Research paperCDH1 and DDR1 common variants confer risk to vitiligo and autoimmune comorbidities
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.
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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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