Impact of vitamin D receptor gene polymorphisms on vitiligo susceptibility and clinical features in a Southeastern European Caucasian population
- Authors:
- Published online on: September 18, 2020 https://doi.org/10.3892/ijmm.2020.4732
- Pages: 1899-1907
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Copyright: © Katsarou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Vitiligo is the most common pigmentary skin disorder affecting 0.5-1% of the population worldwide. It is characterized by selective loss of epidermal melanocytes resulting in the occurrence of patchy depigmentation (1). Though not entirely clear, the pathogenesis of vitiligo is widely believed to reflect a complex interplay between genetic, immunologic, and environmental factors interacting to promote a model of melanocyte-directed autoimmunity (1-3). The current thought is that vitiligo is a multifactorial, polygenic disorder, suggesting that different genes may be involved in the onset and evolution of the disease (4).
Vitamin D has been shown to be involved in multiple biologic processes and pathways. Its role in human carcinogenesis, as well as in osteoporosis is well known (5,6). Given the effects of vitamin D against autoimmunity (7), a potential link between vitamin D deficiency and immune-mediated dermatoses, such as psoriasis and atopic dermatitis, has already been suggested (8,9). In this context, due to the stimulatory and protective action of 1,25(OH)2D3 on melanocytes, as well as its antioxidant and immunomodulatory properties, topical vitamin D and its analogs have been used as repigmentation agents in vitiligo, either alone or combined with other modalities, but reported outcomes have been conflicting (10,11).
Currently, great attention has also been focused on gene-disease associations, opening new perspectives for precision medicine (12,13). As the nuclear vitamin D receptor (VDR) mediates most of the genomic effects of 1,25(OH)2D3, VDR might represent a susceptibility gene for vitiligo (14).
The VDR gene, located on chromosome 12q13.11, has been found to contain more than 200 single-nucleotide poly-morphisms (SNPs) (15). Among these, the rs2228570 (Fokl), rs1544410 (Bsml), and rs731236 (Taql) have been widely studied. The FokI polymorphism, located at exon 2 initiation codon, might result in two forms of the VDR protein, i.e., a long (allele f) and a short (allele F) version, with diverse transcriptional capacity. The Bsml (in intron 8) and Taql (in exon 9) alleles occur in the 3′-untranslated region (3′-UTR) of the gene. Although allelic variations within or near the VDR locus could modify the VDR gene expression and protein function, their clinical relevance remains largely unknown (16,17).
So far, implication of VDR in vitiligo has not been thoroughly explored among Caucasians (16,18), although an association between VDR SNPs and immune-mediated skin diseases, i.e., psoriasis and atopic dermatitis, has been supported (19,20). Moreover, the majority of studies evaluating the influence of VDR polymorphisms on vitiligo susceptibility in certain population settings have reported inconsistent results (16), indicating that ethnicity might be a potential source of heterogeneity.
The current study investigated whether three common SNPs in the VDR gene (FokI, BsmI, and TaqI) may confer susceptibility to vitiligo and influence its main clinical features in a Southeastern European Caucasian (SEC) population.
Patients and methods
Patients and setting
In this single-center, case-control study, a total of 110 unrelated vitiligo patients (42 males, 68 females) with mean ± standard deviation (SD) age of 45.1±13.4 years (age range 18-70 years) were recruited as a case group at the Vitiligo Outpatient Unit of 'A. Sygros' Hospital, Athens, Greece, from October 2018 to November 2019. Inclusion criteria were: i) age ≥18 years; ii) clinically diagnosed vitiligo; and iii) SEC ancestry. First- to third-degree blood relatives were considered ineligible. A group of 509 SEC individuals from the general population (220 males, 289 females) with mean ± SD age of 40.5±11.3 years (age range 18-70 years) served as controls.
The study was conducted according to the principles outlined in the Declaration of Helsinki after obtaining ethics approval from the Institutional Review Board (protocol no. 3044/6-9-2018). All participants provided written informed consent for using their genetic data after de-identification and anonymization of the DNA samples, following the European Medicines Agency guidelines (EMEA/CPMP/3070/01).
