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Arthritis Res Ther. 2015 Oct 13;17:288. doi: 10.1186/s13075-015-0802-3.

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

Author information

1
Department of Biochemistry, University of Otago, Box 56, Dunedin, 9054, New Zealand. cushla.mckinney@otago.ac.nz.
2
Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand. lisa.stamp@cdhb.govt.nz.
3
Department of Medicine, University of Auckland, Auckland, New Zealand. n.dalbeth@auckland.ac.nz.
4
Department of Biochemistry, University of Otago, Box 56, Dunedin, 9054, New Zealand. ruth.topless@otago.ac.nz.
5
School of Medical Sciences, University of New South Wales, Sydney, Australia. r.day@unsw.edu.au.
6
Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia. r.day@unsw.edu.au.
7
School of Medical Sciences, University of New South Wales, Sydney, Australia. r.kannangara@unsw.edu.au.
8
Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia. r.kannangara@unsw.edu.au.
9
School of Medical Sciences, University of New South Wales, Sydney, Australia. ken.williams@unsw.edu.au.
10
Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia. ken.williams@unsw.edu.au.
11
Department of Rheumatology, Rijnstate Hospital, Arnhem, The Netherlands. matthijs.janssen@rijnstate.nl.
12
Department of IQ HealthCare, VieCuri Medical Centre, Venlo, The Netherlands. tim.jansen@radboudumc.ml.
13
Scientific Institute of Quality in HealthCare, Radboud University Medical Centre, Nijmegen, The Netherlands. tim.jansen@radboudumc.ml.
14
Department of Internal Medicine and Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands. l.joosten@aig.umcn.nl.
15
Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, University Medical Centre Utrecht, PO Box 85500, 3508, GA, Utrecht, The Netherlands. tradstake73@googlemail.com.
16
Department of Immunology, University Medical Centre Utrecht, PO Box 85500, 3508, GA, Utrecht, The Netherlands. tradstake73@googlemail.com.
17
Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. priches@staffmail.ed.ac.uk.
18
Department of Rheumatology, University Clinic Carl-Gustav-Carus", Dresden, Germany. anne-kathrin.tausche@uniklinikum-dresden.de.
19
INSERM, UMR-S 1132, Hospital Lariboisière, F-75010, Paris, France. frederic.liote@lrb.aphp.fr.
20
University Paris Diderot (UFR de Médecine), Sorbonne Paris Cité, F-75205, Paris, France. frederic.liote@lrb.aphp.fr.
21
DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé 05-5029, 1011, Lausanne, Switzerland. alexanderkai-lik.so@chuv.ch.
22
Department of Biochemistry, University of Otago, Box 56, Dunedin, 9054, New Zealand. tony.merriman@otago.ac.nz.

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.

PMID:
26462562
PMCID:
PMC4604627
DOI:
10.1186/s13075-015-0802-3
[Indexed for MEDLINE]
Free PMC Article

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