Vitiligo is a common, chronic skin disease characterized by selective destruction of melanocytes. The worldwide disease prevalence ranges from 0.1 to 8.8% with no sex preference 1–3. The pathogenesis of vitiligo is multifactorial and includes genetic, autoimmune, biochemical, and neural factors 4.
Oxidative stress plays an important role in the pathogenesis of vitiligo 5. In vitiligo, the intracellular production of hydrogen peroxide (H2O2) is increased. This is due to the impaired recycling of tetrahydrobiopterin in the epidermis of vitiligo patients 6. Moreover, other reactive oxygen species are increased because of mitochondrial impairment. The defective antioxidant status in vitiligo patients supports the role of oxidative stress in melanocyte destruction 7,8.
Catalase (CAT) is an important endogenous antioxidant enzyme that catalyzes H2O2 detoxification. The human CAT gene is composed of 12 introns and 13 exons. It is located on chromosome 11p13 9. Mutations and single-nucleotide polymorphisms (SNPs) in the CAT gene have been reported to affect the CAT expression, CAT level, enzymatic activity, disease manifestation, and genetic susceptibility to vitiligo 10–12.
CAT gene polymorphism was reported to be associated with susceptibility to different diseases, including vitiligo. The reported distribution of CAT genotypes showed variations between different ethnicities 11. In the same time, various reports have investigated the association between CAT gene polymorphisms and susceptibility to vitiligo. However, the reported results were inconsistent 10–23. Therefore, we aimed to analyze whether CAT 389 T/C and CAT −89 T/A SNPs are associated with vitiligo and to investigate whether these polymorphisms affect the serum level of CAT and malondialdehyde (MDA) in those patients.
Patients and methods
This case–control study included 201 participants: 106 patients with nonsegmental vitiligo and 95 healthy controls. The vitiligo patients were recruited from the dermatology outpatient clinic of Mansoura University Hospital. The inclusion was based on clinical examination.
Each patient was subjected to through history taking, including age, the presence of a positive family history of vitiligo (in a first-degree relative), and the duration and course of the disease. Vitiligo Disease Activity (VIDA) Score was used to evaluate the course of vitiligo. Stable vitiligo includes both VIDA 0 (when disease has remained stable≥1 year) and VIDA −1 (when disease has remained stable with spontaneous repigmentation≥1 year). Progressive vitiligo includes VIDA +1 (active 6–12 months), +2 (active 3–6 months), +3 (active 6 weeks–3 months), and VIDA +4 (active≤6 weeks) 24. The extent of vitiligo was determined according to the rule of nine 25.
The exclusion criteria were as follows: receiving topical or systemic immunomodulatory therapy for vitiligo during the 3 months before the study and presence of other autoimmune diseases or malignancy.
Healthy controls were recruited from blood bank and they were sex and age matched. They were living in the same geographic area and were of the same ethnicity as vitilgo patients. They had no clinical evidence or family history of vitiligo or other autoimmune diseases.
The study was approved by the Research Ethics Committee for experimental and clinical studies at Faculty of Medicine, Mansoura University, Mansoura, Egypt. The importance of the study was explained to all participants and informed written consent was obtained from all participants before performing the study. The study was conducted according to the Declaration of Helsinki Principles.
Venous blood of 5 ml was drawn from patients and controls. Blood of 2 ml was added to sterile EDTA tube and 3 ml of blood was added to a plain tube without anticoagulant. The plain tube samples were left for 10 min at room temperature to clot, and then serum was separated and stored at −20°C until the time of assay of oxidative stress markers: serum CAT and MDA levels. Determination of serum level of MDA was based on colorimetric method depending on the reaction of MDA with thiobarbituric acid 26. Serum CAT level was measured using Human Catalase ELISA Kit (Sunred Biological Technology, Shanghai, China).
Typing of CAT 389 T/C and CAT −89 T/A gene polymorphisms
Genomic DNA was extracted from whole venous EDTA blood using the GeneJET whole blood genomic DNA Purification Mini Kits (lot 00138029; Thermo Scientific, Vilnius, Lithuania) and stored at −20°C until use. The genotypes of CAT SNPs were analyzed using the PCR-restriction fragment length polymorphism method according to Liu et al.12.
