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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2015

Open Access 01-12-2015 | Research article

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

Authors: Cushla McKinney, Lisa K. Stamp, Nicola Dalbeth, Ruth K. Topless, Richard O. Day, Diluk RW Kannangara, Kenneth M. Williams, Matthijs Janssen, Timothy L. Jansen, Leo A. Joosten, Timothy R. Radstake, Philip L. Riches, Anne-Kathrin Tausche, Frederic Lioté, Alexander So, Tony R. Merriman

Published in: Arthritis Research & Therapy | Issue 1/2015

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Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusion

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.
Appendix
Available only for authorised users
Footnotes
1
Note that the Meng et al paper [20] reported positive association with single nucleotide polymorphism (SNP) rs7512998, however the P value for this SNP had been incorrectly calculated - the true P value for rs7512998 was 0.43 - as reported in a corrigendum [61].
 
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Metadata
Title
Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout
Authors
Cushla McKinney
Lisa K. Stamp
Nicola Dalbeth
Ruth K. Topless
Richard O. Day
Diluk RW Kannangara
Kenneth M. Williams
Matthijs Janssen
Timothy L. Jansen
Leo A. Joosten
Timothy R. Radstake
Philip L. Riches
Anne-Kathrin Tausche
Frederic Lioté
Alexander So
Tony R. Merriman
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2015
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-015-0802-3

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