Villani, A.C. et al. Common variants in the NLRP3 region contribute to Crohn’s disease susceptibility. Nat. Genet. 41, 71-76

Division of Gastroenterology, McGill University Health Centre, Montreal General Hospital, Montréal, Québec, Canada.
Nature Genetics (Impact Factor: 29.35). 01/2009; 41(1):71-6. DOI: 10.1038/ng.285
Source: PubMed


We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (P(combined) = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1beta production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.

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    • "Multiple variants of pattern-recognition receptor (PRR) genes that sense pathogen-associated molecular patterns (PAMPs) have been associated with IBD (Kaser et al., 2010; Shih and Targan, 2008), including NOD2 (Nucleotide-binding oligomerization domain containing 2), TLR4 (Toll-like receptor 4) and NLRP3 (NOD-like receptor family, pyrin domain containing 3) (Peeters et al., 2007; Shen et al., 2010; Villani et al., 2009). Several genetic variants in the noncoding region of NLRP3 and decreased expression of the receptor have been associated with increased susceptibility to CD (Villani et al., 2009). NLRP3 is one of the sensors capable to induce the formation of the multi-protein complex inflammasome, which activates caspase-1 through adaptor protein ASC (apoptosis-associated speck-like protein containing a carboxy-terminal CARD) (Franchi et al., 2012), promoting IL-1␤ and IL-18 processing and secretion. "
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    ABSTRACT: Crohn's disease (CD) is a multifactorial pathology associated with the presence of adherent-invasive Escherichia coli (AIEC) and NLRP3 polymorphic variants. The presence of intracellular E. coli in other intestinal pathologies (OIP) and the role of NLRP3-inflammasome in the immune response activated by these bacteria have not been investigated. In this study, we sought to characterize intracellular strains isolated from patients with CD, ulcerative colitis (UC) and OIP, and analyze NLRP3-inflammasome role in the immune response and bactericidal activity induced in macrophages exposed to invasive bacteria. For this, intracellular E. coli isolation from ileal biopsies, using gentamicin-protection assay, revealed a prevalence and CFU/biopsy of E. coli higher in biopsies from CD, UC and OIP patients than in controls. To characterization of bacterial isolates, pulsed-field gel electrophoresis (PFGE) patterns, virulence genes, serogroup and phylogenetic group were analyzed. We found out that bacteria isolated from a given patient were closely related and shared virulence factors; however, strains from different patients were genetically heterogeneous. AIEC characteristics in isolated strains, such as invasive and replicative properties, were assessed in epithelial cells and macrophages, respectively. Some strains from CD and UC demonstrated AIEC properties, but not strains from OIP. Furthermore, the role of NLRP3 in pro-inflammatory cytokines production and bacterial elimination was determined in macrophages. E. coli strains induced IL-1β through NLRP3-dependent mechanism; however, their elimination by macrophages was independent of NLRP3. Invasiveness of intracellular E. coli strains into the intestinal mucosa and IL-1β production may contribute to CD and UC pathogenesis.
    Full-text · Article · May 2014 · International journal of medical microbiology: IJMM
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    • "Indeed, co-housing NLRP3-deficient mice with wild-type mice, which equalized the intestinal microbiota, also equalized the inflammatory responses and disease in both mice (128). In humans, the role of NLRP3 in Crohn’s is equally confusing; polymorphisms associated with NLRP3 were shown to contribute to susceptibility to Crohn’s disease (129, 130), but did not replicate in a separate study (131). More detailed investigation of the interactions between specific members of the microbiota and NLRs may provide deeper insights in the function of NLRs in controlling and shaping the microbiota in health and disease. "
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    ABSTRACT: Nucleotide oligomerization domain (Nod)-like Receptors (NLRs) are cytosolic sensors that mediate the activation of Caspase-1 and the subsequent processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18, as well as an inflammatory cell death termed pyroptosis. While a multitude of bacteria have been shown to activate one or more NLRs under in vitro conditions, the exact impact of NLR activation during the course of colonization, both of pathogenic and commensal nature, is less understood. In this review, we will focus on the role of intestinal NLRs during the various stages of infection with common gastrointestinal bacterial pathogens, as well as NLR function in controlling and shaping the microbiota.
    Full-text · Article · Dec 2013 · Frontiers in Immunology
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    • "The human NLRP3 gene is located in 1q44. Since the discovery that polymorphisms in NLRP3 gene are linked to common immune inflammatory diseases, such as psoriasis (Carlstrom et al., 2012), rheumatoid arthritis (Kastbom et al., 2008), type 1 diabetes (Pontillo et al., 2010), Crohn's disease (Villani et al., 2009) and celiac disease (Pontillo et al., 2011), inflammasome signaling has been dissected at the molecular level. Indeed, the NLRP3 inflammasome has been implicated in several chronic inflammatory diseases as it can sense inflammatory crystals and aggregated proteins, including Aβ (Halle et al., 2008; Menu and Vince, 2011). "
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    ABSTRACT: The innate immunity and inflammatory response plays an important role in AD pathogenesis. Recently, a wealth of information linking the activation of NLRP3 inflammasome to Alzheimer's disease (AD) pathogenesis has emerged. Considering the pivotal role of NLRP3 in the inflammatory process and in AD, we hypothesized that variations in NLRP3 gene may also affect susceptibility to AD. Three selected functional single-nucleotide polymorphisms (SNPs) in NLRP3 gene (rs2027432, rs10754558, rs35829419) were genotyped in 1133 late-onset AD (LOAD) patients and 1159 healthy controls in a large Northern Han Chinese population. Among them, the 5'-flanking rs2027432 polymorphism seemed to be most associated with LOAD risk even after adjusting for age, gender, and ApoE ε4 status. For rs10754558, the genotype frequency differed significantly only in ApoE ε4 carriers. On the other hand, the minor A allele of rs35829419 (Q705K) polymorphism appeared to exert a protective effect against the development of LOAD. Our data support the notion that genetic variation in NLRP3 gene may contribute to LOAD risk in Northern Han Chinese.
    Full-text · Article · Oct 2013 · Journal of neuroimmunology
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