The Missense Variation Q705K in CIAS1 / NALP3 / NLRP3 Gene and an NLRP1 Haplotype Are Associated With Celiac Disease

Abstract

We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.

Inflammasomes

“…Mutations in NLRP3 have been linked to celiac disease (Pontillo et al 2010(Pontillo et al , 2011, and type 1 diabetes (Pontillo et al 2010). Furthermore, NLRP3-, and IL-1R-deficient mice show reduced disease in a mouse model of multiple sclerosis; this effect is likely a result of defective Th17 differentiation (Sutton et al 2006;Gris et al 2010).…”

“…The clearest connection between autoimmunity and the inflammasome is in the case of NLRP1. SNPs in NLRP1 have been linked to vitiligo and vitiligo-associated Addison's disease (Jin et al 2007), Type 1 diabetes (Magitta et al 2009), systemic lupus erythematosus (Pontillo et al 2012b), Kawasaki disease (Onoyama et al 2012), Addison's disease (Magitta et al 2009;Zurawek et al 2010), celiac disease (Pontillo et al 2011), rheumatoid arthritis (Sui et al 2012), systemic sclerosis (Dieude et al 2011), and autoimmune thyroid disease (Alkhateeb et al 2013). Despite these findings, confirmation of the role of NLRP1 in autoimmunity in mice has remained challenging because mice have three orthologs of NLRP1, whereas humans have only one.…”

Innate immunity functional gene polymorphisms and gout susceptibility

“…Ahmad-Nejad et al, 2004;Alvarez-Rodriguez et al, 2011;Brand et al, 2005;Britton et al, 2001;Coenen et al, 2010;Feldmann et al, 2002;Gazouli et al, 2005;Hoffman et al, 2001Hoffman et al, , 2003Neven et al, 2004;Pontillo et al, 2011;Schoultz et al, 2009;Shen et al, 2010;Snelgrove et al, 2007;Villani et al, 2009;Yang et al, 2011)…”

NLRP3 rs35829419 polymorphism is associated with increased susceptibility to multiple diseases in humans

“…Within the NLRP3 gene, approximately 60 single nucleotide polymorphisms (SNPs) have been identified, and the most prevalent polymorphisms among these are rs35829419 (Q705K), rs10754558, rs4612666, rs4925648, and rs10925019 (Schoultz et al, 2009), based on the SNP genotype data available from the US National Institute of Mental Health bipolar disorder (NIMH-BP) database dbGaP. In general, NLRP3 rs35829419 polymorphisms are associated with various inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and celiac disease (Pontillo et al, 2011;Pontillo et al, 2012a;Tan et al, 2013), and the NLRP3 polymorphism Q705K in particular is tightly linked to autoimmune disorders such as atopic dermatitis and systemic lupus erythematosus (Roberts et al, 2010;Tan et al, 2013) and to neuropathies such as late-onset Alzheimer's disease (Ben Hamad et al, 2012). It is well known that inflammatory diseases are characterized by excessive production of nuclear factor-κB (NF-κB)-dependent cytokines such as interleukin (IL)-1β, and that the NLRP3 gene polymorphism Q705K is a gain-of-function variant that leads to hyperactive inflammasomes.…”