Elsevier

Gene

Volume 700, 5 June 2019, Pages 17-22
Gene

Research paper
CDH1 and DDR1 common variants confer risk to vitiligo and autoimmune comorbidities

https://doi.org/10.1016/j.gene.2019.03.026Get rights and content

Highlights

  • The melanocytes adhesion deficit could be an initial step for pigment loss in vitiligo.

  • The CDH1 CC genotype was significantly associated with vitiligo.

  • There was also a significant connection between the DDR1 CC genotype and vitiligo.

  • There might be an association between the adhesion deficit in vitiligo and autoimmune diseases.

Abstract

The weaker expression of the two main proteins adhering melanocytes to the epidermis basal layer, Epithelial Cadherin (E-cadherin) and Discoidin Domain Receptor Tyrosine kinase 1 (DDR1), has been implicated as one of the aggravating factors in the loss of melanocytes in vitiligo. The present study was designed to assess the association between single nucleotide polymorphisms (SNP) in the genes encoding these proteins, CDH1 and DDR1, and the risk of developing vitiligo. The independent case-control study was conducted on the sample including152 patients with vitiligo and 152 matched controls. A questionnaire was completed for recording demographic and clinical characteristics of vitiligo patients. Venous blood samples were taken from all the subjects. Genotype frequencies were determined for CDHI C/T (rs 10431924) and DDRI A/C (rs 2267641) genes polymorphisms using polymerase chain reaction (PCR) amplification method and Restriction Fragment Length Polymorphism (RFLP) analysis. The CDH1 CC genotype was found to be significantly associated with the risk of developing vitiligo. The results of stratified analysis revealed a correlation between CDH1 CC genotype and late age of onset, clinical type of vitiligo, the absence of autoimmune comorbidities and family history of autoimmune disorders. However, the expression level of CDH1 TT genotype increased significantly in patients with autoimmune comorbidities. There was also a significant relationship between the DDR1 CC genotype and the risk of developing vitiligo. The results of stratified analysis revealed a correlation between DDR1 CC genotype and early age of onset, clinical type of vitiligo and absence of family history of autoimmune disorders. The findings of the study confirm the conjecture previously made in the literature regarding the melanocytes' adhesion deficit as an initial step for pigment loss in vitiligo and emphasize the substantial role of friction and koebner phenomenon in the pathogenesis of vitiligo. Moreover, a probable association can be proposed between the adhesion deficit involved in vitiligo and autoimmune disorders.

Introduction

Vitiligo is an acquired, chronic depigmenting disorder of the skin characterized by gradual loss of melanocytes in depigmented areas of the skin. With a worldwide prevalence of 1%, vitiligo is considered to be the most common pigmentation disorder (Tarlé et al., 2014). Vitiligo is classified into two major forms, namely segmental and non-segmental vitiligo. The former is less common and usually occurs with a unilateral and band-shaped distribution. The latter characterized by symmetrical and bilateral white patches occurs with different clinical subtypes, including focal, acrofacial, vulgaris and universal (Ezzedine et al., 2015). Although the molecular basis is not known completely, the disappearance of melanocytes in vitiligo appears to involve with cell adhesion defects (Wagner et al., 2015). This theory has been supported by the weaker expression of two molecules identified in cell-cell adhesion, Epithelial Cadherin (E-cadherin) and Discoidin Domain Receptor Tyrosine kinase 1 (DDR1), in keratinocytes of depigmented vitiligo lesions compared to normal skin (Kim and Lee, 2010; Ricard et al., 2012).

E-cadherin is an adhesive Ca2+ dependent transmembrane protein mediating tight and strong cell-cell adhesion through homophilic interactions. There is strong evidence in favour of the major role of E-cadherin in melanocytes adhesion to keratinocytes in the epidermis (Tang et al., 1994). The expression of E-cadherin in melanocytes in both non-segmental and segmental forms of vitiligo has been shown to be reduced similarly compared to normally pigmented skin emphasizing the cell adhesion defect theory as an initial step for pigment loss in vitiligo (Grill et al., 2018). DDR1 is a transmembrane tyrosine kinase receptor that forms a complex with E-cadherin at cell junctions and plays a physiological role through stabilization of E-cadherin and E-cadherin-mediated cell aggregation (Eswaramoorthy et al., 2010). The results of previous studies showed a significant reduction in DDR1 expression level in lesional compared to non-lesional vitiligo skin which adds to the cumulative evidence pointing to DDR1 as a major factor causing impaired adhesion process involved in vitiligo (Elgarhy et al., 2016; Reichert-Faria et al., 2013).

Despite the substantial evidences in favour of the probable mutation of the CDH1 and DDR1 genes in vitiligo, there are not enough and comprehensive studies on the role of these polymorphisms so far, and the results of the previous studies have not been conclusive (Birlea et al., 2011; Kim et al., 2010; Silva de Castro et al., 2010; Tarlé et al., 2015). Therefore, the present study was designed to assess the association between the risk of developing vitiligo and single nucleotide polymorphisms (SNP) in two important genes involved in the regulation of melanocyte adhesion including CDH1 and DDR1.

Section snippets

Study design and study population

This independent case-control study was carried out between December 2016 and June 2018 on a sample including 152 patients with vitiligo and 152 controls, selected and matched according to age, gender, skin type, and ethnicity. Patients diagnosed with vitiligo were enrolled among patients referring to dermatology clinics of Shohada-e-Tajrish and Loghman-e-Hakim hospitals, Tehran, Iran. Healthy control individuals were recruited from the same hospitals if they were not diagnosed with vitiligo

Characteristics of vitiligo patients and controls

A total sample of 152 unrelated patients with generalized vitiligo and 152 unrelated controls with no history of autoimmune or inflammatory diseases were selected among the patients referring to dermatology clinics of Shohada-e-Tajrish and Loghman-e-Hakim hospitals. There were no significant differences in age, gender and skin type between case and control groups (P > 0.05). The demographic and clinical characteristics related to vitiligo cases and controls are summarised in Table 1, Table 2.

Discussion

The findings of previous studies conducted in recent years have identified vitiligo as a complex, multifactorial and polygenic disease; however, only a few genes have been shown to be consistently and functionally associated with the development of the disease (Tarlé et al., 2014). The pathogenesis of vitiligo has not been completely determined, but regardless of the intrinsic pathomechanism, the presence of the extrinsic pathomechanism including mechanical trauma is necessary for explaining

Conclusion

The findings of this study confirmed the association between CDH1 C/T and DDR1 A/C polymorphisms and the risk of developing vitiligo. The results of the stratified analysis revealed a relationship between CDH1 CC genotype and late age of onset, clinical type of vitiligo, the absence of autoimmune comorbidities and family history of autoimmune disorders. However, CDH1 TT genotype was found to be increased significantly in patients with autoimmune comorbidities. There was also a significant

Funding source

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

Ethical approval

This study was approved by the institution review board of Shahid Beheshti University of Medical Sciences. The research protocol was performed in accordance with the approved guidelines.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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