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Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout.
McKinney, Cushla; Stamp, Lisa K; Dalbeth, Nicola; Topless, Ruth K; Day, Richard O; Kannangara, Diluk Rw; Williams, Kenneth M; Janssen, Matthijs; Jansen, Timothy L; Joosten, Leo A; Radstake, Timothy R; Riches, Philip L; Tausche, Anne-Kathrin; Lioté, Frederic; So, Alexander; Merriman, Tony R.
Afiliação
  • McKinney C; Department of Biochemistry, University of Otago, Box 56, Dunedin, 9054, New Zealand. cushla.mckinney@otago.ac.nz.
  • Stamp LK; Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand. lisa.stamp@cdhb.govt.nz.
  • Dalbeth N; Department of Medicine, University of Auckland, Auckland, New Zealand. n.dalbeth@auckland.ac.nz.
  • Topless RK; Department of Biochemistry, University of Otago, Box 56, Dunedin, 9054, New Zealand. ruth.topless@otago.ac.nz.
  • Day RO; School of Medical Sciences, University of New South Wales, Sydney, Australia. r.day@unsw.edu.au.
  • Kannangara DR; Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia. r.day@unsw.edu.au.
  • Williams KM; School of Medical Sciences, University of New South Wales, Sydney, Australia. r.kannangara@unsw.edu.au.
  • Janssen M; Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia. r.kannangara@unsw.edu.au.
  • Jansen TL; School of Medical Sciences, University of New South Wales, Sydney, Australia. ken.williams@unsw.edu.au.
  • Joosten LA; Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia. ken.williams@unsw.edu.au.
  • Radstake TR; Department of Rheumatology, Rijnstate Hospital, Arnhem, The Netherlands. matthijs.janssen@rijnstate.nl.
  • Riches PL; Department of IQ HealthCare, VieCuri Medical Centre, Venlo, The Netherlands. tim.jansen@radboudumc.ml.
  • Tausche AK; Scientific Institute of Quality in HealthCare, Radboud University Medical Centre, Nijmegen, The Netherlands. tim.jansen@radboudumc.ml.
  • Lioté F; Department of Internal Medicine and Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands. l.joosten@aig.umcn.nl.
  • So A; 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.
  • Merriman TR; Department of Immunology, University Medical Centre Utrecht, PO Box 85500, 3508, GA, Utrecht, The Netherlands. tradstake73@googlemail.com.
Arthritis Res Ther ; 17: 288, 2015 Oct 13.
Article em En | MEDLINE | ID: mdl-26462562
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-1ß (IL-1ß) 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-1ß axis for association with gout.

METHODS:

1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Maori 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-1ß - 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-1ß expression leading to increased production of mature IL-1ß in gout.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de Lipopolissacarídeos / Interleucina-1beta / Proteínas Adaptadoras de Sinalização CARD / Inflamassomos / Gota / Proteínas de Neoplasias Tipo de estudo: Etiology_studies / Risk_factors_studies / Systematic_reviews Limite: Adolescent / Adult / Aged / Aged80 / Child / Female / Humans / Male / Middle aged País/Região como assunto: Europa / Oceania Idioma: En Revista: Arthritis Res Ther Assunto da revista: REUMATOLOGIA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Nova Zelândia

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de Lipopolissacarídeos / Interleucina-1beta / Proteínas Adaptadoras de Sinalização CARD / Inflamassomos / Gota / Proteínas de Neoplasias Tipo de estudo: Etiology_studies / Risk_factors_studies / Systematic_reviews Limite: Adolescent / Adult / Aged / Aged80 / Child / Female / Humans / Male / Middle aged País/Região como assunto: Europa / Oceania Idioma: En Revista: Arthritis Res Ther Assunto da revista: REUMATOLOGIA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Nova Zelândia