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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 1019-1024

Endothelin-1 gene polymorphism in Egyptian patients with vitiligo


1 Department of Dermatology, Andrology and S.T.Ds, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemeistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Dermatology, Andrology and S.T.Ds, Alhaud Al-Marsoud Hospital, Cairo, Egypt

Date of Submission06-Dec-2017
Date of Acceptance29-Jan-2018
Date of Web Publication17-Oct-2019

Correspondence Address:
Douaa S Alsaadany
Tala, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_862_17

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  Abstract 


Objective
The aim was to investigate the association between endothelin-1 (ET-1) gene polymorphism and vitiligo occurrence or increased vitiligo risk in Egyptian population.
Background
ET-1 is a keratinocyte-derived cytokine, which also has been defined as a strong mitogen and melanogen for human melanocytes and a potent stimulant of melanocyte proliferation, melanogenesis, and migration, implying a link with vitiligo.
Patients and methods
This study was conducted on 60 female patients with vitiligo. Their ages ranged from 6 to 70 years Overall, 54 cases presented with nonsegmental vitiligo and six cases presented with segmental vitiligo. Moreover, 40 age-matched and sex-matched apparently healthy volunteers with no past, present, or family history of vitiligo were included as a control group. Every case and control underwent detection of genotyping of ET-1 by restriction fragment length polymorphism-PCR.
Results
AA genotype of ET-1 was significantly associated with cases. It increases the risk of vitiligo by 15.9 folds. GA genotype was prevalent in 36.7% of cases. It increases the risk of vitiligo by 3.3 folds.
Conclusion
There is an association between ET-1 gene polymorphism and vitiligo occurrence.

Keywords: endothelin-1, gene polymorphism, vitiligo


How to cite this article:
Shoeib MA, Bakry OA, El-Hefnawy SM, Alsaadany DS. Endothelin-1 gene polymorphism in Egyptian patients with vitiligo. Menoufia Med J 2019;32:1019-24

How to cite this URL:
Shoeib MA, Bakry OA, El-Hefnawy SM, Alsaadany DS. Endothelin-1 gene polymorphism in Egyptian patients with vitiligo. Menoufia Med J [serial online] 2019 [cited 2019 Nov 14];32:1019-24. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/1019/268856




  Introduction Top


Vitiligo is a depigmenting dermatosis [1], characterized by acquired, milky white macules and patches [2]. Although it is a common disease, its etiology is still debated, and many theories have been proposed [3].

Keratinocytes produce many growth factors and cytokines that control the activation and survival of melanocytes [4]. Among the known keratinocyte-derived cytokines is endothelin (ET)-1 [5].

ET-1 is a potent vasoconstrictor peptide expressed in vascular endothelial cells [5]. In addition, it controls melanocyte growth [6], proliferation [7], melanogenesis [8], and migration [7], implying a link with vitiligo [9]. It can stimulate proliferation and melanization of human melanocytes at concentrations as low as 1 nm/ml [10].

Polymorphism is defined as change in the sequence of nucleotides that affect either the noncoding parts (promotor area and intron) or the coding part (exon) of the gene [11]. The association of a certain polymorphism with a phenotype or disease does not necessarily mean that the polymorphism is causing it [12].

Genetic association studies and gene polymorphism studies are investigative research works to demonstrate the participation of certain genes in disease development. These associations cannot be used for diagnosis or prognosis. They may be used, in future, for clinical interference and prevention or treatment. Therefore, the current study aimed to investigate the association between ET-1 gene polymorphism and vitiligo occurrence or increased vitiligo risk in Egyptian population.


  Patients and Methods Top


Study population and selection of patients

This study was approved by the Ethical Committee of Dermatology and Biochemistry Department, Faculty of Medicine, Menoufia University, during the period from December 2014 to August 2016, and informed consent was obtained from every patient and control. It involved 60 female patients with vitiligo as case group and 40 age-matched and sex-matched apparently healthy volunteers with no past, present, or family history of vitiligo as a control group.

Inclusion criteria

The study included female patients.

Exclusion criteria

The following were the exclusion criteria: patients with dermatological diseases other than vitiligo and those with systemic autoimmune or endocrine disorders.

