Role of the Autoimmune Regulator (AIRE) gene in alopecia areata: Strong association of a potentially functional AIRE polymorphism with alopecia universalis

Abstract

Alopecia areata is characterized by a reversible form of patchy or complete hair loss associated with T-cell infiltration of hair follicles. The lifetime disease risk of approximately 1.4% in the general population is increased to more than 30% in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome (APECED), a recessive condition resulting from a mutation of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. Aire protein is thought to have transcriptional regulatory activity but its role is not well defined at present. In this study, we have examined the possible involvement of AIRE in the pathogenesis of alopecia areata. On screening the AIRE coding sequence, we identified 20 variants. Two of these at positions, G961C and T1029C, give rise to amino acid changes, S278R and V301A, located in the DNA-binding segment (SAND) and PHD1 zinc finger motif, respectively. We found no difference in the frequency of the AIRE T1029C polymorphism between the control and patient groups. We genotyped 202 alopecia areata patients and 175 matched Caucasian controls for the AIRE G961C alleles. The frequency of the rare allele (961G) was 0.08 in the controls and there was a significant increase to 0.13 in alopecia areata overall and 0.20 in severe disease (alopecia universalis). We found no association between the AIRE G961G variant and mild (patchy) alopecia areata or alopecia totalis. However, the AIRE 961G allele is a potent risk factor (> 3) for the severest form of alopecia areata, and for disease of early age at onset (at 30 years). The change from serine to arginine in the SAND domain of AIRE protein may have a significant effect on AIRE DNA-binding activity. Moreover, our results could provide a rational explanation of the unusually high frequency of AA in APECED patients, supporting the concept of AA as an autoimmune disease.

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

“…The Ser278Arg mutation was found to be associated with alopecia in a recent study on 202 patients and 175 controls. 31 The results should be verified in other ethnic cohorts. Three studies, examining the prevalence of the common 13 bp deletion in exon 8 of AIRE (known to cause APS I) failed to show an association in patients with Addison's disease, Graves' disease, type 1 diabetes and hypothyroidism.…”

“…The same SNP was also found in a few patients with alopecia, however in the same frequencies as in healthy controls. 31 The Val/Met variant changes an amino acid in the ubiquitin ligase region of the protein and may have functional consequences, perhaps in histone binding. 32,33 Furthermore, the number of patients with this polymorphism is low, which makes it unlikely that it impacts on the susceptibility to develop AAD.…”

The new immunological methods for diagnostics of type 1 autoimmune polyendocrine syndrome (the first experience in Russia)

“…Мы пришли к выводу, что мутации в гене AIRE и АПС 1 не являются частой причиной изолирован-ной алопеции. Также в некоторых зарубежных рабо-тах проводилось исследование гена AIRE у пациен-тов с изолированной очаговой алопецией и было выявлено несколько полиморфизмов в этом гене, которые чаще встречались у данной группы пациен-тов, но не было обнаружено мутаций [16,17].…”

“…), факторы окружаю-щей среды. Корреляций между тяжестью течения и конкретными полиморфизмами не установлено [15][16][17][18]. Очаговая алопеция может также развивать-ся при других аутоиммунных заболеваниях -рев-матоидном артрите, системной красной волчанке, аутоиммунных заболеваниях эндокринной систе-мы, в том числе при АПС 1, при котором частота алопеции достигает 30% [15,19].…”

The role of AIRE polymorphisms in melanoma

“…On this basis, we decided to analyze SNPs of AIRE gene in order to verify whether peculiar polymorphic genotypes could protect or predispose to the development of melanoma. Among all the AIRE SNPs already identified, five SNPs were selected following two main criteria consisting in their presence at elevated frequency in the European population (rs878081, rs1055311, rs1800520, rs1800525 and rs1800522) [34] and in the already demonstrated association with human autoimmune diseases (rs1800520 and rs1800525 linked to alopecia aerata and systemic sclerosis associated with autoimmune thyroiditis, respectively) [35,36]. Indeed, we reasoned that an AIRE polymorphic genotype potentially predisposing to an autoimmune disease could also be responsible for a lower level of TRAs transcription in the thymus, including that of tumor-specific antigens, subsequently resulting in a less effective negative selection of autoantigen (and tumor antigen)-specific T lymphocytes and to a potentially lower susceptibility to tumor development.…”