title: Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment.
abstract: BACKGROUND
  The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA).
  
  
  METHODS
  Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses.
  
  
  RESULTS
  At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells.
  
  
  CONCLUSIONS
  This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, Chapel Allerton Hospital, UK.
authors.forename: Rebeccah J
authors.initials: RJ
authors.lastname: Mathews
authors.forename: James I
authors.initials: JI
authors.lastname: Robinson
authors.forename: Michele
authors.initials: M
authors.lastname: Battellino
authors.forename: Chi
authors.initials: C
authors.lastname: Wong
authors.forename: John C
authors.initials: JC
authors.lastname: Taylor
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Churchman
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Kimme
authors.initials: K
authors.lastname: Hyrich
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.forename: Sinisa
authors.initials: S
authors.lastname: Savic
authors.forename: Graham P
authors.initials: GP
authors.lastname: Cook
authors.forename: Piercarlo
authors.initials: P
authors.lastname: Sarzi-Puttini
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Michael F
authors.initials: MF
authors.lastname: McDermott
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D020170:Caspase 1 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000071198:Pyrin; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D018501:Antirheumatic Agents; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C000604192:MEFV protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009363:Neoplasm Proteins; C402202:PYCARD protein, human; D000071198:Pyrin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1
keywords: Anti-TNF; Inflammation; Rheumatoid Arthritis; Treatment