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

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

doi:10.1186/s13075-015-0802-3

Abstract

IntroductionThe 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.Methods1,494 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.ResultsEleven 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.ConclusionThere 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0802-3) contains supplementary material, which is available to authorized users.

Highlights

The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals
Eleven single nucleotide polymorphism (SNP) were tested in the TLR2, CD14, IL1B, caspase recruitment domain-containing protein 8 (CARD8), nucleotidebinding oligomerisation domain (NOD)-like receptor pyrin-containing 3 (NLRP3), MYD88, P2RX7, DAPK1 and TNXIP genes
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)

Summary

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. The immediate cause of gout is the deposition of monosodium urate (MSU) crystals in and around body tissues, joints [1] These deposits trigger a localised and self-limiting inflammatory response (acute gouty arthritis), which becomes increasingly frequent and severe, involving multiple joints and associated with fever. The most significant biological cause of hyperuricaemia is relatively low renal clearance of uric acid [2, 3] This is consistent with findings from genome-wide association studies in which 28 loci associated with serum urate levels have been identified, some of which are in genes involved in renal uric acid handling [4, 5]. Most, but not all, of the 28 loci have been associated with gout [4, 6]

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