Study assessments
Vitiligo was clinically diagnosed by experienced dermatologists after physical examination of the affected skin, often under the Wood's lamp. Clinical types of the disease were categorized as focal (one or few lesions in a non-dermatomal pattern), segmental (unilateral segmental distribution), acrofacial (limited to the face and/or distal extremities), generalized or vulgaris (scattered across the body), and universal (over 90% depigmentation), based on the latest criteria of classification (21). Stable vitiligo was defined as no appearance of new and/or progression of existing lesions for at least 1 year before inclusion in the study. Patients were considered to have i) early-onset vitiligo if the age at disease onset was prior or equal to 30 years, and ii) family history if they reported one or more first- to third-degree relatives affected by the condition.
Demographic and clinical disease-specific characteristics (i.e., age, sex, nationality, clinical type, age of onset, family history, duration of vitiligo, disease activity, presence of leukotrichia, Koebner phenomenon, and Sutton nevi, body surface area (BSA), and associated diseases) were retrieved for each patient via a predesigned questionnaire. Peripheral blood samples (5 ml) of all patients were collected in tubes containing ethylenediaminetetraacetic acid (EDTA).
DNA isolation, sample storage and genotyping
Whole blood samples were collected in 5 ml EDTA collection tubes followed by DNA isolation, using PureLink® Genomic DNA Mini kit (Thermo Fisher Scientific, Inc), according to the manufacturer's instructions. All DNA samples were stored in −20°C until genotyping.
Three polymorphisms of VDR [FokI (rs2228570), BsmI (rs1544410), and TaqI (rs731236)] were analyzed both in patients and controls. Genotyping was performed by qPCR (Light Cycler 480; Roche) using simple probes for each SNP (LightSnip Assays; TIBMOLBIOL) and melting curve analysis.
Statistical analysis
Descriptive statistics are presented as mean ± SD, or frequencies (numbers) with percentages (%), as appropriate. Distributions in genotype and allele frequencies in vitiligo cases versus controls were evaluated using the Chi-squared and Fisher's exact tests. The Hardy-Weinberg equilibrium (HWE) for each SNP was calculated among controls. ORs and 95% CIs, were used to investigate the association of the selected polymorphisms with clinical aspects and risk of vitiligo under five genetic models (allele, dominant, recessive, homozygous and heterozygous). All statistical tests were carried out using IBM SPSS Statistics version 22.0 (IBM Corp.). The significance level was set to P<0.05.
Results
Demographic and clinical data
The demographic and clinical disease-specific data of the case group are presented in Table I. Vitiligo vulgaris was the most common clinical form (n=84; 76.4%), followed by acrofacial (n=16; 14.5%), focal (n=7; 6.4%) and universal (n=3; 2.7%) patterns. The mean ± SD age at disease onset was 33.5±15.1 (age range 5-66 years), while vitiligo onset before 30 years of age was reported in 52 (47.3%) cases. Thirty-eight (34.5%) patients with family history of vitiligo were recorded. Koebner phenomenon, leukotrichia, and Sutton nevi were present in 45 (40.9%), 36 (32.7%), and 12 (10.9%) cases, respectively. Stable vitiligo was reported by 69 (62.7%) patients. Regarding comorbidities, thyroid disease was the most common associated disorder (n=50; 45.5%).
Associations between VDR SNPs and vitiligo phenotypes
Subgroup analyses of subsets of patients based on clinical features indicated a significant correlation between the VDR FokI and age at vitiligo onset (Table II). Both the CC geno-type and C allele of FokI SNP were overpresented in cases with vitiligo onset after the age of 30 compared to those with earlier disease onset (48.28 vs. 30.77%, P=0.041, respectively; 69.83 vs. 55.77%, P=0.031, respectively), conferring protection against early-onset vitiligo. Patients carrying the FokI CC genotype or C allele may thus be at lower risk for development of vitiligo up to 30 years of age compared to carriers of the FokI TT genotype or T allele, respectively (TT vs. CC: OR=0.286, 95% CI: 0.083-0.984, P=0.041; T vs. C: OR=0.545, 95% CI: 0.313-0.948, P=0.031).
