ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 3166

Epistatic Interaction of Functional Inflammasome Genetic Variants in Determining the Risk of Gout

Tony R. Merriman1, Lisa K. Stamp2, Nicola Dalbeth3, Ruth Topless4, Richard Day5, Diluk Kannangara5, Kenneth Williams5, Matthijs Janssen6, Tim Jansen7, Leo A. Joosten8, Timothy Radstake9, Philip L. Riches10, Anne-Kathrin Tausche11, Frederic Lioté12, Alex So13,14 and Cushla McKinney4, 1Biochemistry Dept, PO Box 56, University of Otago, Dunedin, New Zealand, 2Medicine, University of Otago, Christchurch, Christchurch, New Zealand, 3Department of Medicine, University of Auckland, Auckland, New Zealand, 4University of Otago, Dunedin, New Zealand, 5University of New South Wales, Sydney, Australia, 6Rheumatology Dept, Ziekenhuis Rijnstate, Arnhem, Netherlands, 7P O Box 581, Haarlem, Netherlands, 8Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 9Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 10Centre for Genomic and Experimental Medicine, Western General Hospital, Edinburgh, United Kingdom, 11Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany, 12Rheumatology Department; Inserm UMR-S606; Paris-Diderot University, hôpital Lariboisiere, Paris, France, 13Service De Rhumatologie, CHUV, Lausanne, Switzerland, 14Department of Rheumatology, CHUV, Lausanne, Switzerland

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords:

Session Information

Date: Tuesday, November 10, 2015

Title: Metabolic and Crystal Arthropathies II: Mechanisms and Associations

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: 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 inflammasome and secretion of
IL-1b by immune cells plays a key role in triggering clinical
inflammation. Genome-wide association studies have yielded insights into
genetic control of the cause of hyperuricaemia. 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-IL1b  axis for association
with gout.

Methods:
1,494 cases of European ancestry and 863 cases of New Zealand (NZ)
Polynesian (Māori and Pacific Island)
ancestry. All people with gout fulfilled the 1977 ARA gout classification
criteria. There were 1,030 Polynesian controls and 10,942 European controls
from the publically-available Atherosclerosis Risk in Communities (ARIC) and
Framingham Heart (FHS) studies. The eleven SNPs were genotyped by Sequenom
MassArray in the gout cases and either genotyped 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 epistatic 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, risk allele T) IL1B
rs1143623 (OR=1.10, P=0.020, risk
allele G) and CD14 rs2569190 (OR=1.08; P=0.036,
risk allele A). There was significant
epistatic interaction between CARD8 and
IL1B (P=0.005) (Table), with the IL1B
risk genotype amplifying the risk effect of CARD8.

Conclusion: There is evidence for association of gout with functional immune
system variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL1-b  – the epistatic interaction with CARD8 would be consistent with a biological scenario of the amount
of pro-IL1-b limiting the amount
of mature IL1-b generated in stimulatory conditions.

Table Genotype combinations of IL1B rs1143623 and CARD8
rs2043211

Combination

Cases (n, %)

Controls (n,%)

OR [95% CI]

P

CC/AA

430 (0.174)

2,821 (0.236)

1.00

CC/AT

488 (0.197)

2,740 (0.229)

1.13 [0.96-1.32]

0.16

CC/TT

136 (0.055)

644 (0.054)

1.26 [0.99-1.62]

0.066

CG/AA

390 (0.157)

2,182 (0.182)

1.10 [0.92-1.31]

0.28

CG/AT

495 (0.200)

1,979 (0.165)

1.48 [1.25-1.75]

4.3×10-6

CG/TT

162 (0.065)

575 (0.048)

1.74 [1.36-2.22]

8.7×10-6

GG/AA

112 (0.045)

425 (0.036)

1.33 [1.00-1.77]

0.049

GG/AT

166 (0.067)

465 (0.039)

1.61 [1.25-2.07]

2.0×10-4

GG/TT

100 (0.040)

147 (0.012)

3.77 [2.65-5.34]

<1.0×10-6

Disclosure: T. R. Merriman, None; L. K. Stamp, None; N. Dalbeth, None; R. Topless, None; R. Day, None; D. Kannangara, None; K. Williams, None; M. Janssen, None; T. Jansen, None; L. A. Joosten, None; T. Radstake, None; P. L. Riches, Menarini, 2; A. K. Tausche, None; F. Lioté, None; A. So, None; C. McKinney, None.

To cite this abstract in AMA style:

Merriman TR, Stamp LK, Dalbeth N, Topless R, Day R, Kannangara D, Williams K, Janssen M, Jansen T, Joosten LA, Radstake T, Riches PL, Tausche AK, Lioté F, So A, McKinney C. Epistatic Interaction of Functional Inflammasome Genetic Variants in Determining the Risk of Gout [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/epistatic-interaction-of-functional-inflammasome-genetic-variants-in-determining-the-risk-of-gout/. Accessed .

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