Dual Role of PTPN22 but Not NLRP3 Inflammasome Polymorphisms in Type 1 Diabetes and Celiac Disease in Children

Abstract

Genetic polymorphisms in genes coding for inflammasome components nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) and caspase recruitment domain-containing protein 8 (CARD8) have been associated with autoinflammatory and autoimmune diseases. On the other hand several studies suggested that NLRP3 inflammasome contributes to maintenance of gastrointestinal immune homeostasis and that activation of NLRP3 is regulated by protein tyrosine phosphatase non-receptor 22 (PTPN22). PTPN22 polymorphism was implicated in the risk for various autoimmune diseases including type 1 diabetes (T1D) but not for celiac disease (CD). The aim of our study was to evaluate the role of inflammasome related polymorphisms in subjects with either T1D or CD as well as in subjects affected by both diseases. We examined PTPN22 rs2476601 (p.Arg620Trp), NLRP3 rs35829419 (p.Gln705Lys), and CARD8 rs2043211 (p.Cys10Ter) in 66 subjects with coexisting T1D and CD, 65 subjects with T1D who did not develop CD, 67 subjects diagnosed only with CD and 127 healthy unrelated Slovenian individuals. All results were adjusted for clinical characteristic and human leukocyte antigen (HLA) risk. PTPN22 rs2476601 allele was significantly more frequent among subjects with T1D (Padj = 0.001) and less frequent in subjects with CD (Padj = 0.039) when compared to controls. In patients with coexisting T1D and CD this variant was significantly less frequent compared to T1D group (Padj = 0.010). Protective effect on CD development in individuals with T1D was observed only within the low risk HLA group. On the other hand, we found no association of NLRP3 rs35829419 and CARD8 rs2043211 with the development of T1D, CD or both diseases together. In conclusion PTPN22 rs2476601polymorphism was significantly associated with the risk of developing T1D in Slovenian population, while no associations of proinflammatory NLRP3 and CARD8 polymorphisms with T1D and CD were observed. Interestingly, the same PTPN22 variant protected from CD. We hypothesize that this effect may be mediated through the NLRP3 inflammasome activation.

Association of NLRP3 rs35829419 and rs10754558 Polymorphisms With Risks of Autoimmune Diseases: A Systematic Review and Meta-Analysis

“…This study focuses on the two most-studied polymorphic sites of NLRP3, including rs35829419, a gainof-function polymorphism associated with pro-inflammatory phenotype (Verma et al, 2012), and rs10754558, which is located in the 3 ′ -untranslated region (3 ′ -UTR) of the NLRP3 gene and has a certain impact on the stability of NLRP3 mRNA (Hitomi et al, 2009). Many studies have explored the association between NLRP3 rs35829419/rs10754558 polymorphisms and AIDs, including multiple sclerosis (MS) (Imani et al, 2018), rheumatoid arthritis (RA) (Kastbom et al, 2010;Ben et al, 2012;Jenko et al, 2016;Addobbati et al, 2018), psoriatic arthritis (PsA) (Juneblad et al, 2020), celiac disease (CD) (Pontillo et al, 2011), type 1 diabetes (T1D) (Pontillo et al, 2010;Smigoc et al, 2019), myasthenia gravis (MG) (Agah et al, 2021), and systemic lupus erythematosus (SLE) (Pontillo et al, 2012;Su et al, 2020). Some studies show that these NLRP3 polymorphism sites are related to the risk of certain AIDs, but other studies suggest that NLRP3 gene polymorphism at these sites exhibit a disease protection effect.…”

The regulation of self-tolerance and the role of inflammasome molecules

“…NLRP1 , NLRP3 , AIM2 ) and inflammasome-related proteins (i.e. PYCARD , CASP1 ) are linked with susceptibility to and/or response to therapy for MS, T1D, RA and SLE ( 75 , 78 , 98 , 119 , 120 , 153 , 297 – 303 ). However, whether the disease-linked SNPs override the normally tight regulation of gene expression and/or function of inflammasome molecules needs to be ascertained.…”

Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

“…Since T1D and coeliac disease share their main susceptibility alleles, HLA-DQ2 and HLA-DQ8, which contribute to the coexistence of both diseases, it is plausible that some other genes also have an influence. Research on the Slovenian population revealed a dual role of PTPN22 rs2476601 polymorphism in increased risk for T1D and protection against coeliac disease [74].…”