Each of the selected patients was subjected to the following:

  1. Full history taking, including personal and family history and clinical history such as onset, course, and duration of the disease
  2. Clinical examination:


    1. General examination
    2. Dermatological examination to determine site, clinical type, presence of leukotrichia
    3. Assessment of lesion extent by vitiligo area scoring index: the percentage of vitiligo involvement is calculated in terms of hand units. One hand unit is approximately equivalent to 1% of the total body surface area. The degree of pigmentation is estimated to the nearest of one of the following percentages:


      1. 100%: complete depigmentation, no pigment is present
      2. 90%: specks of pigment present
      3. 75%: depigmented area exceeds the pigmented area
      4. 50%: pigmented and depigmented areas are equal
      5. 25%: pigmented area exceeds depigmented area
      6. 10%: only specks of depigmentation present


    4. Assessment of disease activity by vitiligo disease activity (VIDA) scoring: the VIDA is a six-point scale for assessing vitiligo activity. Scoring is based on the individual's own opinion of the present disease activity over time. Active vitiligo involves either expansion of existing lesions or appearance of new lesions. Grading is as follows:


      1. VIDA score +4: activity of 6 weeks or less duration
      2. +3: activity of 6 weeks to 3 months
      3. +2: activity of 3–6 months
      4. +1: activity of 6–12 months
      5. 0: stable for 1 year or more
      6. −1: stable with spontaneous repigmentation since 1 year or more. A low VIDA score indicates less activity
      7. Every case and control underwent detection of genotyping of ET-1 gene by restriction fragment length polymorphism-PCR.


Sample collection and preparation

A volume of 2 ml of venous blood was withdrawn from every participant by sterile vein-puncture and transferred into EDTA tube for DNA extraction and PCR.

DNA extraction

DNA was extracted from whole blood using Thermo Scientific Gene JET Genomic DNA purification kit (Thermo Fisher Scientific, Waltham, Massachusetts, US). DNA was stored at −20°C for further PCR procedure.

Principle

Samples are digested with proteinase K in the supplied lysis solution. The lysate is then mixed with ethanol and loaded onto the purification column, where the DNA binds to the silica membrane. Impurities are effectively removed by washing the column with the prepared wash buffers. Genomic DNA is then eluted under low ionic strength conditions with the elution buffer.

Determination of endothelin-1 gene polymorphism

The ET-1 genotype was determined by using a PCR-restriction fragment length polymorphism method. PCR for ET-1 gene was carried out in 25-μl solution, containing 10 μl genomic DNA, 1 μl of each primer, 12.5 μl of Master Mix using Thermo Scientific Dream Taq Green PCR Master Mix (Thermo Fisher Scientific, Waltham, Massachusetts, US), and 0.5 μl distal water.

The (G8002A) polymorphism in intron 4 of ET-1 gene was analyzed using the following designed primers (Midland, Texas, USA):

  1. Forward: 5'-CAAACCGATGTCCTCTGTA-3'
  2. Reverse: 5'-ACCAAACACATTTCCCTATT-3'.


PCR amplification for ET-1 gene was performed separately using Applied Bio systems 2720 thermal cycler (Thermo Fisher Scientific, Waltham, Massachusetts, US).

PCR condition consisted of one cycle of amplification at 95°C for 10 min followed by 40 cycles at 95°C for 1 min, 64°C for 2 min, 72°C for 1.5 min, and one final cycle of extension at 72°C for 7 min.

The amplification products were separated by electrophoresis through 3% agarose gel stained with ethidium bromide and visualized on transilluminator with positive band at 353bp [Figure 1].
Figure 1: Agarose gel electrophoresis of amplification product of ET-1 gene (a) and digestion products of ET-1 gene by Taq I restriction enzyme (b).

Click here to view


Statistical analysis

Data collected were tabulated and analyzed by statistical package for the social sciences (SPSS, version 20; SPSS Inc., Chicago, Illinois, USA) on IBM personal computer. The following statistics were applied: descriptive statistics, for example, percentage, mean and SD, and range, and analytic statistics, for example, χ2-test, Fisher's exact test, Student's t-test, and Mann–Whitney test. P value of less than 0.05 was considered to be significant. Spearman's correlation coefficient (r) was used to measure the relation between two quantitative variables.


