Rasheed, HumairaMcKinney, CushlaStamp, Lisa K.Dalbeth, NicolaTopless, Ruth K.Day, RichardKannangara, DilukWilliams, KennethSmith, MalcolmJanssen, MatthijsJansen, Tim L.Joosten, Leo A.Radstake, Timothy R.Riches, Philip L.Tausche, Anne-KathrinLioté, FredericLu, LeoStahl, Eli A.Choi, HyonSo, AlexanderMerriman, Tony R.2016-03-012016Rasheed, H., C. McKinney, L. K. Stamp, N. Dalbeth, R. K. Topless, R. Day, D. Kannangara, et al. 2016. “The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets.” PLoS ONE 11 (1): e0147939. doi:10.1371/journal.pone.0147939. http://dx.doi.org/10.1371/journal.pone.0147939.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:25658435Deposition 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.en-USMedicine and Health SciencesInflammatory DiseasesGoutRheumatologyPeople and PlacesPopulation GroupingsEthnicitiesPolynesiansBiology and Life SciencesImmunologyImmune System ProteinsImmune ReceptorsToll-like ReceptorsBiochemistryProteinsCell BiologySignal TransductionPeople and placesPopulation groupingsHan ChineseComputational BiologyGenome AnalysisGenome-Wide Association StudiesGeneticsGenomicsHuman GeneticsInflammasomesCell SignalingMembrane Receptor SignalingImmune Receptor SignalingGeographical locationsOceaniaNew ZealandJournal Article2016-03-0110.1371/journal.pone.0147939