6 research outputs found
Association between AIRE gene polymorphism and rheumatoid arthritis: a systematic review and meta-analysis of case-control studies.
Autoimmune regulator (AIRE) is a transcription factor that functions as a novel player in immunological investigations. In the thymus, it has a pivotal role in the negative selection of naive T-cells during central tolerance. Experimental studies have shown that single nucleotide polymorphism (SNP) alters transcription of the AIRE gene. SNPs thereby provide a less efficient negative selection, propagate higher survival of autoimmune T-cells, and elevate susceptibility to autoimmune diseases. To date, only rheumatoid arthritis (RA) has been analysed by epidemiological investigations in relation to SNPs in AIRE. In our meta-analysis, we sought to encompass case-control studies and confirm that the association between SNP occurrence and RA. After robust searches of Embase, PubMed, Cochrane Library, and Web of Science databases, we found 19 articles that included five independent studies. Out of 11 polymorphisms, two (rs2075876, rs760426) were common in the five case-control studies. Thus, we performed a meta-analysis for rs2075876 (7145 cases and 8579 controls) and rs760426 (6696 cases and 8164 controls). Our results prove that rs2075876 and rs760426 are significantly associated with an increased risk of RA in allelic, dominant, recessive, codominant heterozygous, and codominant homozygous genetic models. These findings are primarily based on data from Asian populations
The AIRE-230Y Polymorphism Affects AIRE Transcriptional Activity: Potential Influence on AIRE Function in the Thymus
Background
The autoimmune regulator (AIRE) is expressed in the thymus, particularly in thymic medullary
epithelial cells (mTECs), and is required for the ectopic expression of a diverse range of
peripheral tissue antigens by mTECs, facilitating their ability to perform negative selection
of auto-reactive immature T-cells. The expression profile of peripheral tissue antigens is affected
not only by AIRE deficiency but also with variation of AIRE activity in the thymus.
Method and Results
Therefore we screened 591bp upstream of the AIRE transcription start site including AIRE
minimal promoter for single nucleotide polymorphism (SNPs) and identified two SNPs
-655R (rs117557896) and -230Y (rs751032) respectively. To study the effect of these variations
on AIRE promoter activity we generated a Flp-In host cell line which was stably transfected
with a single copy of the reporter vector. Relative promoter activity was estimated by
comparing the luciferase specific activity for lysates of the different reporter AIRE promoterreporter
gene constructs including AIRE-655G AIRE-230C, AIRE-655G AIRE-230T and
AIRE-655A AIRE-230C. The analysis showed that the commonest haplotype AIRE-655G
AIRE-230C has the highest luciferase specific activity (p<0.001). Whereas AIRE-655G
AIRE-230T has a luciferase specific activity value that approaches null. Both AIRE promoter
polymorphic sites have one allele that forms a CpG methylation site which we determined
can be methylated in methylation assays using the M.SssI CpG methyltransferase.
Conclusion
AIRE-230Y is in a conserved region of the promoter and is adjacent to a predicted WT1 transcription
factor binding site, suggesting that AIRE-230Y affects AIRE expression by influencing
the binding of biochemical factors to this region. Our findings show that AIRE655GAIRE-230T haplotype could dramatically alter AIRE transcription and so have an effect on the process of negative selection and affect susceptibility to autoimmune conditions