Genomic DNA from the cases and controls was subjected to PCR analysis of the CAT genes using the following primers: for CAT 389 T/C – forward primer 5′-GCCGCCTTTTTGCCTATCCT-3′ and reverse primer 5′-TCCCGCCCATCTGCTCCAC-3′ – and for CAT −89 T/A – forward primer 5′-AATCAGAAGGCAGTCCTCCC-3′ and reverse primer 5′-TCGGGGAGCACAGAGTGTAC-3′. Reaction volume was 25 µl: 5 µl DNA at 100 ng/µl, 15.0 µl of Dream-Taq Green PCR master mix (lot 00141171; Fermentas GmbH, St Leon-Rot, Germany), 0.5 µl of each primer (25 pmol/µl), and 4.0 µl H2O.
Reaction conditions were carried out in thermocycler PTC-100 (Biorad, Hercules, California, USA) with the following cycling parameters: for CAT 389 T/C – 94°C for 10 min, 30 cycles at 94°C for 55 s, 69°C for 55 s, 72°C for 90 s, and a final extension at 72°C for 10 min; and for CAT−89 T/A – at 94°C for 10 min, 30 cycles at 94°C for 55 s, 66°C for 55 s, 72°C for 90 s, and a final extension at 72°C for 10 min. To check for the PCR products, 10 µl of PCR products was resolved in 2% agarose gel. CAT 389 T/C band was at 202 bp and CAT −89 T/A was at 250 bp.
RFLP analysis was performed using FastDigest BstXI for CAT 389 T/C and HinfI for CAT−89 T/A (Fermentas GmbH). The total reaction mixture was 30 µl: 10 µl of PCR products+1.0 µl of restriction enzyme+2.0 µl 10× FastDigest green buffer+17 µl nuclease-free water. The mixture was incubated at 37°C for 10 min followed by heating at 65°C for 10 min. DNA fragments were resolved in 2% agarose gels. In the case of CAT389 T/C polymorphism, an undigested 202 bp fragment showed CC genotype, whereas two digested fragments of 108 and 94 bp showed TT genotype, and three fragments of 202, 108, and 94 bp indicated heterozygous CT genotype. With regard to the CAT−89 T/A polymorphism, AA genotype produces 250 bp, whereas TT genotype generates two digested fragments of 177 and 73 bp, and heterozygous AT genotype produces three fragments of 250, 177, and 73 bp.
The statistical analysis of data was performed using statistical package for social science program, version 20 (SPSS Inc., Chicago, Illinois, USA). Qualitative data were presented as number and percentage. The χ2-test and Fisher’s exact test were used to compare groups. Quantitative data were presented as mean, SD, or median and range. For comparison between two groups, Student’s t-test and the Mann–Whitney test (for nonparametric) were used. For comparison between more than two groups, the analysis of variance or Kruskal–Wallis tests (for nonparametric) were used. Deviations from Hardy–Weinberg equilibrium (HWE) expectations were determined using the χ2-test. Odds ratio and 95% confidence interval were calculated. The correlations between different parameters were analyzed using the Spearman rank correlation coefficient. A P value of 0.05 or less was considered statistically significant. Bonferroni’s correction was for the P value of multiple comparisons.
Demographics and baseline characteristics of vitilgo patients are summarized in Table 1. The present sample of individuals was selected randomly from the population living in lower Delta, Egypt. On applying HWE, CAT SNPs in controls were independent (i.e. they were in HWE). There is no evidence to reject the assumption of HWE in the sample) (P=0.17 and 0.41).
Analysis of the distribution of CAT 389 polymorphism in vitilgo patients and controls demonstrated that the T allele and homozygous TT genotype were significantly higher (P=0.02 and 0.04, respectively) and the C allele was significantly lower (P=0.02) in patients when compared with healthy controls. In the same time, the frequency of CC genotype was higher in controls than in patients, but the statistical significance was only marginal (P=0.051). However, when applying the Bonferroni’s correction, the genotype (TT and CC) significance was lost and the allele (T and C) significance was retained (Pc=0.04) (Table 2).
