The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets
Identifieur interne : 000599 ( Pmc/Corpus ); précédent : 000598; suivant : 000600The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets
Auteurs : Humaira Rasheed ; Cushla Mckinney ; Lisa K. Stamp ; Nicola Dalbeth ; Ruth K. Topless ; Richard Day ; Diluk Kannangara ; Kenneth Williams ; Malcolm Smith ; Matthijs Janssen ; Tim L. Jansen ; Leo A. Joosten ; Timothy R. Radstake ; Philip L. Riches ; Anne-Kathrin Tausche ; Frederic Lioté ; Leo Lu ; Eli A. Stahl ; Hyon K. Choi ; Alexander So ; Tony R. MerrimanSource :
- PLoS ONE [ 1932-6203 ] ; 2016.
Abstract
Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism
Url:
DOI: 10.1371/journal.pone.0147939
PubMed: 26808548
PubMed Central: 4726773
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Toll-Like Receptor 4 (TLR4) Variant <italic>rs2149356</italic> and Risk of Gout in European and Polynesian Sample Sets</title><author><name sortKey="Rasheed, Humaira" sort="Rasheed, Humaira" uniqKey="Rasheed H" first="Humaira" last="Rasheed">Humaira Rasheed</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Biochemistry, University of Otago, Dunedin, New Zealand</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>University of Engineering and Technology, Lahore, Pakistan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mckinney, Cushla" sort="Mckinney, Cushla" uniqKey="Mckinney C" first="Cushla" last="Mckinney">Cushla Mckinney</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Biochemistry, University of Otago, Dunedin, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stamp, Lisa K" sort="Stamp, Lisa K" uniqKey="Stamp L" first="Lisa K." last="Stamp">Lisa K. Stamp</name><affiliation><nlm:aff id="aff003"><addr-line>Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dalbeth, Nicola" sort="Dalbeth, Nicola" uniqKey="Dalbeth N" first="Nicola" last="Dalbeth">Nicola Dalbeth</name><affiliation><nlm:aff id="aff004"><addr-line>Department of Medicine, University of Auckland, Auckland, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Topless, Ruth K" sort="Topless, Ruth K" uniqKey="Topless R" first="Ruth K." last="Topless">Ruth K. Topless</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Biochemistry, University of Otago, Dunedin, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Day, Richard" sort="Day, Richard" uniqKey="Day R" first="Richard" last="Day">Richard Day</name><affiliation><nlm:aff id="aff005"><addr-line>School of Medical Sciences, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kannangara, Diluk" sort="Kannangara, Diluk" uniqKey="Kannangara D" first="Diluk" last="Kannangara">Diluk Kannangara</name><affiliation><nlm:aff id="aff005"><addr-line>School of Medical Sciences, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Williams, Kenneth" sort="Williams, Kenneth" uniqKey="Williams K" first="Kenneth" last="Williams">Kenneth Williams</name><affiliation><nlm:aff id="aff005"><addr-line>School of Medical Sciences, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Smith, Malcolm" sort="Smith, Malcolm" uniqKey="Smith M" first="Malcolm" last="Smith">Malcolm Smith</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Medicine, Flinders Medical Centre and Repatriation General Hospital, Adelaide, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Janssen, Matthijs" sort="Janssen, Matthijs" uniqKey="Janssen M" first="Matthijs" last="Janssen">Matthijs Janssen</name><affiliation><nlm:aff id="aff008"><addr-line>Department of Rheumatology, Rijnstate Hospital, Arnhem, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jansen, Tim L" sort="Jansen, Tim L" uniqKey="Jansen T" first="Tim L." last="Jansen">Tim L. Jansen</name><affiliation><nlm:aff id="aff009"><addr-line>Department of IQ HealthCare, VieCuri Medical Centre, Venlo, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Joosten, Leo A" sort="Joosten, Leo A" uniqKey="Joosten L" first="Leo A." last="Joosten">Leo A. Joosten</name><affiliation><nlm:aff id="aff010"><addr-line>Department of Internal Medicine and Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Radstake, Timothy R" sort="Radstake, Timothy R" uniqKey="Radstake T" first="Timothy R." last="Radstake">Timothy R. Radstake</name><affiliation><nlm:aff id="aff011"><addr-line>Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, Department of Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Riches, Philip L" sort="Riches, Philip L" uniqKey="Riches P" first="Philip L." last="Riches">Philip L. Riches</name><affiliation><nlm:aff id="aff012"><addr-line>Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tausche, Anne Kathrin" sort="Tausche, Anne Kathrin" uniqKey="Tausche A" first="Anne-Kathrin" last="Tausche">Anne-Kathrin Tausche</name><affiliation><nlm:aff id="aff013"><addr-line>Department of Rheumatology, University Clinic “Carl-Gustav-Carus”, Dresden, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liote, Frederic" sort="Liote, Frederic" uniqKey="Liote F" first="Frederic" last="Lioté">Frederic Lioté</name><affiliation><nlm:aff id="aff014"><addr-line>INSERM, UMR-S 1132, Hospital Lariboisière, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff015"><addr-line>University Paris Diderot (UFR de Médecine), Sorbonne Paris Cité, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lu, Leo" sort="Lu, Leo" uniqKey="Lu L" first="Leo" last="Lu">Leo Lu</name><affiliation><nlm:aff id="aff016"><addr-line>Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stahl, Eli A" sort="Stahl, Eli A" uniqKey="Stahl E" first="Eli A." last="Stahl">Eli A. Stahl</name><affiliation><nlm:aff id="aff017"><addr-line>Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Choi, Hyon K" sort="Choi, Hyon K" uniqKey="Choi H" first="Hyon K." last="Choi">Hyon K. Choi</name><affiliation><nlm:aff id="aff016"><addr-line>Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="So, Alexander" sort="So, Alexander" uniqKey="So A" first="Alexander" last="So">Alexander So</name><affiliation><nlm:aff id="aff018"><addr-line>DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé, Lausanne, Switzerland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Merriman, Tony R" sort="Merriman, Tony R" uniqKey="Merriman T" first="Tony R." last="Merriman">Tony R. Merriman</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Biochemistry, University of Otago, Dunedin, New Zealand</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26808548</idno><idno type="pmc">4726773</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726773</idno><idno type="RBID">PMC:4726773</idno><idno type="doi">10.1371/journal.pone.0147939</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000599</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000599</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Toll-Like