Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (The Swedish TIRA project)

Kastbom, Alf; Verma, Deepti; Eriksson, Per; Skogh, Thomas; Wingren, Gun; Söderkvist, Peter

doi:10.1093/rheumatology/kem372

Cited by 122 publications

(122 citation statements)

References 22 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…119 Moreover, in a Swedish cohort, RA susceptibility and severity are significantly influenced by the combination of the Q705K variant of NLRP3, already known for its low-penetrance in FCAS, and the C10X variant of caspase recruitment domain family, member 8. 120 Notably, these two polymorphisms are highly recurrent: Q705K polymorphism in NLRP3 was found in 6.5% of the Caucasian population and CARD-8 gene polymorphism C10X is present in 40%. 121,122 However, their penetrance in the pathogenesis of immune-immune mediated disorders is very low, and leads to susceptibility to autoimmunity only when in combination.…”

Section: Adaptive Immunity-mediated Diseasesmentioning

confidence: 99%

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

2011

View full text Add to dashboard Cite

Nucleotide-binding oligomerization domain (NOD)-containing protein-like receptors (NLRs) are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition. Some NLRs form the framework for cytosolic platforms called inflammasomes, which orchestrate the early inflammatory process via IL-1b activation. Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases. Moreover, the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis. In this review, we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders.

show abstract

Section: Adaptive Immunity-mediated Diseasesmentioning

confidence: 99%

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

2011

View full text Add to dashboard Cite

show abstract

“…Genetic variants in the genes encoding for proteins of the NLRP3 inflammasome have been studied in association with various inflammatory diseases (6)(7)(8)(9)(10)(11). Germline alterations in the NLRP3 gene encoding the NLRP3 protein have been associated with susceptibility to different inflammatory disorders such as hereditary periodic fever syndromes including familial cold urticaria, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and arthropathy syndrome) (4,(11)(12)(13) leading to the constitutive activation of NLRP3 and subsequent overproduction of IL-1β (3).…”

Section: Introductionmentioning

confidence: 99%

“…Germline alterations in the NLRP3 gene encoding the NLRP3 protein have been associated with susceptibility to different inflammatory disorders such as hereditary periodic fever syndromes including familial cold urticaria, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and arthropathy syndrome) (4,(11)(12)(13) leading to the constitutive activation of NLRP3 and subsequent overproduction of IL-1β (3). Several recent studies have also revealed the association of the Q705K polymorphism in the NLRP3 gene (rs35829419) with various inflammatory diseases including celiac disease (9), diabetes type-1 (8), abdominal aortic aneurysms (14), Crohn's disease (15) and rheumatoid arthritis (10 CARD8 (C10X) genes was found to be associated with rheumatoid arthritis (10) and Crohn's disease (15,16). Considering a possible key role of the NLRP3 inflammasome in promoting myocardial inflammation (17) and athero sclerosis through the production of pro-inflammatory cytokine IL-1β (18), the aim of the present study was to investigate the effect of Q705K polymorphism in NLRP3 gene and the risk of developing MI in a northern Swedish population.…”

