title: The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets.
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 rs2149356 in TLR4 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, P = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, P = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion TLR4 SNP rs2143956 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.
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.|University of Engineering and Technology, Lahore, Pakistan.
authors.forename: Humaira
authors.initials: H
authors.lastname: Rasheed
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Cushla
authors.initials: C
authors.lastname: McKinney
authors.affiliation: Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dalbeth
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Ruth K
authors.initials: RK
authors.lastname: Topless
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, Australia.|Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Day
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, Australia.|Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia.
authors.forename: Diluk
authors.initials: D
authors.lastname: Kannangara
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, Australia.|Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Williams
authors.affiliation: Department of Medicine, Flinders Medical Centre and Repatriation General Hospital, Adelaide, Australia.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Smith
authors.affiliation: Department of Rheumatology, Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Janssen
authors.affiliation: Department of IQ HealthCare, VieCuri Medical Centre, Venlo, The Netherlands.
authors.forename: Tim L
authors.initials: TL
authors.lastname: Jansen
authors.affiliation: Department of Internal Medicine and Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, Department of Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Radstake
authors.affiliation: Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Riches
authors.affiliation: Department of Rheumatology, University Clinic "Carl-Gustav-Carus", Dresden, Germany.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Tausche
authors.affiliation: INSERM, UMR-S 1132, Hospital Lariboisière, Paris, France.|University Paris Diderot (UFR de Médecine), Sorbonne Paris Cité, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lioté
authors.affiliation: Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Leo
authors.initials: L
authors.lastname: Lu
authors.affiliation: Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Eli A
authors.initials: EA
authors.lastname: Stahl
authors.affiliation: Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Hyon K
authors.initials: HK
authors.lastname: Choi
authors.affiliation: DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé, Lausanne, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: So
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
mesh_terms: D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D006073:Gout / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D051197:Toll-Like Receptor 4