Receptor 4 (TLR4) Variant <italic>rs2149356</italic> and Risk of Gout in European and Polynesian Sample Sets</title><author><name sortKey="Rasheed, Humaira" sort="Rasheed, Humaira" uniqKey="Rasheed H" first="Humaira" last="Rasheed">Humaira Rasheed</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Biochemistry, University of Otago, Dunedin, New Zealand</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>University of Engineering and Technology, Lahore, Pakistan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mckinney, Cushla" sort="Mckinney, Cushla" uniqKey="Mckinney C" first="Cushla" last="Mckinney">Cushla Mckinney</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Biochemistry, University of Otago, Dunedin, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stamp, Lisa K" sort="Stamp, Lisa K" uniqKey="Stamp L" first="Lisa K." last="Stamp">Lisa K. Stamp</name><affiliation><nlm:aff id="aff003"><addr-line>Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dalbeth, Nicola" sort="Dalbeth, Nicola" uniqKey="Dalbeth N" first="Nicola" last="Dalbeth">Nicola Dalbeth</name><affiliation><nlm:aff id="aff004"><addr-line>Department of Medicine, University of Auckland, Auckland, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Topless, Ruth K" sort="Topless, Ruth K" uniqKey="Topless R" first="Ruth K." last="Topless">Ruth K. Topless</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Biochemistry, University of Otago, Dunedin, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Day, Richard" sort="Day, Richard" uniqKey="Day R" first="Richard" last="Day">Richard Day</name><affiliation><nlm:aff id="aff005"><addr-line>School of Medical Sciences, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kannangara, Diluk" sort="Kannangara, Diluk" uniqKey="Kannangara D" first="Diluk" last="Kannangara">Diluk Kannangara</name><affiliation><nlm:aff id="aff005"><addr-line>School of Medical Sciences, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Williams, Kenneth" sort="Williams, Kenneth" uniqKey="Williams K" first="Kenneth" last="Williams">Kenneth Williams</name><affiliation><nlm:aff id="aff005"><addr-line>School of Medical Sciences, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Smith, Malcolm" sort="Smith, Malcolm" uniqKey="Smith M" first="Malcolm" last="Smith">Malcolm Smith</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Medicine, Flinders Medical Centre and Repatriation General Hospital, Adelaide, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Janssen, Matthijs" sort="Janssen, Matthijs" uniqKey="Janssen M" first="Matthijs" last="Janssen">Matthijs Janssen</name><affiliation><nlm:aff id="aff008"><addr-line>Department of Rheumatology, Rijnstate Hospital, Arnhem, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jansen, Tim L" sort="Jansen, Tim L" uniqKey="Jansen T" first="Tim L." last="Jansen">Tim L. Jansen</name><affiliation><nlm:aff id="aff009"><addr-line>Department of IQ HealthCare, VieCuri Medical Centre, Venlo, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Joosten, Leo A" sort="Joosten, Leo A" uniqKey="Joosten L" first="Leo A." last="Joosten">Leo A. Joosten</name><affiliation><nlm:aff id="aff010"><addr-line>Department of Internal Medicine and Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Radstake, Timothy R" sort="Radstake, Timothy R" uniqKey="Radstake T" first="Timothy R." last="Radstake">Timothy R. Radstake</name><affiliation><nlm:aff id="aff011"><addr-line>Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, Department of Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Riches, Philip L" sort="Riches, Philip L" uniqKey="Riches P" first="Philip L." last="Riches">Philip L. Riches</name><affiliation><nlm:aff id="aff012"><addr-line>Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tausche, Anne Kathrin" sort="Tausche, Anne Kathrin" uniqKey="Tausche A" first="Anne-Kathrin" last="Tausche">Anne-Kathrin Tausche</name><affiliation><nlm:aff id="aff013"><addr-line>Department of Rheumatology, University Clinic “Carl-Gustav-Carus”, Dresden, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liote, Frederic" sort="Liote, Frederic" uniqKey="Liote F" first="Frederic" last="Lioté">Frederic Lioté</name><affiliation><nlm:aff id="aff014"><addr-line>INSERM, UMR-S 1132, Hospital Lariboisière, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff015"><addr-line>University Paris Diderot (UFR de Médecine), Sorbonne Paris Cité, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lu, Leo" sort="Lu, Leo" uniqKey="Lu L" first="Leo" last="Lu">Leo Lu</name><affiliation><nlm:aff id="aff016"><addr-line>Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stahl, Eli A" sort="Stahl, Eli A" uniqKey="Stahl E" first="Eli A." last="Stahl">Eli A. Stahl</name><affiliation><nlm:aff id="aff017"><addr-line>Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Choi, Hyon K" sort="Choi, Hyon K" uniqKey="Choi H" first="Hyon K." last="Choi">Hyon K. Choi</name><affiliation><nlm:aff id="aff016"><addr-line>Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="So, Alexander" sort="So, Alexander" uniqKey="So A" first="Alexander" last="So">Alexander So</name><affiliation><nlm:aff id="aff018"><addr-line>DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé, Lausanne, Switzerland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Merriman, Tony R" sort="Merriman, Tony R" uniqKey="Merriman T" first="Tony R." last="Merriman">Tony R. Merriman</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Biochemistry, University of Otago, Dunedin, New Zealand</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism <italic>rs2149356</italic> in <italic>TLR4</italic> is a risk factor associated with gout in a Chinese study. Our aim was to replicate this observation in participants of European and New Zealand Polynesian (Māori and Pacific) ancestry. A total of 2250 clinically-ascertained prevalent gout cases and 13925 controls were used. Non-clinically-ascertained incident gout cases and controls from the Health Professional Follow-up (HPFS) and Nurses Health Studies (NHS) were also used. Genotypes were derived from genome-wide genotype data or directly obtained using Taqman. Logistic regression analysis was done including age, sex, diuretic exposure and ancestry as covariates as appropriate. The T-allele increased the risk of gout in the clinically-ascertained European samples (OR = 1.12, <italic>P</italic> = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, <italic>P</italic> = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion <italic>TLR4</italic> SNP <italic>rs2143956</italic> associates with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets to determine if there is genuine evidence for association.