Influence of ancestry and genetic variability of the MITF transcription factor and its targets TYR, TYRP1 and DCT on the development of vitiligo in a Brazilian population sample

• Autor(a) principal: Marcorin, Letícia
• Data de Publicação: 2021
• Tipo de documento: Tese
• Idioma: eng
• Título da fonte: Biblioteca Digital de Teses e Dissertações da USP
• Texto Completo: https://www.teses.usp.br/teses/disponiveis/17/17135/tde-06122021-122111/
• topic: Ancestralidade genômica; Ancestralidade local; Dopachrome tautomerase; Dopacromo tautomerase; Genomic ancestry; Local ancestry; Melanocyte inducing transcription factor; Melanocyte inducing transcription factor; Proteína relacionada à tirosinase; Tirosinase; Tyrosinase; Tyrosinase related protein 1; Vitiligo; Vitiligo

Vitiligo is a multifactorial pigmentation disorder characterized by depigmented patches in the skin and mucosa. It affects up to 2% of the population worldwide and have different prevalence depending on geographical location. In Brazil, it affects about 0.57% of the population, with higher prevalence in individuals self-declared as non-European. Vitiligo is universally considered an autoimmune disease, but oxidative stress, genetic predisposition and environmental factors are also known to affect vitiligo onset and progression. Oxidative stress is an important factor in vitiligo development and there is evidence that it may induce the autoimmunity. Although there are other sources of oxidative stress, melanogenesis is particularly interesting, as melanin has antioxidative properties and reduces UV radiation induced damages, but its synthesis is a highly oxidative process itself. In this study, the association between hundreds of variation sites from four melanogenic genes, MITF, TYR, TYRP1 and DCT, and vitiligo predisposition was evaluated through logistic regression and gene-gene interactions. The correlation between global and local ancestry with the disease was also investigated. The results were corrected for multiple testing and some significant associations involving regulatory loci remained, such as: a) a SNP-SNP interaction involving independent MITF variants, rs200471673*A and rs7651218*G (p = 0.0220 for local ancestry adjustment), that lead to upregulation of the gene; b) TYR rs11824466*T (p = 0.0001 and p = 0.0006, for global and local ancestry adjustment, respectively), whose effect on gene expression regulation was not determined; c) a gene-gene interaction between TYRP1 rs71329877*ATAAG and DCT rs177919224*G and rs9590016*A (p = 0.0400 and p = 0.0110 for global and local ancestry adjustment, respectively), leading to TYRP1 upregulation and DCT downregulation. African and Native American ancestry were also linked with vitiligo development. These results could explain the different prevalence of the disease in different geographical locations, although further investigation is needed to evaluate the associated variants effect in the regulation of the studied genes by transcription factors and miRNAs. To our knowledge, this is the first study to identify genetic variants in genes MITF, TYRP1 and DCT associated with vitiligo, and the first study to evaluate ancestry contribution for the predisposition to the disease in an admixed population.