title: Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: relation to common inflammatory diseases?
abstract: OBJECTIVE
  NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1-mediated interleukin-1beta (IL-1beta) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic-resistant fever carried mutations in the genes encoding the NALP3 inflammasome.
  
  
  METHODS
  Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD-8) was performed on genomic DNA from the patient and from a population-based collection of DNA (806 subjects). For in vitro studies of IL-1beta production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL-1 receptor antagonist, as well as from 5 healthy age- and sex-matched control subjects.
  
  
  RESULTS
  Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD-8 (C10X) genes. The allele frequencies of these single-nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL-1beta measured in samples from the patient returned to normal levels after treatment with anakinra.
  
  
  CONCLUSIONS
  Our results indicate that the patient's symptoms were due to elevated levels of IL-1beta, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL-1beta levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.
authors.affiliation: Linköping University, Linköping, Sweden.
authors.forename: Deepti
authors.initials: D
authors.lastname: Verma
authors.forename: Maria
authors.initials: M
authors.lastname: Lerm
authors.forename: Robert
authors.initials: R
authors.lastname: Blomgran Julinder
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.forename: Eva
authors.initials: E
authors.lastname: Särndahl
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D020170:Caspase 1 / Q000378:metabolism; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D013548:Sweden
chemical_list: D018501:Antirheumatic Agents; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D002352:Carrier Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009363:Neoplasm Proteins; D017472:Receptors, Interleukin-1; D020170:Caspase 1