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Kottgen, A" uniqKey="Kottgen A">A Kottgen</name></author><author><name sortKey="Albrecht, E" uniqKey="Albrecht E">E Albrecht</name></author><author><name sortKey="Teumer, A" uniqKey="Teumer A">A Teumer</name></author><author><name sortKey="Vitart, V" uniqKey="Vitart V">V Vitart</name></author><author><name sortKey="Krumsiek, J" uniqKey="Krumsiek J">J Krumsiek</name></author><author><name sortKey="Hundertmark, C" uniqKey="Hundertmark C">C Hundertmark</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Phipps Green, A" uniqKey="Phipps Green A">A 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26808548</article-id><article-id pub-id-type="pmc">4726773</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0147939</article-id><article-id pub-id-type="publisher-id">PONE-D-15-39310</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Inflammatory Diseases</subject><subj-group><subject>Gout</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Rheumatology</subject><subj-group><subject>Gout</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>People and Places</subject><subj-group><subject>Population Groupings</subject><subj-group><subject>Ethnicities</subject><subj-group><subject>Polynesians</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Signal Transduction</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>People and places</subject><subj-group><subject>Population groupings</subject><subj-group><subject>Ethnicities</subject><subj-group><subject>Han Chinese</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Computational Biology</subject><subj-group><subject>Genome Analysis</subject><subj-group><subject>Genome-Wide Association Studies</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Genomics</subject><subj-group><subject>Genome Analysis</subject><subj-group><subject>Genome-Wide Association Studies</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Human Genetics</subject><subj-group><subject>Genome-Wide Association Studies</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Inflammasomes</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Inflammasomes</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Inflammasomes</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Signal Transduction</subject><subj-group><subject>Cell Signaling</subject><subj-group><subject>Membrane Receptor Signaling</subject><subj-group><subject>Immune Receptor Signaling</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>People and places</subject><subj-group><subject>Geographical locations</subject><subj-group><subject>Oceania</subject><subj-group><subject>New Zealand</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>The Toll-Like Receptor 4 (TLR4) Variant <italic>rs2149356</italic> and Risk of Gout in European and Polynesian Sample Sets</article-title><alt-title alt-title-type="running-head">The TLR4 Gene and Gout</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Rasheed</surname><given-names>Humaira</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>McKinney</surname><given-names>Cushla</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stamp</surname><given-names>Lisa K.</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dalbeth</surname><given-names>Nicola</given-names></name><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Topless</surname><given-names>Ruth K.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Day</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kannangara</surname><given-names>Diluk</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Williams</surname><given-names>Kenneth</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Malcolm</given-names></name><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Janssen</surname><given-names>Matthijs</given-names></name><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jansen</surname><given-names>Tim L.</given-names></name><xref ref-type="aff" rid="aff009"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Joosten</surname><given-names>Leo A.</given-names></name><xref ref-type="aff" rid="aff010"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Radstake</surname><given-names>Timothy R.</given-names></name><xref ref-type="aff" rid="aff011"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Riches</surname><given-names>Philip L.</given-names></name><xref ref-type="aff" rid="aff012"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tausche</surname><given-names>Anne-Kathrin</given-names></name><xref ref-type="aff" rid="aff013"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lioté</surname><given-names>Frederic</given-names></name><xref ref-type="aff" rid="aff014"><sup>14</sup></xref><xref ref-type="aff" rid="aff015"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lu</surname><given-names>Leo</given-names></name><xref ref-type="aff" rid="aff016"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stahl</surname><given-names>Eli A.</given-names></name><xref ref-type="aff" rid="aff017"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Choi</surname><given-names>Hyon K.</given-names></name><xref ref-type="aff" rid="aff016"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>So</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="aff018"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>Merriman</surname><given-names>Tony R.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Biochemistry, University of Otago, Dunedin, New Zealand</addr-line></aff><aff id="aff002"><label>2</label><addr-line>University of Engineering and Technology, Lahore, Pakistan</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Department of Medicine, University of Auckland, Auckland, New Zealand</addr-line></aff><aff id="aff005"><label>5</label><addr-line>School of Medical Sciences, University of New South Wales, Sydney, Australia</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Sydney, Australia</addr-line></aff><aff id="aff007"><label>7</label><addr-line>Department of Medicine, Flinders Medical Centre and Repatriation General Hospital, Adelaide, Australia</addr-line></aff><aff id="aff008"><label>8</label><addr-line>Department of Rheumatology, Rijnstate Hospital, Arnhem, The Netherlands</addr-line></aff><aff id="aff009"><label>9</label><addr-line>Department of IQ HealthCare, VieCuri Medical Centre, Venlo, The Netherlands</addr-line></aff><aff id="aff010"><label>10</label><addr-line>Department of Internal Medicine and Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands</addr-line></aff><aff id="aff011"><label>11</label><addr-line>Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, Department of Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands</addr-line></aff><aff id="aff012"><label>12</label><addr-line>Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom</addr-line></aff><aff