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 (Pcombined = 3.49 × 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-1β production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders1,2. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.

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

“…Interestingly, an association between Crohn's disease and NLRP3 polymorphisms leading to impaired IL-1b secretion has been proposed. [85][86][87] However, recent studies in a larger patient group failed to replicate this observation. 88 Further work is needed to clarify the possible association of inflammasome genetics to multifactorial diseases.…”

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

“…Indeed, polymorphisms in the gene encoding one of the inflammasome-activating PRRs, NLR nucleotide-binding domain, leucine-rich and Pyrin containing 3 (Nlrp3), are associated with an increased risk for IBD development in humans. 9-11 Later, studies using genetic mouse models proposed inflammasomes as major regulators of the intestinal microbiota. 12 , 13 Indeed, deletion of apoptosis-associated speck-like protein containing a CARD (ASC, encoded by Pycard ), an adaptor protein needed for activating the Nlrp3 and also other inflammasomes, resulted in intestinal dysbiosis when compared to non-littermate separately housed C57BL/6 mice.…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…Human caspase-1 induced mature IL-1b production (Chae et al 2006), and the caspase-1 inflammasome contributes to inflammatory disorders such as familial Mediterranean fever (Chae et al 2006), Crohn's disease (Villani et al 2009) and Muckle-Wells autoinflammatory disorder (Agostini et al 2004). …”