RESUMEN
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.
RESUMEN
Shared susceptibility alleles in the HLA region contribute to the co-existence of type 1 diabetes (T1D) and celiac disease (CD). The aim of our study was to identify HLA genotype variations that influence co-occurrence of T1D and CD (T1D + CD) and the order of their onset. Totally 244 patients, 67 with T1D, 68 with CD and 69 with T1D + CD, (split into "T1D first" and "CD first"), were analyzed. Control group consisted of 130 healthy unrelated individuals. Two-tailed Fisher's exact test was used for statistical analysis. The genetic background of Slovenian CD patients resembled more northern than southern European populations with DR3-DQ2/DR3-DQ2 (odds ratio [OR] = 19.68) conferring the highest risk. The T1D + CD was associated with DR3-DQ2/DR3-DQ2 (OR = 45.53) and even more with DR3-DQ2/DR4-DQ8 (OR = 93.76). DR3-DQ2/DR7-DQ2 played a neutral role in susceptibility for T1D + CD. The order of the onset of T1D or CD in patients with co-occurring diseases was not influenced by HLA risk genotype profile. DR3-DQ2/DR3-DQ2 was associated with an increased risk for developing CD in patients with T1D, whereas patients with CD carrying DR3-DQ2/DR4-DQ8 were at higher risk for developing T1D. In addition to other genetic factors including HLA class I alleles present on DR3-DQ2 extended haplotype, the second extended haplotype may moderate the risk for T1D + CD conferred by DR3-DQ2. Our results suggested that individuals carrying high-risk genotypes DR3-DQ2/DR3-DQ2 or DR3-DQ2/DR4-DQ8 would more likely develop both T1D and CD than either disease alone.