id="aff013"><label>13</label><addr-line>Department of Rheumatology, University Clinic “Carl-Gustav-Carus”, Dresden, Germany</addr-line></aff><aff id="aff014"><label>14</label><addr-line>INSERM, UMR-S 1132, Hospital Lariboisière, Paris, France</addr-line></aff><aff id="aff015"><label>15</label><addr-line>University Paris Diderot (UFR de Médecine), Sorbonne Paris Cité, Paris, France</addr-line></aff><aff id="aff016"><label>16</label><addr-line>Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America</addr-line></aff><aff id="aff017"><label>17</label><addr-line>Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></aff><aff id="aff018"><label>18</label><addr-line>DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé, Lausanne, Switzerland</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>O'Rourke</surname><given-names>Dennis</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Utah, UNITED STATES</addr-line></aff><author-notes><fn fn-type="conflict" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: HR CM TRM. Performed the experiments: HR CM RKT. Analyzed the data: HR CM LL EAS HKC. Contributed reagents/materials/analysis tools: LKS ND RD DK KW MS MJ TLJ LAJ TRR PLR AKT FL HKC AS. Wrote the paper: HR CM LKS ND RKT RD DK KW MS MJ TLJ LAJ TRR PLR AKT FL LL EAS HKC AS TRM.</p></fn><corresp id="cor001">* E-mail: <email>tony.merriman@otago.ac.nz</email></corresp></author-notes><pub-date pub-type="epub"><day>25</day><month>1</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>11</volume><issue>1</issue><elocation-id>e0147939</elocation-id><history><date date-type="received"><day>8</day><month>9</month><year>2015</year></date><date date-type="accepted"><day>11</day><month>1</month><year>2016</year></date></history><permissions><license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/"><license-p>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/publicdomain/zero/1.0/">Creative Commons CC0</ext-link> public domain dedication.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="pone.0147939.pdf"></self-uri><abstract><p>Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism <italic>rs2149356</italic> in <italic>TLR4</italic> is a risk factor associated with gout in a Chinese study. Our aim was to replicate this observation in participants of European and New Zealand Polynesian (Māori and Pacific) ancestry. A total of 2250 clinically-ascertained prevalent gout cases and 13925 controls were used. Non-clinically-ascertained incident gout cases and controls from the Health Professional Follow-up (HPFS) and Nurses Health Studies (NHS) were also used. Genotypes were derived from genome-wide genotype data or directly obtained using Taqman. Logistic regression analysis was done including age, sex, diuretic exposure and ancestry as covariates as appropriate. The T-allele increased the risk of gout in the clinically-ascertained European samples (OR = 1.12, <italic>P</italic> = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, <italic>P</italic> = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion <italic>TLR4</italic> SNP <italic>rs2143956</italic> associates with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets to determine if there is genuine evidence for association.</p></abstract><funding-group><funding-statement>This work was supported by the Health Research Council of New Zealand (11/1075, 14/527), Arthritis New Zealand, New Zealand Lottery Health, the University of Otago and Arthritis Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Atherosclerosis Risk in Communities study is supported by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Framingham Heart Study and the Framingham SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University.</funding-statement></funding-group><counts><fig-count count="0"></fig-count><table-count count="3"></table-count><page-count count="8"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>We are restricted by consent in making individual level phenotype and genotype information freely available without restriction. Data may be made available upon request. Requests for data can be sent to the corresponding author (<email>tony.merriman@otago.ac.nz</email>).</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>We are restricted by consent in making individual level phenotype and genotype information freely available without restriction. Data may be made available upon request. Requests for data can be sent to the corresponding author (<email>tony.merriman@otago.ac.nz</email>).</p></notes></front><body><sec sec-type="intro" id="sec001"><title>Introduction</title><p>Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. Genome-wide association studies of serum urate have confirmed uric acid transporters SLC2A9 and ABCG2 as important loci, that are also associated with gout, with weaker effects from other uric acid transporters [<xref rid="pone.0147939.ref001" ref-type="bibr">1</xref>–<xref rid="pone.0147939.ref003" ref-type="bibr">3</xref>]. Given that many individuals with hyperuricaemia do not develop gout, other factors must exist controlling the progression from hyperuricaemia to gout [<xref rid="pone.0147939.ref004" ref-type="bibr">4</xref>]. However, very little is known about the genetic basis of the progression from hyperuricaemia to MSU crystal deposition to symptomatic gout [<xref rid="pone.0147939.ref005" ref-type="bibr">5</xref>]. The auto-inflammatory nature of gout involves the activation of the innate immune response by MSU crystals. A central pathway is primability and actual activation of the NLRP3 inflammasome and subsequent release of mature interleukin-1β [<xref rid="pone.0147939.ref006" ref-type="bibr">6</xref>, <xref rid="pone.0147939.ref007" ref-type="bibr">7</xref>]. An important question is whether or not genetic regulation of this pathway is a risk factor for gout.</p><p>Toll-like receptors (TLRs) are transmembrane pattern recognition receptors expressed by innate immune cells that trigger an innate immune response by controlling distinct signaling pathways [<xref rid="pone.0147939.ref008" ref-type="bibr">8</xref>]. In addition to microbial ligands, these receptors also trigger innate immune response against endogenous ligands including MSU crystals [<xref rid="pone.0147939.ref009" ref-type="bibr">9</xref>]. To date ten functional human TLRs (TLR1-10) have been identified [<xref rid="pone.0147939.ref010" ref-type="bibr">10</xref>] of which TLR4 is a prominent member and which has been associated with a number of auto-inflammatory conditions [<xref rid="pone.0147939.ref011" ref-type="bibr">11</xref>]. This receptor activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway. A <italic>TLR4</italic> single nucleotide polymorphism (SNP; <italic>rs2149356</italic>) has been reported to be associated with gout in a Han Chinese sample set [<xref rid="pone.0147939.ref012" ref-type="bibr">12</xref>], where the TT-genotype was associated with an increased risk of gout (OR = 1.96 [95% CI 1.40–2.74]). The same genotype was associated with increased TLR4 mRNA expression and increased IL1β expression [<xref rid="pone.0147939.ref012" ref-type="bibr">12</xref>]. Our aim was to replicate the genetic association of <italic>rs2149356</italic> with gout in individuals of European and New Zealand Polynesian ancestry.