  Results Top


The age of the patients ranged from 6 to 70 years, with 31.72 ± 17.51 as the mean ± SD value and 34.0 years as the median value. A total of 50 (83.3%) cases presented with lesions on extremities, 14 (23.3%) cases had lesions on the face, six (10%) cases presented with lesions on the neck, and 39 (65%) cases presented with lesions on the trunk. A total of 54 (90%) cases presented with nonsegmental vitiligo (NSV), comprising 28 (46.7%) cases with generalized type, nine (15.0%) cases with focal type, 11 (18.3%) acrofacial, and six (10.0%) universal type, whereas six (10%) cases presented with segmental vitiligo (SV). Family history was positive in 20 (33.3%) cases. The course was stationary in 18 (30%) cases, progressive in 39 (65%), regressive in two (3.3%) cases, and relapsing in one (1.7%) case. In total, 20 (93.3%) cases had active course and 40 (66.7%) cases had inactive course. A total of four (6.7%) cases showed leukotrichia. The duration of the disease ranged between 4 and 240 months, with 40.85 ± 41.47 months as a mean ± SD value and 30.0 months as a median value. The extension of the lesions ranges from 5 to 90%, with mean ± SD value of 33.98 ± 26.34 and median value of 35.0. The last activity of the disease ranged from 1 to 180 months with mean ± SD of 13.10 ± 31.5 and median value of 3.0. VIDA scoring of the disease ranged from 0.0 to 4.0, with mean ± SD value of 1.95 ± 1.33 and median value of 2.0 [Table 1].
Table 1: Clinical data of studied cases (n=60)

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Normal (GG) genotype was more prevalent among control group than patients with vitiligo (55 vs. 6.7%). Polymorphism (AA) genotype was significantly associated with patients with vitiligo (51.7 vs. 12.5%). It increases risk of occurrence of vitiligo by 34.1 folds. Mosaic (GA) genotype was present in 41.7% of cases and 32.5% of control. It increases the risk of vitiligo by 32.32 folds. G allele was more prevalent among control than patient group (71.3 vs. 27.5%). A allele was significantly associated with patient group (70.0 vs. 33.8%). A allele increases risk of occurrence of vitiligo by 6.533 folds [Table 2].
Table 2: Prevalence of endothelin-1 genotypes and alleles in cases and controls

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  Discussion Top


Vitiligo is a common skin disorder characterized by white macules and patches [13]. It is an acquired, idiopathic, and progressive disease that causes circumscribed hypomelanosis of the skin and hair [2]. It occurs in ∼0.5–1% of world's population, with an average age of onset of approximately 24 years. It affects men and women equally [14],[15].

Vitiligo is classified according to Taieb and Picardo [15],[16] into four types: NSV, SV, mixed NSV and SV, and unclassifiable types. NSV is divided into subtypes: focal at onset, mucosal, acrofacial, generalized, and universal. Generalized vitiligo may begin later in life with predilection to sites of pressure, friction, and/or trauma and it becomes progressive with flare-ups. Leukotrichia occurs at later stages [17].

Many theories have been proposed to explain vitiligo pathogenesis, but none of them unravel the complexity of this disease [3]. It remains unclear what causes damage or death to melanocytes. There are many potential pathophysiological theories involving autoimmune [18], neural, autocytotoxic [19], biochemical [20], viral infection [21], oxidative stress [22], melanocytorrhagy [23], and decreased melanocyte survival hypotheses [4].

There is a positive family history in approximately 20% of cases and similar concordance in identical twins. Vitiligo is considered a complex trait, involving the interaction of multiple genes with nongenetic factors, both environmental and host. There is strong support for relatively few susceptibility genes, including certain HLA genes, PTPN22, NALP1, and perhaps cytotoxic T-lymphocyte antigen-4. These are all associated with a tendency to autoimmunity [24].

ET-1 is the most abundantly and widely expressed member of the endothelin family of proteins (ET-1, ET-2, and ET-3) [25].

The biological effects of these proteins are mediated by their binding to specific cell surface receptors known as ETAR and ETBR that belong to the family of G-protein-coupled receptors [26].

