The toll-like receptor 4 (TLR4) variant rs2149356 and risk of gout in European and polynesian sample sets

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 SoTony R. Merriman

Research output: Contribution to journalArticleAcademicpeer-review


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 tolllike receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-KB 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 (M ori 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.

Original languageEnglish
Article numbere0147939
Number of pages8
JournalPLoS ONE [E]
Issue number1
Publication statusPublished - 1 Jan 2016


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