</p></sec><sec id="sec002"><title>Subjects and Methods</title><sec id="sec003"><title>Subjects</title><p>Demographic and clinical data are presented in <xref ref-type="table" rid="pone.0147939.t001">Table 1</xref>. All gout cases were clinically ascertained according to the 1977 American Rheumatism Association (ARA) classification criteria [<xref rid="pone.0147939.ref013" ref-type="bibr">13</xref>]. European cases (n = 1614) were recruited from New Zealand (n = 647), by the Eurogout consortium within the European Crystal Network (n = 779) [<xref rid="pone.0147939.ref014" ref-type="bibr">14</xref>] and by the Arthritis Genomics Recruitment Initiative in Australasia (AGRIA; n = 188). These cases were 84.1% male with average age of 63.0 (20–97) years. European non-gouty controls (n = 13005), after exclusion criteria applied as described below, were recruited from NZ (n = 875) and sourced from the Atherosclerosis Risk in Communities (ARIC; n = 8781) and Framingham Heart (FHS; n = 3349 Generation 3 only) studies. The controls were 46.5% male with average age of 50.2 (17–95) years. There were 636 New Zealand Māori and Pacific Island (Polynesian) cases (87.5% male with average age of 49.9 (17–100) years) and 920 controls (46.7% male with average age of 41.1 (17–85) years). Individuals who ever self-reported as having gout or taking urate-lowering medication were excluded from the ARIC and FHS sample sets. The New Zealand Multi-Region Ethics Committee (MEC/105/10/130) and these institutional committees in Europe and Australia granted ethical approval: Research and Ethics Committee, Repatriation General Hospital, South Australia (32/08); Research Ethics Committee, University of New South Wales; Ethikkommission, Technische Universität Dresden (EK 8012012); South East Scotland Research Ethics Committee (04/S1102/41); Commission Cantonale (VD) D'éthique de la Recherche sur l'être Humain, Université de Lausanne; Commissie Mensgebonden Onderzoek regio Arnhem—Nijmegen; Partners Health Care System Institutional Review Board. All subjects gave written informed consent. The Database of Genotype and Phenotype (<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/gap">www.ncbi.nlm.nih.gov/gap</ext-link>) approval number was #834 for accessing data from the ARIC and FHS studies.</p><table-wrap id="pone.0147939.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0147939.t001</object-id><label>Table 1</label><caption><title>Demographic and clinical data of participants.</title></caption><alternatives><graphic id="pone.0147939.t001g" xlink:href="pone.0147939.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"> </th><th align="center" colspan="2" rowspan="1">European</th><th align="center" colspan="2" rowspan="1">NZ Polynesian</th><th align="center" colspan="2" rowspan="1">HPFS</th><th align="center" rowspan="1" colspan="1">NHS</th><th align="center" rowspan="1" colspan="1"></th></tr><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">Control</th><th align="left" rowspan="1" colspan="1">Gout</th><th align="left" rowspan="1" colspan="1">Control</th><th align="left" rowspan="1" colspan="1">Gout</th><th align="left" rowspan="1" colspan="1">Control</th><th align="left" rowspan="1" colspan="1">Gout</th><th align="left" rowspan="1" colspan="1">Control</th><th align="left" rowspan="1" colspan="1">Gout</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Number</td><td align="left" rowspan="1" colspan="1">13005</td><td align="left" rowspan="1" colspan="1">1614</td><td align="left" rowspan="1" colspan="1">920</td><td align="left" rowspan="1" colspan="1">636</td><td align="left" rowspan="1" colspan="1">3445</td><td align="left" rowspan="1" colspan="1">726</td><td align="left" rowspan="1" colspan="1">6317</td><td align="left" rowspan="1" colspan="1">351</td></tr><tr><td align="left" rowspan="1" colspan="1">Male (%)</td><td align="left" rowspan="1" colspan="1">6049 (46.52)</td><td align="left" rowspan="1" colspan="1">1332 (84.14)</td><td align="left" rowspan="1" colspan="1">419 (45.89)</td><td align="left" rowspan="1" colspan="1">546 (87.50)</td><td align="left" rowspan="1" colspan="1">3445 (100)</td><td align="left" rowspan="1" colspan="1">726 (100)</td><td align="left" rowspan="1" colspan="1">00 (0.00)</td><td align="left" rowspan="1" colspan="1">00 (0.00)</td></tr><tr><td align="left" rowspan="1" colspan="1">Age</td><td align="left" rowspan="1" colspan="1">50.23±10.08</td><td align="left" rowspan="1" colspan="1">62.95±13.24</td><td align="left" rowspan="1" colspan="1">41.12±14.45</td><td align="left" rowspan="1" colspan="1">49.88±13.18</td><td align="left" rowspan="1" colspan="1">62.02±8.52<xref ref-type="table-fn" rid="t001fn003">**</xref></td><td align="left" rowspan="1" colspan="1">61.73±9.60<xref ref-type="table-fn" rid="t001fn003">**</xref></td><td align="left" rowspan="1" colspan="1">67.99±6.70<xref ref-type="table-fn" rid="t001fn003">**</xref></td><td align="left" rowspan="1" colspan="1">64.95±9.85<xref ref-type="table-fn" rid="t001fn003">**</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">BMI</td><td align="left" rowspan="1" colspan="1">26.82±5.00 (12491)<xref ref-type="table-fn" rid="t001fn002">*</xref></td><td align="left" rowspan="1" colspan="1">30.04±6.60 (1323)</td><td align="left" rowspan="1" colspan="1">32.67±7.26 (813)</td><td align="left" rowspan="1" colspan="1">35.79±7.69 (570)</td><td align="left" rowspan="1" colspan="1">25.84±3.34<xref ref-type="table-fn" rid="t001fn003">**</xref></td><td align="left" rowspan="1" colspan="1">27.20±3.73<xref ref-type="table-fn" rid="t001fn003">**</xref></td><td align="left" rowspan="1" colspan="1">26.31±5.15<xref ref-type="table-fn" rid="t001fn003">**</xref></td><td align="left" rowspan="1" colspan="1">30.16±6.34<xref ref-type="table-fn" rid="t001fn003">**</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Serum Urate (mmol/L)</td><td align="left" rowspan="1" colspan="1">0.336±0.087 (12483)</td><td align="left" rowspan="1" colspan="1">0.399±0.136 (1118)</td><td align="left" rowspan="1" colspan="1">0.373±0.088 (680)</td><td align="left" rowspan="1" colspan="1">0.436±0.119 (484)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Gout Duration (Years)</td><td align="left" rowspan="1" colspan="1">_</td><td align="left" rowspan="1" colspan="1">15.19±12.56 (1289)</td><td align="left" rowspan="1" colspan="1">_</td><td align="left" rowspan="1" colspan="1">13.21±11.09 (548)</td><td align="left" rowspan="1" colspan="1">_</td><td align="left" rowspan="1" colspan="1">Incident Cases</td><td align="left" rowspan="1" colspan="1">_</td><td align="left" rowspan="1" colspan="1">Incident Cases</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>All values aside from sex are expressed as mean ± SD.