Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: relation to common inflammatory diseases?

Arthritis Rheum. 2008 Mar;58(3):888-94. doi: 10.1002/art.23286.


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.

Conclusion: 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antirheumatic Agents / therapeutic use
  • Arthritis / drug therapy
  • Arthritis / genetics*
  • Arthritis / metabolism*
  • CARD Signaling Adaptor Proteins / genetics
  • Carrier Proteins / genetics*
  • Case-Control Studies
  • Caspase 1 / metabolism
  • DNA Mutational Analysis
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Interleukin-1beta / metabolism*
  • Male
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neoplasm Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Sweden


  • Antirheumatic Agents
  • CARD Signaling Adaptor Proteins
  • CARD8 protein, human
  • Carrier Proteins
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Neoplasm Proteins
  • Receptors, Interleukin-1
  • Caspase 1