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 116 publications

(117 citation statements)

References 22 publications

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“…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%

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

et al. 2013

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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...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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“…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

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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.

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“…CARD8 was originally described as a member of the NLRP3 inflammasome (114) but this has not been confirmed in subsequent studies. However, the link between CARD8 and NLRP3 is supported by the fact that polymorphisms in CARD8 together with NLRP3 polymorphisms have been implicated in several diseases including Crohn's disease, psoriasis and rheumatoid arthritis (284,(302)(303)(304). Lastly, there are also regulatory proteins that can promote inflammasome assembly or are required for NLRP3 activation.…”

Section: Regulation Of the Inflammasome And Il-1β Productionmentioning

confidence: 99%

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

Eklund¹

2013

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Mycobacterium tuberculosis is a very successful pathogen and tuberculosis constitutes a major threat to global health worldwide. The World Health Organization (WHO) estimates that almost nine million new cases and 1.5 million deaths occur annually and the situation is worsened by increased antibiotic resistance and an extreme synergism with the HIV pandemic. M. tuberculosis primarily affects the lungs where the infection can lead to either eradication of the bacteria or the initiation of an immune response that culminates in the formation of a large cluster of immune cells termed granulomas. In these granulomas, the bacteria can either replicate and cause disease with the ultimate goal of spreading to new hosts or cause latent tuberculosis, which can persist for decades. The tools available to manage the disease are currently suboptimal and include lengthy antibiotic treatments and an inefficient vaccine resulting in poor protection. On a cellular level, M. tuberculosis primarily infects the cell designed to recognize, ingest and eradicate bacteria, namely the human macrophage. Following recognition, the macrophage phagocytoses the bacterium and tries to kill it using an array of different effector mechanisms including acidification of the bacterium-containing vacuole, different degradative enzymes and the generation of radicals. However, the bacterium is able to circumvent many of these harmful effects, leading to a tug-of-war between the bacterium and host macrophage. This thesis aims at studying the interaction between the human macrophage and M. tuberculosis to identify host factors critical for controlling growth of the bacteria. More specifically, it focuses on the role of an intracellular receptor protein called NLRP3 and its downstream effects. NLRP3 is activated in human macrophages infected by M. tuberculosis and upon activation it forms a multi-protein complex known as the inflammasome. This protein complex is known to induce the production of the proinflammatory cytokine IL-1β and specialized forms of macrophage cell death. We hypothesized that stimulating this pathway would have a beneficial effect for the host macrophage during infection with M. tuberculosis. To allow us to follow interaction between M. tuberculosis and the human macrophage, we first developed a luminometry-based method of measuring bacterial numbers and following bacterial growth over several days in infected cells. With this new assay we showed that low numbers of bacteria induced very low levels of IL-1β and failed to induce any type of cell death in the macrophage. However, when a critical number of bacteria were reached, the infected macrophages underwent necrosis, which was accompanied by high levels of IL-1β. We were also able to show that addition of vitamin D, which has been implicated as an important factor for increased killing capacity of infected macrophages, increased the production of IL-1β, which coincided with increased killing of M. tuberculosis. This effect was seen specifically in cells from patients with active...

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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 116 publications

References 22 publications

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

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

Association of CARD8 with inflammatory bowel disease in Koreans

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

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