</p></fn><fn id="t001fn002"><p>* For BMI, SU and gout duration, the figure inside the brackets represents the number of subjects with available data.</p></fn><fn id="t001fn003"><p>** Obtained at the time of gout onset among cases and at the mid-point time of cohort follow-up among controls.</p></fn></table-wrap-foot></table-wrap><p>A separate data set, previously described in ref [<xref rid="pone.0147939.ref015" ref-type="bibr">15</xref>], of European Caucasian individuals was investigated consisting of 726 incident male cases and 3445 controls from the Health Professionals Follow-up Study (HPFS) and 351 incident female cases and 6317 controls from the Nurses Health Study (NHS) (<xref ref-type="table" rid="pone.0147939.t001">Table 1</xref>). All cases were ascertained according to 1977 ARA classification criteria [<xref rid="pone.0147939.ref013" ref-type="bibr">13</xref>] using a self-administered gout questionnaire as previously described [<xref rid="pone.0147939.ref016" ref-type="bibr">16</xref>]. As summarised in ref [<xref rid="pone.0147939.ref015" ref-type="bibr">15</xref>] evaluation of medical records by two board-certified rheumatologists in a random audit set of 50 HPFS men demonstrated 94% (47/50) concordance of the diagnosis of gout between the self-administered questionnaire and the review of medical records and 91% (51/56) concordance in an audit sample of 56 NHS women.</p></sec><sec id="sec004"><title>Genotyping</title><p>Taqman genotyping for rs2149356 was performed for the sample sets excepting ARIC, FHS, HPFS and NHS using a Lightcycler 480 Real-Time Polymerase Chain Reaction System (Roche Applied Science, Indianapolis, USA) in 384-well plates. The FHS cohort had been genotyped by the Affymetrix SNP 5 platform and a custom-designed gene-centric 50K SNP platform and <italic>rs2149356</italic> genotype was imputed using MACH1 v1.0.15 with the HapMap CEU sample set as reference haplotypes. In the ARIC sample set <italic>rs2149356</italic> had been genotyped on the Affymetrix SNP 6 platform. The HPFS and NHS sample sets were genotyped using the Illumina Infinium OmniExpress and genotypes were imputed using MACH (imputation quality Rsq = 0.989). This resulted in N = 10807 non-missing genotype calls (1.5% missing). There was no evidence for departure from Hardy Weinberg equilibrium in any of the sample sets presented in Tables <xref ref-type="table" rid="pone.0147939.t002">2</xref> and <xref ref-type="table" rid="pone.0147939.t003">3</xref> (<italic>P</italic><sub>HWE</sub>>0.01).</p><table-wrap id="pone.0147939.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0147939.t002</object-id><label>Table 2</label><caption><title><italic>Rs2149356</italic> genotype and association with risk of gout in NZ and Europe sample sets using ARIC and FHS controls.</title></caption><alternatives><graphic id="pone.0147939.t002g" xlink:href="pone.0147939.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1">Gout</th><th align="center" rowspan="1" colspan="1">All Controls</th><th align="center" rowspan="1" colspan="1">Adjusted OR[95%CI]<xref ref-type="table-fn" rid="t002fn001"><sup>1</sup></xref></th><th align="center" rowspan="1" colspan="1">P</th></tr></thead><tbody><tr><td align="center" rowspan="1" colspan="1">European</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="center" rowspan="1" colspan="1">GG</td><td align="center" rowspan="1" colspan="1">716 (0.444)</td><td align="center" rowspan="1" colspan="1">6093 (0.469)</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="center" rowspan="1" colspan="1">GT</td><td align="center" rowspan="1" colspan="1">700 (0.434)</td><td align="center" rowspan="1" colspan="1">5529 (0.425)</td><td align="center" rowspan="1" colspan="1">1.068 [0.940–1.214]</td><td align="center" rowspan="1" colspan="1">0.32</td></tr><tr><td align="center" rowspan="1" colspan="1">TT</td><td align="center" rowspan="1" colspan="1">198 (0.122)</td><td align="center" rowspan="1" colspan="1">1383 (0.106)</td><td align="center" rowspan="1" colspan="1">1.317 [1.082–1.605]</td><td align="center" rowspan="1" colspan="1">0.006</td></tr><tr><td align="center" rowspan="1" colspan="1">T</td><td align="center" rowspan="1" colspan="1">1096 (0.340)</td><td align="center" rowspan="1" colspan="1">8295 (0.319)</td><td align="center" rowspan="1" colspan="1">1.122 [1.025–1.227]</td><td align="center" rowspan="1" colspan="1">0.012</td></tr><tr><td align="center" rowspan="1" colspan="1">NZ Polynesian</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="center" rowspan="1" colspan="1">GG</td><td align="center" rowspan="1" colspan="1">181 (0.285)</td><td align="center" rowspan="1" colspan="1">241 (0.262)</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td align="center" rowspan="1" colspan="1">GT</td><td align="center" rowspan="1" colspan="1">317 (0.498)</td><td align="center" rowspan="1" colspan="1">437 (0.475)</td><td align="center" rowspan="1" colspan="1">0.950 [0.710–1.272]</td><td align="center" rowspan="1" colspan="1">0.73</td></tr><tr><td align="center" rowspan="1" colspan="1">TT</td><td align="center" rowspan="1" colspan="1">138 (0.217)</td><td align="center" rowspan="1" colspan="1">242 (0.263)</td><td align="center" rowspan="1" colspan="1">0.634 [0.450–0.895]</td><td align="center" rowspan="1" colspan="1">0.009</td></tr><tr><td align="center" rowspan="1" colspan="1">T</td><td align="center" rowspan="1" colspan="1">593 (0.466)</td><td align="center" rowspan="1" colspan="1">921 (0.501)</td><td align="center" rowspan="1" colspan="1">0.800 [0.674–0.949]</td><td align="center" rowspan="1" colspan="1">0.011</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>1 Adjusted by age, sex and (for Polynesian) STRUCTURE estimate of Polynesian ancestry [<xref rid="pone.0147939.ref017" ref-type="bibr">17</xref>].</p></fn></table-wrap-foot></table-wrap><table-wrap id="pone.0147939.t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0147939.t003</object-id><label>Table 3</label><caption><title><italic>Rs2149356</italic> genotype and association with risk of gout in the HPFS and NHS sample sets.</title></caption><alternatives><graphic id="pone.0147939.t003g" xlink:href="pone.0147939.