As regards the association of CAT −89 gene polymorphism with vitilgo, nonsignificant associations were found. However, it was observed that the frequency of heterozygous genotype AT was higher in controls than in patients (48 vs. 33%, respectively) and the difference was significant before Bonferroni’s correction (P=0.026 and Pc=0.052) (Table 2).
The distribution of combined genotypes and haplotypes in patients and controls showed a decreased frequency of CCAT combined genotype in patients than in controls and the differences were statistically significant even after Bonferroni’s correction (P=0.007 and Pc=0.014) (Tables 3 and 4).
The relation between different genotypes and haplotypes of the studied CAT SNPs and disease activity or extent and serum levels of CAT and MDA were analyzed and revealed nonsignificant associations (Tables 5 and 6).
Analysis of the serum levels of CAT and MDA in vitilgo patients and controls was performed and it was found that the serum level of CAT was lower and the serum level of MDA was higher in patients than in controls (P≤0.001). However, no correlations were found between serum levels of CAT and MDA and age of patients, disease extent, duration, and activity (Table 7).
The vitiligo is still a topic of debate, and disease etiology and origin are still unclear. Vitiligo pathogenesis is complex and includes the interaction of multiple variables. Many hypotheses have been suggested to explain the pathogenesis of vitiligo. These include genetic, neural, biochemical, viral, zinc-α2-glycoprotein deficiency, intrinsic, and autoimmune 27–30.
The analysis of genetics of nonsegmental vitiligo documented about 36 susceptibility loci. These loci are localized either within or near to biological candidate genes. These genes encode immunoregulatory or melanocyte protein. These proteins create a dense network that regulate the immune system and pathways that influence the susceptibility to develop vitiligo 30,31.
CAT plays an important role in protecting cells against the toxic effects of H2O2. CAT converts H2O2 into molecular oxygen and water. Accumulation of H2O2 is harmful for cells and initiates aging, inflammation, and cancer 32. In humans, CAT has been implicated in different pathological conditions. The polymorphisms of CAT gene affect the potential functions of CAT 11. There are about 245 SNPs that were detected in different regions of the CAT gene. Significant correlations between the studied SNPs of the CAT and various diseases including vitilgo were reported 10,33.
The results of the present work on a sample of Egyptian individuals revealed a significant increase in the T allele in vitilgo patients and a significant increase in the C allele of the CAT 389 in healthy controls (P=0.02 and Pc=0.04). These findings suggest that the T allele may be a susceptibility risk factor and the C allele may be protective against the development of vitilgo [odds ratio (OR)=1.7 and 0.6, respectively]. Although the significance of homozygous TT genotype of CAT 389 and heterozygous AT genotype of CAT −89 was lost after Bonferroni’s correction, the TT genotype of CAT 389 has a trend for association with vitiligo (OR=4.3) and the AT genotype has a marginal significance (Pc=0.052) and a trend for protection against vitilgo (OR=0.5) (Table 2). In the same time, the combined CCAT genotype can be considered a protective factor against the development of vitiligo (Pc=0.014) (Tables 3 and 4).
The reported results that were investigating the association between the CAT389 C/T SNP and susceptibility to vitiligo were inconsistent even in the same population. Positive associations were reported by Casp et al.20 on nonsegmental vitiligo patients and their family members from USA and Canada. The CT genotype was reported to be overrepresented in English vitiligo patients 21. Moreover, the meta-analysis of Lv et al.11 confirmed the association of CT plus the TT genotype with susceptibility to vitiligo. The drawback of this meta-analysis was the inclusion of only four studies with a small sample size and no subgroup analyses. However, negative associations were reported in Turkish 19,22, Indian 23, Korean 18, Chinese 12, and even Egyptian populations 13,14.
In the same time, the results of the two most recent meta-analyses were contradictory 16,17. The meta-analysis is used to provide an estimate of the genetic risk effect with a reduced uncertainty. It is also used to explore the trend of risk effect as evidence accumulates 34,35. The meta-analysis by Lu et al.16 included seven studies with 1531 vitiligo patients and 1608 controls. They documented that the CT genotype may be a risk factor for susceptibility and the CC genotype may be protective against the development of vitiligo in western Europeans. Moreover, they suggested that 389 C/T polymorphisms in the CAT gene are not associated with the risk for vitiligo in Asians and Turkish populations. They observed that the positive association was with people from Western Europe and the negative association was with people from Eastern Europe (i.e. may include Asian populations). They concluded that difference in ethnicity, life habit, and geographical environment may explain the large difference between various studies.