Section: Introductionmentioning

confidence: 99%

Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals

et al. 2013

View full text Add to dashboard Cite

Abstract. Inflammation is a multifaceted process that underlies the pathophysiology of acute myocardial infarction (MI). Variations in the inflammasome-related NLRP3 gene have been associated with risk for a number of different inflammatory diseases. Therefore, Q705K polymorphism in NLRP3 gene likely confers susceptibility to risk for MI. A First-ever myocardial Infarction study in Ac-county (FIA) cohort comprising 555 MI patients and 1,016 controls was used to genotype rs35829419 in the NLRP3 gene by TaqMan single-nucleotide polymorphism assay. C-reactive protein (CRP) was measured in the study participants by ELISA. The results showed no significant association between the variant rs35829419 and MI. However, the minor A allele of the rs35829419 polymorphism conferred a protective effect against the risk of developing MI in females. The minor A allele of rs35829419 polymorphism was also associated with increased CRP levels in males. Results of the study suggested a gender-specific deregulation of NLRP3 gene mediated by rs35829419 polymorphism that confers protection against MI in females but has no effect on MI susceptibility in males. However, the rs35829419 polymorphism was associated with increased CRP levels among the male subjects, thereby demonstrating the possible effect of the Q705K polymorphism in elevating the basal active state of innate immune response. IntroductionCoronary artery disease, including myocardial infarction (MI), is known to be a leading cause of mortality worldwide. The individual's genetic constitution as well as environmental factors are crucial in the pathological progression of the disease (1). Among the known etiological factors, inflammation is a major contributor for the progression of atherosclerosis and the subsequent rupture of the unstable plaque, resulting in MI (2). Defense mechanisms against inflammation serve as a defense tool of innate immune response against both exogenous pathogens and endogenous sterile injury. However, the uncontrolled inflammatory response often suppresses the repair mechanism, thereby leading to the clinical manifestation of the inflammatory disease characterized by elevated levels of inflammatory markers, such as interleukin (IL)-1β, IL-18, interferon γ, tumor necrosis factor-α and C-reactive protein (CRP). The recent finding regarding the NLRP3-induced production of the proinflammatory cytokine IL-1β in individuals with a mutation in the NLRP3 gene has placed much focus on the NLRP3 inflammasome (3,4). The NLRP3 inflammasome, an intracellular macromolecular complex, which consists of the NLRP3 scaffold, the adaptor protein apoptosis speck-like protein contaning CARD and caspase-1, processes the immature proinflammatory cytokine IL-1β to its active form and renders the recognition of pathogen and danger-derived molecules in the cytosol (5).Genetic variants in the genes encoding for proteins of the NLRP3 inflammasome have been studied in association with various inflammatory diseases (6-11). Germline alterations in the NLRP3 gene encoding the NLR...

show abstract

“…5,27,28 Subsequent reports found that patients homozygous for the C10X polymorphism still expressed an immunoreactive isoform of CARD8, although at a reduced level. 29 Recently, variants in another component of the NALP3 inflammasome, NALP3 and/or NOD2, and a combination of NALP3 (Q705K) and CARD8 (C10X) genotypes, were found to be associated with disease severity of rheumatoid arthritis 30,31 and CD in the absence of NOD2 mutations. 32,33 Analysis of CARD8, NALP3 and NOD2 in the Korean UC and CD patients of this study found no evidence of NALP3 or NOD2 association with either disease.…”

Section: Introductionmentioning

confidence: 99%

Association of CARD8 with inflammatory bowel disease in Koreans

et al. 2011

View full text Add to dashboard Cite

Caspase recruitment domain (CARD)-containing protein 8 (CARD8) is a potential candidate risk gene for inflammatory bowel disease (IBD) because of its role as a component of the NALP3 inflammasome and as an inhibitor of nuclear factor-kappa B. Previous studies examining the association of a CARD8 single-nucleotide polymorphism (SNP) (rs2043211, p.Cys10X) with IBD yielded mixed results in Caucasians that may result from interaction with NALP3 or NOD2 (nucleotide-binding oligomerization domain 2) variants. To understand the genetic association between CARD8/NALP3 and IBD in Koreans, we investigated seven CARD8, four NALP3 and four NOD2 SNPs in 650 Crohn's disease (CD), 660 ulcerative colitis (UC) patients and 688 controls from the Korean population. rs2043211 of CARD8 showed significant association with UC (P¼0.011; odds ratio¼1.50, 95% confidence intervals¼1.12-2.00, P¼0.006 under recessive model). In contrast, an SNP in intron 1, rs1972619, was associated with CD only (P¼0.033). None of the NALP3 or NOD2 SNPs was significantly associated with CD or UC in the Korean populations. The stop allele of rs2043211 was associated with higher serum interleukin-1b levels only in female patients with UC (P¼0.027). Our data suggest that CARD8 variants might have roles in the pathogenesis of CD and UC in Koreans.

show abstract

Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (The Swedish TIRA project)

Abstract: Compound polymorphisms in CIAS1 and TUCAN associate with RA susceptibility and severity. The cryopyrin inflammasome needs further attention regarding a possible aetiopathogenetic connection with RA.

Cited by 122 publications

References 22 publications

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals

Association of CARD8 with inflammatory bowel disease in Koreans

Contact Info

Product

Resources

About