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="center" rowspan="1" colspan="1">Genotype</th><th align="center" rowspan="1" colspan="1">Total</th><th align="center" rowspan="1" colspan="1">Gout</th><th align="left" rowspan="1" colspan="1">Unadjusted RR[95% CI]</th><th align="center" rowspan="1" colspan="1">P</th><th align="center" rowspan="1" colspan="1">Adjusted RR<xref ref-type="table-fn" rid="t003fn001"><sup>1</sup></xref> [95% CI]</th><th align="center" rowspan="1" colspan="1">P</th></tr></thead><tbody><tr><td align="center" rowspan="1" colspan="1"><italic>HPFS</italic></td><td align="center" rowspan="1" colspan="1">N = 4171</td><td align="center" rowspan="1" colspan="1">N = 726</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="center" rowspan="1" colspan="1">GG</td><td align="center" rowspan="1" colspan="1">1920</td><td align="center" rowspan="1" colspan="1">336</td><td align="center" rowspan="1" colspan="1">1.00</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">1.00</td><td align="center" rowspan="1" colspan="1">-</td></tr><tr><td align="center" rowspan="1" colspan="1">GT</td><td align="center" rowspan="1" colspan="1">1824</td><td align="center" rowspan="1" colspan="1">315</td><td align="center" rowspan="1" colspan="1">0.98 [0.84–1.14]</td><td align="center" rowspan="1" colspan="1">0.78</td><td align="center" rowspan="1" colspan="1">0.99 [0.84–1.15]</td><td align="center" rowspan="1" colspan="1">0.84</td></tr><tr><td align="center" rowspan="1" colspan="1">TT</td><td align="center" rowspan="1" colspan="1">427</td><td align="center" rowspan="1" colspan="1">75</td><td align="center" rowspan="1" colspan="1">1.03 [0.80–1.32]</td><td align="center" rowspan="1" colspan="1">0.83</td><td align="center" rowspan="1" colspan="1">1.05 [0.82–1.35]</td><td align="center" rowspan="1" colspan="1">0.70</td></tr><tr><td align="center" rowspan="1" colspan="1">T</td><td align="center" rowspan="1" colspan="1">2251</td><td align="center" rowspan="1" colspan="1">390</td><td align="center" rowspan="1" colspan="1">0.99 [0.85–1.14]</td><td align="center" rowspan="1" colspan="1">0.85</td><td align="center" rowspan="1" colspan="1">1.00 [0.86–1.15]</td><td align="center" rowspan="1" colspan="1">0.94</td></tr><tr><td align="center" rowspan="1" colspan="1"><italic>NHS</italic></td><td align="center" rowspan="1" colspan="1">N = 6668</td><td align="center" rowspan="1" colspan="1">N = 351</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"></td></tr><tr><td align="center" rowspan="1" colspan="1">GG</td><td align="center" rowspan="1" colspan="1">3137</td><td align="center" rowspan="1" colspan="1">176</td><td align="center" rowspan="1" colspan="1">1.00</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1">1.00</td><td align="center" rowspan="1" colspan="1">-</td></tr><tr><td align="center" rowspan="1" colspan="1">GT</td><td align="center" rowspan="1" colspan="1">2901</td><td align="center" rowspan="1" colspan="1">143</td><td align="center" rowspan="1" colspan="1">0.88 [0.70–1.10]</td><td align="center" rowspan="1" colspan="1">0.25</td><td align="center" rowspan="1" colspan="1">0.89 [0.71–1.11]</td><td align="center" rowspan="1" colspan="1">0.29</td></tr><tr><td align="center" rowspan="1" colspan="1">TT</td><td align="center" rowspan="1" colspan="1">630</td><td align="center" rowspan="1" colspan="1">32</td><td align="center" rowspan="1" colspan="1">0.93 [0.64–1.36]</td><td align="center" rowspan="1" colspan="1">0.71</td><td align="center" rowspan="1" colspan="1">0.97 [0.66–1.42]</td><td align="center" rowspan="1" colspan="1">0.87</td></tr><tr><td align="center" rowspan="1" colspan="1">T</td><td align="center" rowspan="1" colspan="1">3531</td><td align="center" rowspan="1" colspan="1">175</td><td align="center" rowspan="1" colspan="1">0.88 [0.72–1.09]</td><td align="center" rowspan="1" colspan="1">0.24</td><td align="center" rowspan="1" colspan="1">0.90 [0.73–1.11]</td><td align="center" rowspan="1" colspan="1">0.31</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t003fn001"><p>1 Adjusted by age and diuretic usage.</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec005"><title>Statistical analysis</title><p>All logistic regression analysis was done using Intercooled STATA software version 8.0 (College Station, TX 77845, USA). Allelic and genotypic odds ratios for gout were calculated and all analyses were adjusted by age and sex, with the Polynesian analysis additionally adjusted by an estimate of Polynesian ancestry calculated as previously described in order to account for admixture with other ancestral groups [<xref rid="pone.0147939.ref017" ref-type="bibr">17</xref>]. A threshold of <italic>P</italic> < 0.05 was used to declare nominal statistical significance.</p></sec></sec><sec sec-type="results" id="sec006"><title>Results</title><p>In European and Polynesian subjects, the T-allele of <italic>rs2149356</italic> was associated with the risk of gout when compared to controls unstratified by urate level, but in an opposing direction of association (<xref ref-type="table" rid="pone.0147939.t002">Table 2</xref>; OR<sub>European</sub> = 1.12, <italic>P</italic> = 0.012 and OR<sub>Polynesian</sub> = 0.80, <italic>P</italic> = 0.011). The TT-genotype was also associated with risk of gout when compared to the GG genotype, again in an opposing direction of association (<xref ref-type="table" rid="pone.0147939.t001">Table 1</xref>; OR<sub>European</sub> = 1.32, <italic>P</italic> = 0.006 and OR<sub>Polynesian</sub> = 0.63, <italic>P</italic> = 0.009). <italic>Rs2149356</italic> was then tested for association with gout in the HPFS and NHS studies (<xref ref-type="table" rid="pone.0147939.t003">Table 3</xref>). There was no evidence for association in either the allelic or genotypic analyses in either of the studies (<italic>P</italic>≥0.31).</p></sec><sec sec-type="conclusions" id="sec007"><title>Discussion</title><p>Here we attempted to replicate the previously reported association with gout of <italic>TLR4</italic> variant <italic>rs2149356</italic> in Han Chinese in sample sets of European and Polynesian ancestry. In the NZ and Europeans recruited from Europe the association was replicated but with opposing direction in the Polynesian sample set. A similar opposing direction of association between European and Polynesian is also evident at other urate- and gout-associated loci <italic>PRKAG2</italic> and <italic>HLF</italic> [<xref rid="pone.0147939.ref002" ref-type="bibr">2</xref>]. Why this is the case is not resolved, discussed further below. The third sample set (HPFS and NHS) provided no evidence to support association of <italic>rs2149356</italic> with gout. Two characteristics of this sample set would have reduced chances of detecting association, should genuine association exist. First, only ~90% have clinically-ascertained gout [<xref rid="pone.0147939.ref016" ref-type="bibr">16</xref>]. Second, the sample set are incident gout cases (with minimum age of male cases 40 years and female cases 30 years [<xref rid="pone.0147939.ref016" ref-type="bibr">16</xref>]). Prevalent cases are excluded—these excluded cases would be expected to have an earlier age of onset and a stronger heritable component. On balance we are unable to conclude that the <italic>TLR4</italic> locus to be the first replicated genetic risk factor in gout outside of those that influence gout risk via modulation of serum urate levels. However, given the very strong prior functional candidacy of <italic>TLR4</italic>, we do consider that our study provides evidence consistent with a causal role for <italic>TLR4</italic> in gout.