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Clinical Dermatology Open Access Journal Research Article 12 min read

Genetic Variants of Vitiligo

Gokdogan Edgunlu T and Demir Pektas S
ISSN: 2574-7800  10.23880/cdoaj-16000162  Received: October 11, 2018  Published: November 26, 2018
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Keywords
Vitiligo Genetic variants Etiology
Abstract

Vitiligo is a progressive skin disorder characterized by white and depigmented formations. The etiology is still unknown but genetic hypothesis a positive family history for vitiligo has been reported. Most important hypothesis is autoimmune hypothesis and neural hypothesis. Numerous additional HLA association studies have been published in Vitiligo. Genetic studies associated with vitiligo are not only related to the identification of genes that are susceptible to disease, but can also lead to the identification of genes associated with clinical aspects of the disease, the dynamics of the disease process or the time of manifestation of the first skin lesion. Continuous research on susceptibility genes is important to better understand the underlying mechanisms of vitiligo pathogenesis.

Introduction

Vitiligo is a progressive skin disorder characterized by white and depigmented formations occur and continue to increase over time. It is caused by the disappearance of melanocytes in the epidermis and the absence of melanin [1]. The condition can be cosmetically disfiguring and sunburns. Regardless of gender and race, it affects 0.1-2% of the world population. Although there is no complete therapeutic method for vitiligo, many options are available. Treatment as well as medical and surgical repigmentation. Medical treatments include narrowband ultraviolet B (UVB), broadband UVB, psoralen plus UVA, corticosteroids and other new approaches. When medical treatment is insufficient position, surgical treatment consisting of autologous transplantation is generally recommended for stable / focal vitiligo [2].

The etiology is still unknown, but some hypotheses have been proposed to explain the loss of melanocytes in the epidermis. Genetic hypothesis a positive family history for vitiligo has been reported. In fact, family clustering of cases is not uncommon, because about 20% of patients have at least one affected first-degree relative, a multi-factor, non-Mendelian model suggesting polygenic inheritance [3]. Segregation analysis suggests that multiple interactive genes are involved in different populations [4]. Several candidate genes and chromosomal location have been proposed as effective for vitiligo [5]. In particular, various HLA abnormalities have been associated with vitiligo, including A30, B13, Dr4, BW35 [6]. A recent large epidemiological study supports the role of both genetic and non-genetic factors in the pathogenesis of the disease. Some genetic factors may be associated with other autoimmune diseases [5].

Autoimmune Hypothesis

This hypothesis suggests that immune system damage causes the destruction of melanocytes. First, many autoimmune disorders (thyroid diseases, Sutton's, juvenile diabetes mellitus, pernicious anemia, and Addison's disease) are supported by frequent observation of vitiligo. In particular, the association of thyroid dysfunction and / or thyroid antibodies with a prominent vitiligo has been shown [7]. Regarding humoral immunity, surface antibodies and cytoplasmic antigens of melanocytes have been found in vitiligo patients mainly belonging to the IgG class. The most common autoantigens are HLA class I molecules, tyrosinase, tyrosinase associated protein (TRP) -1 and TRP-2 (the last three melanocyte-specific antigens) related antigens. The pathogenic role of antimelanocyte antibodies is still unclear. Serum levels of antibodies to melanocyte antigens, the activity and extent of the disease, and the presence of other immune disorders and seems to be related to the reduction in patients with vitiligo responding to treatment [8, 9]. Both humoral and cellular immunity are likely to cooperate in the elimination of melanocytes. Regarding cellular immunity, the underlying infiltrate of pigmented lesion skin has an important role to play in detecting CD4 and CD8 positive T cells as well as expressing activation molecules [10]. A significant number of infiltrating T cells express the typical cutaneous lymphocyte antigen (CLA) of homing T cells in the skin, and in a recent study localized CLA positive cytotoxic T cells cause the disappearance of melanocytes lost in the percutaneous skin [11]. Melanin-A / Mart1 (melanosomal antigen) specific CD8 positive T cells were detected in peripheral blood in vitiligo patients. Melan-A / Mart1-specific CD8-positive T-cell clones in patients with melanoma infused Melan-A / Mart1-specific CD8-positive T lymphocytes in inflammatory lesions of melanocyte destruction following infusion [11, 12].

