Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout

Show simple item record McKinney, C en Stamp, LK en Dalbeth, Nicola en Topless, RK en Day, RO en Kannangara, DR en Williams, KM en Janssen, M en Jansen, TL en Joosten, LA en Radstake, TR en Riches, PL en Tausche, AK en Lioté, F en So, A en Merriman, TR en 2016-09-28T04:12:51Z en 2015-01 en
dc.identifier.citation Arthritis Research and Therapy 17:Article number 288 Jan 2015 en
dc.identifier.issn 1478-6354 en
dc.identifier.uri en
dc.description.abstract The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1β (IL-1β) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1β axis for association with gout.1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Māori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set.Eleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P < 0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8.There is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1β - the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1β expression leading to increased production of mature IL-1β in gout. en
dc.format.medium Electronic en
dc.language eng en
dc.publisher BioMed Central en
dc.relation.ispartofseries Arthritis Research and Therapy en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
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dc.rights.uri en
dc.title Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout en
dc.type Journal Article en
dc.identifier.doi 10.1186/s13075-015-0802-3 en
pubs.volume 17 en
dc.description.version VoR - Version of Record en
dc.identifier.pmid 26462562 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 522638 en Medical and Health Sciences en School of Medicine en Medicine Department en
dc.identifier.eissn 1478-6362 en
pubs.number 288 en
pubs.record-created-at-source-date 2016-09-28 en
pubs.dimensions-id 26462562 en

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