Common variants in the NLRP3 region contribute to Crohn's disease susceptibility.
ABSTRACT 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.
Full-textDOI: · Available from: Paul R Fortin, Jun 03, 2015
SourceAvailable from: Geena Paramel[Show abstract] [Hide abstract]
ABSTRACT: The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease.Mediators of Inflammation 02/2015; 2015:10. DOI:10.1155/2015/846782 · 2.42 Impact Factor
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ABSTRACT: Immature myeloid cells, also known as myeloid-derived suppressor cells (MDSCs), include neutrophilic and monocytic myeloid cells, and are found in inflammatory loci and secondary lymphoid organs in mice with intestinal inflammation, inflammatory bowel disease (IBD) patients, and tumor tissues. However, the roles of MDSCs in IBD are not yet well understood, and there are controversies regarding their immunosuppressive functions in IBD. In addition, recent studies have suggested that endoplasmic reticulum (ER) stress in intestinal epithelial cells, especially in Paneth cells, is closely associated with the induction of IBD. However, the ER stress in MDSCs accumulated in the inflamed tissues of IBD patients is not yet fully understood. In the current review, we discuss the presence of accumulated MDSCs in the intestines of IBD patients, and further speculate on their physiological roles in the inflammatory condition with interleukin 17-producing cells, including Th17 cells. In particular, we will discuss the divergent functions of MDSCs in ER stressed intestinal environments, including their pro-inflammatory or immunosuppressive roles, based on the consideration of unfolded protein responses initiated in intestinal epithelial cells by ER stress.04/2015; 13(2):105-11. DOI:10.5217/ir.2015.13.2.105
Vascular Pharmacology 05/2012; 56(5-6):377. DOI:10.1016/j.vph.2011.08.194 · 4.62 Impact Factor