Neural Hypothesis

This hypothesis suggests that some neurochemical mediators, possibly secreted from adjacent nerve endings, are cytotoxic to pigment cells. This theory is supported by the presence of a segmental variant of vitiligo affecting the onset of disease and the onset of disease in patients with vitiligo and neurological disorders or peripheral nerve damage after a serious emotional stress period [13, 14]. Abnormalities of neuropeptides have been observed in the blood of peril skin and vitiligo patients [15]. In addition, increased catecholamine discharge or synthesis has been associated with disease activity and suggests the role of catecholamines in the depigmentation process [16]. Significant support for this theory has been demonstrated by demonstrating morphological and functional communication between epidermal melanocytes and the nervous system [17]. Autocytotoxic / metabolic hypothesis It has been suggested that oxidative stress is the initial pathogenic event in melanocyte degeneration [18, 19] with H2O2 accumulation in the epidermis of patients with active disease. Defective recycling of tetrahydrobiopterin, vitiligo associated with intracellular production of H2O2 has been reported in the epidermis [18]. In addition, a change in the antioxidant pattern with a significant reduction in catalase activity has been demonstrated in both the lesion and the non- lesion epidermis and melanocytes [19]. However, the antioxidant imbalance was also confirmed in peripheral blood mononuclear cells of active vitiligo patients; It was associated with increased intracellular production of reactive oxygen species and appeared to be due to mitochondrial disorder [20]. These findings support a possible systemic oxidative stress concept in vitiligo. Hypothesis related to the new microenvironment The cytokine imbalance in epidermal microenvironment in the skin with active vitiligo is shown. This can disrupt the normal life and activity of melanocytes. A decrease in cytokines inducing melanocytes and an increase in cytokines inhibiting melanocytes (especially tumor necrosis factorα) were detected in depressed lesions [21]. According to this hypothesis, a central role is given to the cutaneous microenvironment. Convergence theory. The identification of many reliable ingredients against the pathogenesis of vitiligo has led to this theory that different causal elements may act synergistically or independently to provoke the loss of melanocytes. Genetic factors, oxidative stress, autoimmunity, mutations, altered cellular environment may contribute to the disease [22].

Genome-Wide Association Studies

Numerous additional HLA association studies have been published in Vitiligo. However, the relationship between vitiligo and genetic variation of the class I and class II gene regions of the Major Histocompatibility Complex (MHC) was investigated. Detailed molecular genetics and genome wide association studies (GWAS) were performed. Kemp, et al. reported the first vitiligo non-MHC candidate gene association. CTLA4 encoding a T cell co-receptor associated with other autoimmune diseases, which are involved in the regulation of T-cell activation and which are associated epidemiologically with vitiligo. In fact, CTLA4 incorporation was the highest in vitiligo patients with other comorbid autoimmune diseases [23], a finding that was later amplified by another study and meta-analysis [24]. A second significant non-MHC candidate gene association, also reported by Kemp [25], was also with PTPN22 encoding LYP protein tyrosine phosphatase, which was genetically related to many different autoimmune diseases. Again, this review was replicated in most of the other European- based whites [26, 27] and other studies by GWAS, but not in many other populations. Thus, in conjunction with HLA class II, CTLA4 and PTPN22 are two of the genes underlying the epidemiological relationship of vitiligo, possibly with at least other European autoimmune diseases, in whites of European origin. Genomewide studies Candidate gene analysis is based on a bias based on the selection of genes for study. In contrast, genomic analysis of polygenic, multifactorial diseases is, in principle, neutral, beyond the assumption that genetic factors play a role. There are three approaches to genetic analysis of genome analysis. Genome-bond linkage analysis for collecting polymorphic markers between families with multiple affected relatives and among these families. Such families are rare, the genetic resolution of the link is low, and genetic assays require a few important assumptions that may not be accurate. For reasons that are not clear, the connection and GWAS often do not detect the same genetic signals. Genome wide or exome DNA sequencing studies can be constructed similarly to linkage or GWAS, but are much more expensive and have not yet been applied to vitiligo.

