinedTerm
198 sg:grant.2423976 http://pending.schema.org/fundedItem sg:pub.10.1038/76048
199 rdf:type schema:MonetaryGrant
200 sg:grant.2436260 http://pending.schema.org/fundedItem sg:pub.10.1038/76048
201 rdf:type schema:MonetaryGrant
202 sg:grant.2502968 http://pending.schema.org/fundedItem sg:pub.10.1038/76048
203 rdf:type schema:MonetaryGrant
204 sg:grant.2503086 http://pending.schema.org/fundedItem sg:pub.10.1038/76048
205 rdf:type schema:MonetaryGrant
206 sg:grant.2536905 http://pending.schema.org/fundedItem sg:pub.10.1038/76048
207 rdf:type schema:MonetaryGrant
208 sg:journal.1103138 schema:issn 1061-4036
209 1546-1718
210 schema:name Nature Genetics
211 rdf:type schema:Periodical
212 sg:person.01133350735.39 schema:affiliation https://www.grid.ac/institutes/grid.214572.7
213 schema:familyName Frees
214 schema:givenName Kathy
215 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01133350735.39
216 rdf:type schema:Person
217 sg:person.01221371403.67 schema:affiliation https://www.grid.ac/institutes/grid.214572.7
218 schema:familyName Lorenz
219 schema:givenName Eva
220 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01221371403.67
221 rdf:type schema:Person
222 sg:person.01254764155.51 schema:affiliation https://www.grid.ac/institutes/grid.214572.7
223 schema:familyName Jones
224 schema:givenName Michael
225 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01254764155.51
226 rdf:type schema:Person
227 sg:person.013175314377.51 schema:affiliation https://www.grid.ac/institutes/grid.214572.7
228 schema:familyName Watt
229 schema:givenName Janet L.
230 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.013175314377.51
231 rdf:type schema:Person
232 sg:person.01354006524.80 schema:affiliation https://www.grid.ac/institutes/grid.214572.7
233 schema:familyName Schutte
234 schema:givenName Brian C.
235 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01354006524.80
236 rdf:type schema:Person
237 sg:person.0634304176.73 schema:affiliation https://www.grid.ac/institutes/grid.214572.7
238 schema:familyName Kline
239 schema:givenName Joel N.
240 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0634304176.73
241 rdf:type schema:Person
242 sg:person.0637453473.51 schema:affiliation https://www.grid.ac/institutes/grid.214572.7
243 schema:familyName Schwartz
244 schema:givenName David A.
245 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0637453473.51
246 rdf:type schema:Person
247 sg:person.0715343137.38 schema:affiliation https://www.grid.ac/institutes/grid.214572.7
248 schema:familyName Zabner
249 schema:givenName Joseph
250 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0715343137.38
251 rdf:type schema:Person
252 sg:person.0756173755.72 schema:affiliation https://www.grid.ac/institutes/grid.214572.7
253 schema:familyName Arbour
254 schema:givenName Nancy C.
255 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0756173755.72
256 rdf:type schema:Person
257 sg:pub.10.1038/287440a0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1030742343
258 https://doi.org/10.1038/287440a0
259 rdf:type schema:CreativeWork
260 sg:pub.10.1038/41131 schema:sameAs https://app.dimensions.ai/details/publication/pub.1048300852
261 https://doi.org/10.1038/41131
262 rdf:type schema:CreativeWork
263 https://app.dimensions.ai/details/publication/pub.1074357839 schema:CreativeWork
264 https://app.dimensions.ai/details/publication/pub.1079358096 schema:CreativeWork
265 https://app.dimensions.ai/details/publication/pub.1079547684 schema:CreativeWork
266 https://app.dimensions.ai/details/publication/pub.1082957603 schema:CreativeWork
267 https://app.dimensions.ai/details/publication/pub.1083072552 schema:CreativeWork
268 https://doi.org/10.1002/0471142905.hg0704s15 schema:sameAs https://app.dimensions.ai/details/publication/pub.1027383377
269 rdf:type schema:CreativeWork
270 https://doi.org/10.1006/exnr.1994.1028 schema:sameAs https://app.dimensions.ai/details/publication/pub.1018892097
271 rdf:type schema:CreativeWork
272 https://doi.org/10.1016/0022-2836(87)90292-0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1014427071
273 rdf:type schema:CreativeWork
274 https://doi.org/10.1073/pnas.95.2.588 schema:sameAs https://app.dimensions.ai/details/publication/pub.1053189019
275 rdf:type schema:CreativeWork
276 https://doi.org/10.1074/jbc.274.16.10689 schema:sameAs https://app.dimensions.ai/details/publication/pub.1028648474
277 rdf:type schema:CreativeWork
278 https://doi.org/10.1084/jem.189.11.1777 schema:sameAs https://app.dimensions.ai/details/publication/pub.1052892932
279 rdf:type schema:CreativeWork
280 https://doi.org/10.1086/301956 schema:sameAs https://app.dimensions.ai/details/publication/pub.1046389040
281 rdf:type schema:CreativeWork
282 https://doi.org/10.1126/science.1439770 schema:sameAs https://app.dimensions.ai/details/publication/pub.1062482219
283 rdf:type schema:CreativeWork
284 https://doi.org/10.1126/science.282.5396.2085 schema:sameAs https://app.dimensions.ai/details/publication/pub.1016546809
285 rdf:type schema:CreativeWork
286 https://doi.org/10.1136/oem.46.6.412 schema:sameAs https://app.dimensions.ai/details/publication/pub.1034339178
287 rdf:type schema:CreativeWork
288 https://doi.org/10.1164/ajrccm.151.1.7812571 schema:sameAs https://app.dimensions.ai/details/publication/pub.1017503885
289 rdf:type schema:CreativeWork
290 https://doi.org/10.1164/ajrccm.152.2.7633714 schema:sameAs https://app.dimensions.ai/details/publication/pub.1019110746
291 rdf:type schema:CreativeWork
292 https://doi.org/10.1164/ajrccm.154.6.8970348 schema:sameAs https://app.dimensions.ai/details/publication/pub.1017738562
293 rdf:type schema:CreativeWork
294 https://doi.org/10.1164/ajrccm.160.1.9808144 schema:sameAs https://app.dimensions.ai/details/publication/pub.1047100992
295 rdf:type schema:CreativeWork
296 https://doi.org/10.1164/ajrccm.160.4.9901062 schema:sameAs https://app.dimensions.ai/details/publication/pub.1037951693
297 rdf:type schema:CreativeWork
298 https://doi.org/10.1165/ajrcmb.19.4.3176 schema:sameAs https://app.dimensions.ai/details/publication/pub.1000846240
299 rdf:type schema:CreativeWork
300 https://doi.org/10.1172/jci2732 schema:sameAs https://app.dimensions.ai/details/publication/pub.1009096766
301 rdf:type schema:CreativeWork
302 https://www.grid.ac/institutes/grid.214572.7 schema:alternateName University of Iowa
303 schema:name Department of Biostatistics, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA.
304 Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA.
305 Department of Pediatrics, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA.
306 rdf:type schema:Organization
 




Preview window. Press ESC to close (or click here)


...