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

## TL;DR

This study finds that genetic variations in the AIRE gene are linked to rheumatoid arthritis risk in a Hungarian population, suggesting early immune system development plays a role.

## Contribution

The study identifies novel associations between AIRE gene polymorphisms and rheumatoid arthritis in a European population.

## Key findings

- Polymorphisms in rs878081, rs1003854, and rs1003853 were significantly associated with rheumatoid arthritis risk.
- Genotypic subgroups of rs878081 and rs1055311 correlated with disease activity in RA patients.
- In silico analysis suggests altered transcription factor binding may influence RA development.

## Abstract

It is a fundamental question: what is the earliest commencement of autoimmune diseases? In recent years, one process deemed to be essential is central self-tolerance during the neonatal period, when the immune system selects and destroys autoimmune T-cells. This mechanism is genetically governed by the master gene AIRE. Genetic variations in this gene may cause a less efficient clearance of autoimmune T-cells, causing severe autoimmune diseases decades later. According to numerous research studies and our preliminary results, genetic polymorphisms in this master gene may be at the root of several autoimmune diseases. Although the interaction of genes and disease has been well studied in Asian populations, results are scarce in European populations. Our study is intended to analyse the association between genetic variations in this master gene and rheumatoid arthritis in subjects of Hungarian origin. We successfully identified an association between polymorphisms and the disease, reinforcing the notion that immunologic events during the neonatal period may contribute to autoimmune diseases. A further strength of our research is that in the future, because of its neonatal involvement, AIRE can be used as a risk biomarker in cases in which other regular markers cannot predict the disease risk.

Background: Rheumatoid arthritis (RA) is chronically persistent synovitis and systemic inflammation. Although multiple contributors are detected, only one is pivotal in the neonatal period: the negative selection of autoimmune naïve T-cells by the autoimmune regulator (AIRE) transcriptional factor. Methods: Single-nucleotide polymorphisms (SNPs) in the DNA-binding site of AIRE may determine its function and expression. We intended to analyse site-specific allelic polymorphisms in two exon (rs878081 and rs1055311) and three intron (rs1003853, rs2075876, and rs1003854) loci with an RA risk. Our analytical case-control study analysed 270 RA patients and 322 control subjects in five different genetic models using quantitative real-time PCR (qPCR) with TaqMan® assays. Results: Statistically significant differences were found between the odds of allelic polymorphisms in the loci of rs878081, rs1003854, and rs1003853 among the controls and RA patients, and the disease activity seemed to be significantly associated with the genotypic subgroups of rs878081 and rs1055311. Our in silico analysis supported this, suggesting that allele-specific alterations in the binding affinity of transcriptional factor families might determine RA activity. Conclusion: Our findings highlight the involvement of neonatal self-tolerance in RA pathogenesis, providing novel insights into disease development and paving the way for an analysis of further site-specific genetic polymorphisms in AIRE to expand the intervention time for RA.