The most recent meta-analysis by He et al.17 included 2923 vitiligo patients and 4237 healthy controls from eight case–control studies. The results indicated no association between CAT 389 polymorphism and vitiligo. Moreover, in their stratification into subgroup (i.e. ethnicity), a nonsignificant association was found in either Asians or Whites. They concluded that CAT 389 did have an effect on susceptibility to vitiligo. They recommended carrying out large studies with the consideration of gene–gene and gene–environment interactions. However, the authors mentioned several limitations for their work. In the ethnicity subgroup analysis, less than three case–control studies were included in some subgroups; the number of studies was too small to recognize the association. There was some publication bias due to missed data either unpublished or published in other languages. Data stratification by age and sex was not carried out. They did not study linkage disequilibrium of CAT 389 with other CAT gene mutations.
Drysdale et al. 36 reported that the biological phenotype may be affected by the interaction of multiple SNPs within a haplotype. Liu et al. 12 observed the increased distribution of the CAT 389 and −89 SNPs haplotypes in vitiligo Chinese patients (P<0.001), especially the T-containing haplotypes. Moreover, patients carrying two risk genotypes of −89AT and 389TT (combined ATTT genotype) had an odds ratio larger than patients carrying only one risk genotype. These results suggested that, in individuals with combined genotype, the interaction between the risk genotypes intensifies the risk of developing vitiligo.
Allele and genotype frequency showed similar and different distribution between Egyptians and other populations and even among Egyptian population. This can be explained by the difference in sample size, difference in disease phenotype, difference in the technique of SNP typing, and difference in the ethnicity and genetic background of the Egyptians. The analysis of Y-chromosome gene pool in the modern Egyptian population was performed by Manni et al.37. They confirmed the mixed ethnicity of Egyptians and the presence of a mixture of European, Middle Eastern, and African genetic characteristics in Egyptians genetics. In the same time, a more specific analysis of Y-chromosome haplotypes was performed in Lower Egypt, Upper Egypt, and Nubia 37–39. Different distribution of different haplotypes was found between people living in Upper Egypt and those living in Lower Egypt (Delta region of the present study). This finding confirms the different ethnic origins of both Egyptian populations.
The serum level of CAT was lower and the serum level of MDA was higher in the studied sample of Egyptian vitiligo patients (P≤0.001). No correlations and relations were found between the CAT genotypes and serum levels of these markers or age of patients, disease extent, duration and activity. However, it is observed that the lowest level of CAT was with TT genotype of CAT 389 and the highest level of MDA was with AA genotype of CAT –89 (Tables 5–7).
Mehaney et al.13 reported a significant decrease in CAT levels and an increase in MDA levels in the serum of Egyptian vitiligo patients. Furthermore, Khan et al.40 reported a significantly higher MDA level in the serum of vitiligo patients from India. These results indicated that there is oxidative stress in vitiligo patients. The cause of CAT deficiency in patients with vitiligo may result from environmental conditions such as inhibitory levels of hydrogen peroxide in the epidermis of vitiligo patients 41,42.
Decreased CAT activity was found in the epidermis of vitiligo patients with subsequently higher sensitivity of melanocytes to oxidative stress 41. Low CAT levels may be due to inactivation by high concentrations of H2O2 and the effect of CAT gene polymorphism on the expression or function of CAT 43. The study by Liu et al. 12 on Chinese patients with vitiligo suggested that the −89AT genotype play an important role in protection from oxidative damage and individuals with higher CAT activity and AT genotypes have a minor risk for developing vitiligo.
The T allele of CAT 389 may be a susceptibility risk factor for vitiligo and the combined CCAT genotype may be protective in the studied sample of Egyptian patients. Decreased levels of CAT with increased levels of MDA may indicate increased oxidative stress in nonsegmental vitiligo patients. Further large and population-based studies are recommended to verify these results.
Conflicts of interest
There are no conflicts of interest.
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