</p><p>Regarding the inconsistent direction of association with gout between Polynesian, and Han Chinese and European, the simplest explanation is that <italic>rs2149356</italic> is not the causal variant but in linkage disequilibrium with the causal variant, with a Polynesian-specific ancestral recombination event distinguishing the Polynesian haplotypic background around <italic>rs2149356</italic> from European and Han Chinese, resulting in the other (G) allele of <italic>rs2149356</italic> being on the Polynesian risk haplotype. The Polynesian population could be important in trans-ancestral genetic fine-mapping of the etiological variant in <italic>TLR4</italic> with the variant expected to be in a genomic segment with the same alleles associated with gout between Han Chinese, European and Polynesian. Other possibilities are that this marker is subject to stratification effects that have not been adequately controlled in the Polynesian sample set, that there are non-genetic interactors (e.g. alcohol and sugar-sweetened beverage consumption [<xref rid="pone.0147939.ref018" ref-type="bibr">18</xref>–<xref rid="pone.0147939.ref020" ref-type="bibr">20</xref>]) that are unaccounted for and that would generate inconsistent <italic>rs2149356</italic> main effects or that these are chance findings given the modest level of significance.</p><p>SNP <italic>rs2149356</italic> is a common genetic variant of weak effect (OR≤1.4). More than 70% of genetic variants for common phenotypes identified by genome-wide association studies map to regulatory regions of the genome [<xref rid="pone.0147939.ref021" ref-type="bibr">21</xref>]. While it is possible that less common non-synonymous functional variants in <italic>TLR4</italic>, that have been associated with other auto-inflammatory conditions [<xref rid="pone.0147939.ref022" ref-type="bibr">22</xref>, <xref rid="pone.0147939.ref023" ref-type="bibr">23</xref>], may also associate with gout, it is likely that the effect of <italic>rs2149356</italic> on the risk of gout is via an influence on expression of TLR4, either the amount of TLR4 produced and/or relative levels of isoforms. Direct evidence of this was supplied by Qing et al. [<xref rid="pone.0147939.ref012" ref-type="bibr">12</xref>] who associated the TT-genotype <italic>rs2149356</italic> with increased levels of TLR4 mRNA in peripheral blood mononuclear cells (PBMCs) and increased serum interleukin-1β levels in people with acute gout. Conversely the TT-genotype associated with reduced levels of TLR4 mRNA in PBMCs from people with intercritical gout. These important findings are consistent with the increased risk observed for the TT-genotype for gout. Understanding how the T-allele controls expression of TLR4 will be important for improved molecular understanding of the pathogenic role of the TLR4-pathway in gout. Our data, with an opposing direction of association in Polynesian, suggest that <italic>rs2149356</italic> is not causal but in linkage disequilibrium (LD) with, and a marker for, the causal variant. <italic>Rs2149356</italic> maps to intron 4 of <italic>TLR4</italic> but is in strong LD with two SNPs in the promoter of <italic>TLR4</italic> (<italic>rs2737190</italic>, r<sup>2</sup> = 0.92 in Europeans and 0.97 in Asians, ‘-2570’ [<xref rid="pone.0147939.ref024" ref-type="bibr">24</xref>]; <italic>rs1927914</italic>, r<sup>2</sup> = 0.93 in Europeans and 0.97 in Asians, -2026’ [<xref rid="pone.0147939.ref024" ref-type="bibr">24</xref>]). The gout risk allele (T) of <italic>rs2149356</italic> would be present (co-inherited) on a haplotype with the minor allele of each of these promoter SNPs. The minor allele (G) of <italic>rs2737190</italic> is predicted to create a v-Myb transcription factor binding site and the minor allele (G) of <italic>rs1927914</italic> is predicted to remove Oct-1 and C/EBP transcription factor binding sites [<xref rid="pone.0147939.ref024" ref-type="bibr">24</xref>]. When studied individually <italic>in vitro</italic>, the <italic>rs2737190</italic> G allele had no effect, but the <italic>rs1927914</italic> G allele significantly decreased basal expression from the TLR4 promoter and increased response to challenge with a uropathogenic <italic>Escherichia coli</italic> strain [<xref rid="pone.0147939.ref024" ref-type="bibr">24</xref>], which is consistent with the observed expression pattern from Qing et al. [<xref rid="pone.0147939.ref012" ref-type="bibr">12</xref>]. This genetic variant is therefore a candidate functional etiological variant for gout.</p><p>In conclusion, <italic>TLR4</italic> SNP <italic>rs2143956</italic> is associated with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese [<xref rid="pone.0147939.ref012" ref-type="bibr">12</xref>]. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets.</p></sec></body><back><ack><p>The authors would like to thank Jill Drake, Roddi Laurence, Christopher Franklin, Meaghan House and Gabrielle Sexton for recruitment. We thank Labtests (Auckland) for their assistance in recruitment. Matthew Brown, Linda Bradbury and The Arthritis Genomics Recruitment Initiative in Australia network are acknowledged. The European Crystal Network was formed after the first European Crystal Workshop in Paris, March 2010 (Prof Frédéric Lioté, Paris, and Prof Alexander So, Lausanne, convenors). The Atherosclerosis Risk in Communities and Framingham Heart study analyses (project #834) were approved by the relevant Database of Genotype and Phenotype (dbGaP; <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nim.nih/gov/dbgap">www.ncbi.nim.nih/gov/dbgap</ext-link>) Data Access Committees. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute. The authors thank the staff and participants of the ARIC study for their important contributions. The Framingham SHARe data used for the analyses described in this manuscript were obtained through dbGaP. 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