Affecting ∼0.5%‒2% of the world population, and with a global prevalence of ∼0.06%–8.8%,1,2 vitiligo is an autoimmune disorder characterized by the selective Oss of melanocytes that results in skin depigmentation. The development of vitiligo has a strong genetic component and several gene polymorphisms have been associated with the autoimmune response and melanogenesis typically observed in this disease.2 During this process, the melanocytes, the melanin cells in the epidermis, are destroyed by T-cells, which constitute one of the key mediators in the autoimmune response creating areas of depigmentation.3 A member of the immunoglobulin superfamily, the cytotoxic T-Lymphocyte Antigen 4 (CTLA4) gene, found in locus 2q33,4 encodes a key inhibitory receptor whose function is that of a potent negative regulator of T-cell response during the priming phase of the immune response.5 Therefore, CTLA4 gene variants have been associated with several autoimmune diseases, such as autoimmune thyroid disease, Graves’ disease, Hashimoto’s thyroiditis, Type 1 diabetes,6 psoriasis,7 Behçet’s disease,8 and alopecia areata, although the latter remains controversial.9

Two CTLA4 genetic variants have been linked with the development of vitiligo, i.e., +49A/G (rs231775), an exon 1 missense variation leading to a threonine to alanine substitution at codon 17 (T17A); and CT60 A/G (rs3087243), located 236 bp downstream of the CTLA4 3′-UTR.10 However, these variants and their association with vitiligo vary widely and seem to be heavily dependent upon the analyzed population.10–12

Thus, this study explores whether the CTLA4 +49 A/G and CT60 A/G gene variants are associated with vitiligo in a Mexican population.

Vitiligo is a complex skin disorder in which the melanocytes are progressively and selectively destroyed.14 Multiple internal and external factors have been associated with the development of vitiligo, including autoimmune alterations, genetic factors, epidermal trauma, emotional stress, infections, among other risk factors that could act independently of each other or in combination.2,15 In addition, it is thought that vitiligo may have a non-Mendelian hereditary pattern, incomplete penetrance, multiple susceptibility loci, and genetic heterogeneity.16

Vitiligo has been associated with multiple gene variants, several of which are involved in immune response pathways, mainly in relation with the Human Leukocyte Antigen (HLA) class I and class II gene regions of the Major Histocompatibility Complex (MHC) and non-MHC candidate genes.17 Regarding the latter, the CTLA4 gene encodes a T-cell co-receptor expressed by both CD4+ and CD8+ T-cells, which is involved in T-cell activation; further, this co-receptor is a critical negative regulator of T-cell response, thus playing an essential protection role against autoimmunity.18 The autoimmune response mediated by CD8+ T-cells is key during the depigmentation process of vitiligo, as these cells are directly responsible for the destruction of the melanocytes, creating the typically observed areas of skin depigmentation.3

The association between the CTLA4 +49 G/A and CT60 gene variants and the development of different autoimmune diseases have been previously suggested. 19,20 However, the results have been inconsistent in dermatological diseases; for instance, in cases of psoriasis, their participation or lack of influence has been reported.21 A similar condition has been observed in Alopecia Areata (AA), where a previous association study proposed the involvement of CTLA4 polymorphisms as a risk factor in its development in a European population;22 however, another study revealed that these polymorphisms were irrelevant for the development of AA in a Mexican population.9

In Latin America, CTLA4 genetic variants have only been correlated with the development of obesity in northeastern Brazil,23 type 1 diabetes mellitus in Chile,24 FVIII inhibitor development in hemophilia A (HA) patients from Argentina,25 diffuse cutaneous leishmaniasis in Venezuela, 26 and hepatitis C virus27 and rheumatoid arthritis in Mexico.28

Although the participation, or lack of influence, of both gene polymorphisms has been reported for vitiligo, a meta-analysis study including 1252 cases in four European, three Asian, and two Turkish populations, revealed that the CTLA4 CT60 A/G gene variants confers susceptibility to vitiligo only in the European population.10

In previous studies, we observed the role of TNFα 29 and PTPN22 https://www.sciencedirect.com/science/article/pii/S0365059620300921 - bib0195 30 genetic variants as risk factors in the development of active forms of vitiligo in a Mexican population. Both genes are related to the regulation of immune mechanisms. However, the influence of CTLA4 gene variants in the development of vitiligo has not been analyzed in Mexican patients. Perhaps unsurprisingly, this study has shown no association of either rs231775 or rs3087243 polymorphisms with vitiligo, suggesting that these gene variants do not constitute a major risk factor in this regard within a northeastern Mexican population.

In conclusion, the CTLA4 gene variants rs231775 and rs3087243 do not constitute a risk factor in the development of vitiligo in the analyzed northeastern Mexican population. Further, these genetic variants do not correlate with the personal history of autoimmune diseases, family history of vitiligo, or the sex of the included subjects.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Mauricio Salinas-Santander: Study conception, design, and planning; collection, analysis, and data interpretation; writing; critical literature review and critical review of the manuscript; approval of the final version of the manuscript.

Víctor Suárez-Valencia: Analysis, and data interpretation; writing; critical literature review and critical review of the manuscript; approval of the final version of the manuscript.

Mayela del Ángel-Martínez: Data interpretation; writing; critical literature review and critical review of the manuscript; approval of the final version of the manuscript.

David Kubelis-Lopez: Data interpretation; critical review of the manuscript; approval of the final version of the manuscript.

Natalia Zapata-Salazar: Data interpretation; critical review of the manuscript; approval of the final version of the manuscript.

Jorge Ocampo-Garza: Critical review of the manuscript; approval of the final version of the manuscript.

Jorge Ocampo-Candiani: Critical review of the manuscript; approval of the final version of the manuscript.

None declared.