ET-1 is a keratinocyte-derived cytokine. It is originally known to be a potent vasoconstrictor peptide expressed in vascular endothelial cells and has been implicated in several diseases such as hypertension, atherosclerosis, malignant arrhythmia, and chronic heart failure [5]. The ET-1 gene is localized on chromosome 6, spans 5.5 kb in length, and contains five exons and four introns [27].

ET-1 has been shown to control melanocyte growth and function [6]. It has also been defined as a strong mitogen and melanogen for human melanocytes [8] and a potent stimulant of melanocyte proliferation [7], melanogenesis [9], and migration [7], implying a link with vitiligo [28]. ET-1 and its receptor ET-B, and stem cell factor (SCF) and its receptor KIT proto-oncogene, receptor tyrosine kinase (KIT), have been shown to substantially contribute to UVB-induced melanosis [29].

ET-1 was found to be increased in patients undergoing psoralen and ultraviolet A treatment [30]. It induces melanocyte mitosis, enhances dendricity, and prevents apoptotic cell death following ultraviolet injury. So, it was suggested that ET-1 plays an essential role in melanocyte proliferation in the narrowband UVB light therapy of vitiligo [5].

Besides, it is a strong vasoconstrictive agent that may contribute in controlling inflammatory process. Indeed, blocking the ET-1/ET AR signaling resulted in the loss of pigmentation in vivo [30]. It activates tyrosinase and increasing the level of tyrosinase-related protein 1 in mature melanocytes [7].

Polymorphism is defined as change in the sequence of nucleotides, without change in phenotype. The change of the nucleotide sequence in polymorphism affects either the noncoding parts (promotor area and intron) or the coding part (exon) and is named silent mutation, in which the change of nucleotides codes for the same amino acid [11].

Polymorphisms of ET-1 and ETAR genes have been investigated in autoimmune diseases such as Hashimoto's thyroiditis [31], Graves' disease [32], scleroderma [33], primary biliary cirrhosis, and psoriasis. There are studies in the literature examining the relationship between ET-1 gene polymorphisms and vitiligo, with controversial results [34].

Results revealed that AA genotype of ET-1 was significantly associated with cases. It increases the risk of vitiligo by 15.9 folds. GA genotype was prevalent in 41.7% of cases. It increases the risk of vitiligo by 32.32 folds [Figure 2].
Figure 2: Endothelin-1 genotypes and alleles in cases and controls.

Click here to view


These findings conflict with Kim et al. [5] and Bingül et al. [35] who found that ET-1 gene polymorphism did not differ between vitiligo cases and healthy controls. These different outcomes can be explained by different clinical characters of studied cases and different ethnic backgrounds. Moreover, only two previous studies have been done on the same gene, but did not act on the same site of polymorphism, as the study by Bingül et al. [35] was done on G5665T and T1370G, whereas the study by Kim et al. [5] was done on G8002A polymorphism.

It was reported that AA polymorphism of ET-1 gene causes failure of prevention of apoptotic cell death and restoration of incidentally injured melanocytes, suggesting a role in vitiligo development [5],[36],[37].


  Conclusion Top


From this study, we can conclude that ET-1 gene polymorphism is associated with vitiligo. AA genotyping increases vitiligo risk by 15.943 folds. This association can be explained by failure to prevent apoptotic cell death and restore incidentally injured melanocytes by the altered ET-1 gene. Therefore, ET-1 gene polymorphism may be considered as a novel risk factor in vitiligo in Egyptian population. The current study is the first to report such association, which was denied in previous similar studies, as mentioned previously.

Recommendations

Further studies on larger scales are recommended to expand and validate our findings and investigate the other types of ET-1 gene polymorphism and ETAR polymorphisms and its association with vitiligo. Future studies on different populations and ethnicities are recommended. As vitiligo is a multifactorial disease, studying gene – gene and gene – environment interactions in disease pathogenesis is also needed in future genetic – epidemiologic researches to apply more comprehensive insight into the role of ET-1 gene in its pathogenesis.

To the best of our knowledge, the effect of endothelin gene polymorphism on serum endothelin was not studied before. Therefore, this point needs further research to be clarified.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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