Genetic analysis of autoimmune regulator haplotypes in alopecia areata

Abstract

Alopecia areata is an immune-mediated disorder, occurring with the highest observed frequency in the rare recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome caused by mutations of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. We have previously detected association between alopecia areata and a single nucleotide polymorphism (SNP) in the AIRE gene in patients without APECED, and we now report the findings of an extended examination of the association of alopecia areata with haplotype analysis including six SNPs in the AIRE gene: C-103T, C4144G, T5238C, G6528A, T7215C and T11787C. In Caucasian groups of 295 patients and 363 controls, we found strong association between the AIRE 7215C allele and AA [P = 3.8 x 10(-8), OR (95% CI): 2.69 (1.8-4.0)]. The previously reported association between AA and the AIRE 4144G allele was no longer significant on correction for multiple testing. The AIRE haplotypes CCTGCT and CGTGCC showed a highly significant association with AA [P = 6.05 x 10(-6), 9.47 (2.91-30.8) and P = 0.001, 3.51 (1.55-7.95), respectively]. To select the haplotypes most informative for analysis, we tagged the polymorphisms using SNPTag software. Employing AIRE C-103T, G6528A, T7215C and T11787C as tag SNPs, two haplotypes were associated with AA; AIRE CGCT and AIRE CGCC [P = 3.84 x 10(-7), 11.40 (3.53-36.9) and P = 3.94 x 10(-4), 2.13 (1.39-3.24) respectively]. The AIRE risk haplotypes identified in this study potentially account for a major component of the genetic risk of developing alopecia areata.

Tumor necrosis factor alpha promoter‐308G/A polymorphism in Mexican patients with patchy alopecia areata

“…Previous research in the Mexican population has described the association between this polymorphism and pathologies such as rheumatic heart disease, 25 ulcerative colitis, 26 spondyloarthritis, 27 and systemic lupus erythematosus, 30 as well as genetic susceptibility to Chagas’ disease 31 and risk of restenosis after coronary stent placement 28 . Because the TNFα gene encodes one of the most powerful proinflammatory cytokines, which also acts as an autoimmune modulator, this gene constitutes an important candidate for determining genetic susceptibility to the development of AA, because it has been proposed that this disease has characteristics in common with autoimmune diseases 32 . The association of AA with other autoimmune/inflammatory diseases, the presence of lymphocytes T CD4 around the hair follicle, the presence of circulating autoantibodies against the components of the hair follicle and, importantly, the response to immunosuppressant and immunomodulator therapies add weight to this theory 6 …”

The role of AIRE polymorphisms in melanoma

“…In fact, it determines the amino acid change S278R in the SAND domain of the AIRE protein. This domain is responsible for AIRE binding to DNA [54] and for the nuclear localization of AIRE [55,56]. Therefore, mutations at this domain could destabilize the binding of AIRE to TRAs promoter, thus lowering TRAs expression in thymic epithelial cells.…”

An update on alopecia areata

“…Several groups have investigated the association of the AIRE gene with alopecia areata in patients without APECED, some finding an association, others not. Most recently, Wengraf et al [10 ] systematically screened AIRE for single nucleotide polymorphisms (SNPs), constructed haplotypes with these SNPs, and established several haplotypes with strong association with alopecia areata.…”