Candidate Gene Association Studies

Recently, candidate gene association studies involving many candidate genes: ACE, AIRE, CAT, CD4, CLEC11A, COMT, CTLA4, C12orf10, DDR1, EDN1, ESR1, FAS, FBXO11, FOXD3, FOXP3, GSTM1, GSTT1, IL1RN, IL10, KITLG, MBL2, NFE2L2, PDGFRA-KIT, PTGS2, STAT4, TAP1-PSMB8, TGFBR2, TNF, TSLP, TXNDC5, UVRAG, VDR, XBP1 TNFA TNFB, IL4, NLRP1, MYG1, ICAM1, HLA SOD, CAT, GPX1, FOXO3a, SIRT1,IFNG, IL1B, PSMB8, VDR, DR4. Also some studies have shown genetic variants of DEFB1, SOD2, GSTM1/T1 genes are related with vitiligo [29, 30, 31, 32, 33, 34, 35]. The effect of these genes on the pathogenesis of vitiligo is not yet clear. Significant pathogenic effects of candidate gene PTPN22 and HLA have been proposed in the development of vitiligo [29]. Generally cytokines, antigen processing and presentation, redox homeostasis related genes were studied. These studies shown that these genes are associated with vitiligo disease.

Conclusion

Genetic studies associated with vitiligo are not only related to the identification of genes that are susceptible to disease, but can also lead to the identification of genes associated with clinical aspects of the disease, the dynamics of the disease process or the time of manifestation of the first skin lesion. Most of the studies conducted so far have been evaluated as reliable biological candidate genes. Approximately 90% of them encode immunoregulatory proteins, while approximately 10% encode melanocyte proteins. The proteins of the melanocytes are probably autoantigens identified by the immune system and identified and eliminated by the immune system. These proteins form a dense network that fully regulates the immune system, emphasizing the system and pathways that have an effect on the development of sensitivity to vitiligo [36]. Continuous research on susceptibility genes is important to better understand the underlying mechanisms of vitiligo pathogenesis. The presence of various relationships between vitiligo and other autoimmune diseases can provide new information about the causes of many disorders through genetic research. Samples inhaled the inverse relationship between vitiligo and melanoma genetics, which in the future could lead to new opportunities for the treatment of this extremely dangerous skin neoplasm. The main objective of all research is to find new and optimal therapeutic strategies for vitiligo and other autoimmune diseases. In the future, these investigations are likely to find new prevention methods in this particular disease group.

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@article{gokdogan2018,
  title   = {Genetic Variants of Vitiligo},
  author  = {Gokdogan Edgunlu T and Demir Pektas S},
  journal = {Clinical Dermatology Open Access Journal},
  year    = {2018},
  volume  = {3},
  number  = {3},
  doi     = {10.23880/cdoaj-16000162}
}
Gokdogan Edgunlu T and Demir Pektas S (2018). Genetic Variants of Vitiligo. Clinical Dermatology Open Access Journal, 3(3). https://doi.org/10.23880/cdoaj-16000162
TY  - JOUR
TI  - Genetic Variants of Vitiligo
AU  - Gokdogan Edgunlu T and Demir Pektas S
JO  - Clinical Dermatology Open Access Journal
PY  - 2018
VL  - 3
IS  - 3
DO  - 10.23880/cdoaj-16000162
ER  -