title: Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry, University of Otago, Box 56, Dunedin, 9054, New Zealand. cushla.mckinney@otago.ac.nz.
authors.forename: Cushla
authors.initials: C
authors.lastname: McKinney
authors.affiliation: Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand. lisa.stamp@cdhb.govt.nz.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand. n.dalbeth@auckland.ac.nz.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dalbeth
authors.affiliation: Department of Biochemistry, University of Otago, Box 56, Dunedin, 9054, New Zealand. ruth.topless@otago.ac.nz.
authors.forename: Ruth K
authors.initials: RK
authors.lastname: Topless
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, Australia. r.day@unsw.edu.au.|Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia. r.day@unsw.edu.au.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Day
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, Australia. r.kannangara@unsw.edu.au.|Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia. r.kannangara@unsw.edu.au.
authors.forename: Diluk Rw
authors.initials: DR
authors.lastname: Kannangara
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, Australia. ken.williams@unsw.edu.au.|Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia. ken.williams@unsw.edu.au.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Williams
authors.affiliation: Department of Rheumatology, Rijnstate Hospital, Arnhem, The Netherlands. matthijs.janssen@rijnstate.nl.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Janssen
authors.affiliation: Department of IQ HealthCare, VieCuri Medical Centre, Venlo, The Netherlands. tim.jansen@radboudumc.ml.|Scientific Institute of Quality in HealthCare, Radboud University Medical Centre, Nijmegen, The Netherlands. tim.jansen@radboudumc.ml.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Jansen
authors.affiliation: Department of Internal Medicine and Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands. l.joosten@aig.umcn.nl.
authors.forename: Leo A
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: 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.|Department of Immunology, University Medical Centre Utrecht, PO Box 85500, 3508, GA, Utrecht, The Netherlands. tradstake73@googlemail.com.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Radstake
authors.affiliation: Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. priches@staffmail.ed.ac.uk.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Riches
authors.affiliation: Department of Rheumatology, University Clinic Carl-Gustav-Carus", Dresden, Germany. anne-kathrin.tausche@uniklinikum-dresden.de.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Tausche
authors.affiliation: INSERM, UMR-S 1132, Hospital Lariboisière, F-75010, Paris, France. frederic.liote@lrb.aphp.fr.|University Paris Diderot (UFR de Médecine), Sorbonne Paris Cité, F-75205, Paris, France. frederic.liote@lrb.aphp.fr.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lioté
authors.affiliation: DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé 05-5029, 1011, Lausanne, Switzerland. alexanderkai-lik.so@chuv.ch.
authors.forename: Alexander
authors.initials: A
authors.lastname: So
authors.affiliation: Department of Biochemistry, University of Otago, Box 56, Dunedin, 9054, New Zealand. tony.merriman@otago.ac.nz.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002648:Child; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006073:Gout / Q000235:genetics* / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D053583:Interleukin-1beta / Q000235:genetics*; D018950:Lipopolysaccharide Receptors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009520:New Zealand; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011114:Polynesia; D055815:Young Adult
chemical_list: D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; D009363:Neoplasm Proteins