Association BetweenAIREPolymorphisms rs870881(C>T), rs1003854(T>C) and Rheumatoid Arthritis Risk: A Hungarian Case-control Study

Abstract

Background/Aim: Autoimmune regulator (AIRE) is a transcription factor that plays pivotal role in controlling autoimmunity. In the thymus, it supports the presentation of peripheral tissue antigens to developing T cells, where recognition of these self-antigens negatively selects the autoimmune naïve T-cells by central tolerance. Studies demonstrated that single-nucleotide polymorphisms (SNPs) in AIRE alter transcription and propagate clonal survival of autoimmune T cells, therefore increase susceptibility to autoimmune diseases. This study intended to identify SNPs in exon and intron sequences that determine AIRE transcription, where their genotypes are associated with rheumatoid arthritis (RA) risk and clinical parameters. Patients and Methods: After a thorough in silico research, we enrolled 100 patients with RA and 100 healthy controls to analyze the association of SNP rs870881(C>T) and rs1003854(T>C) in AIRE coding sequence with RA risk by using five different genetic models and selected clinical parameters. Multiplex quantitative polymerase chain reaction was used to determine allelic discrimination of SNPs. RA risk was assessed by odds ratios (ORs) and confidence intervals (CIs). Results: In a recessive model of rs878081, minor allele TT homozygotes were associated with RA (p=0.032, OR=5.44,; in a recessive model of rs1003854, minor allele CC homozygotes were associated with RA (p=0.047, OR=4.84,. Higher C-reactive protein (CRP) levels in patients with RA were significantly associated with minor allele homozygotes in recessive and codominant genetic models (p=0.029 and p=0.043, respectively) of rs1003854. Conclusion: Genotypes for minor alleles of rs878081 and rs1003854 might be involved in RA pathogenesis and risk prediction.

Genetic Polymorphisms in Exon 5 and Intron 5 and 7 of AIRE Are Associated with Rheumatoid Arthritis Risk in a Hungarian Population

“…Out of the 14 exons in AIRE , Exon 5 and Exon 6 encode the SAND structural domain in particular, which is responsible for binding AIRE and its partners to mTECs’ DNA and further governing the pGE of TRAs by protein–protein interactions with CBP [ 32 ]. Mutations in SAND-encoding Exon 5 and Exon 6 and the splice site between them of Intron 5 cause autoimmune APECED [ 49 , 50 , 51 , 52 ]. In light of the importance of the SAND region in negative selection and autoimmunity, our scope of interest included the analysis of SNPs in Exons 5–6.…”

“…Our total population includes 592 individuals, 270 patients with RA, and 322 healthy controls. Among these, 100-100 participants were preliminarily investigated in our pilot study for allelic polymorphisms rs878081 and rs1003854 to see their tendencies of MAFs and to test our genotyping workflow and chances of detectability [ 50 ]. From then on, we formed two groups as follows: Group 1 was the total population with 270 RA patients and 322 controls for the rs1003853, rs2075876, and rs1055311 loci; and Group 2 had 170 RA patients and 222 controls, which was the subpopulation of Group 1 for rs878081 and rs1003854 because the results for 100 RA patients and 100 controls of rs878081 and rs1003854 from the total population in Group 1 had already been published.…”