 | Table IIGenotype and allele frequencies of VDR FokI polymorphism in vitiligo cases according to age at disease onset. |
For TaqI polymorphism, the variant C allele frequency was significantly higher in vitiligo cases devoid of leukotrichia compared to cases with concurrent leukotrichia (41.89 vs. 27.78%, P=0.042). Using the T allele as reference, the C allele was found to adversely affect the risk for occurrence of leukotrichia; TaqI C allele carriers were ~1.9 times less prone to develop leukotrichia compared to T allele carriers (T vs. C: OR=1.874, 95% CI: 1.018-3.451, P=0.042) (Table III). Either FokI, BsmI, or TaqI loci had no obvious correlation with other vitiligo-related clinical variables in our sample (data not shown).
| Table IIIGenotype and allele frequencies of VDR TaqI polymorphism in vitiligo cases according to presence of leukotrichia. |
Genotypic and allelic distributions of VDR polymorphisms.The genotype and allele frequencies of the selected VDR SNPs among cases and general population controls, as well as their associations with vitiligo susceptibility are summarized in Table IV. The relevant genotype frequencies were in accor-dance with the HWE equilibrium among the controls (P=0.909 for FokI; P=0.966 for BsmI; and P=0.970 for TaqI).
| Table IVGenotype and allele frequencies of selected VDR polymorphisms among cases and controls and their association with vitiligo risk. |
In overall analysis, no statistically significant differences between vitiligo cases and general population controls were observed for the VDR FokI, BsmI, and TaqI polymorphisms in any of the genetic models used, indicating a lack of association between the studied SNPs and susceptibility to vitiligo in this cohort.
A schematic diagram of study design and summary of results is provided in Fig. 1.
Discussion
This study investigated associations of the FokI, BsmI, and TaqI SNPs in the VDR gene with the risk of vitiligo and its clinical features. The results showed that the VDR FokI SNPs (CC genotype and C allele) seemed to reduce the risk of vitiligo onset until the age of 30, while the TaqI C allele may confer a lower risk for leukotrichia. Our data also showed that either FokI, BsmI, or TaqI loci are not involved in the occurrence and development of vitiligo.
To date, genetic studies have identified over 50 vitiligo susceptibility loci, emphasizing the importance of genetic factors in the onset and evolution of the depigmentation process (2,4). In this regard, a limited number of studies covering mostly Latin American, African, and Asian populations have previously examined the role of VDR gene polymorphisms in vitiligo (16,18,22-27), but the reported findings have been controversial and inconclusive (Table V). In addition, studies investigating the BsmI, TaqI, and FokI SNPs in vitiligo patients are fewer compared to those conducted on ApaI (18), making it more difficult to yield meaningful results, especially among Caucasian subjects.
| Table VCharacteristics of main studies on the effect of VDR gene polymorphisms (BsmI, FokI, and TaqI) on vitiligo risk. |
With respect to VDR SNPs effect on vitiligo phenotypes, two studies investigating the relationship of the VDR FokI, BsmI, and TaqI with clinical characteristics of vitiligo failed to demonstrate a link between the studied VDR SNPs and age at disease onset (22,26). In contrast, our intra-patient analysis showed that the VDR FokI SNPs could have a protective effect against early-onset vitiligo, as carriers of the CC genotype or C allele of FokI exhibited a 71.4% and a 45.5% decreased risk of developing vitiligo before the age of 30 compared to patients carrying the FokI TT genotype or T allele, respectively. Although not related to vitiligo per se, VDR FokI appears to delay the onset of vitiligo until the age of 30 and may thus be a potential biomarker providing prognostic clues for early detection of this condition.
In addition, using the T allele as reference, we observed a protective effect of the VDR TaqI C allele against leukotrichia. This finding contrasts with previous data demonstrating no association between the VDR FokI/BsmI/TaqI poly-morphisms and leukotrichia (22). Given that the active melanocytes located into the black hair follicles can serve as a main source of perifollicular repigmentation, the presence of leukotrichia is known to predict a poor response to traditional treatments, pointing towards a surgical solution (28-30). In this sense, it seems possible that the VDR TaqI might indirectly be implicated in treatment decision making despite its lack of association with vitiligo per se. Moreover, since the TaqI polymorphism is located in the gene's regulatory region (CpG site), leukotrichia also appears as a clinical feature that can be influenced not only by genetic regulation but also by epigenetic factors that may affect VDR expression levels (Fig. 2) (31).
Contrary to Ochoa-Ramírez et al (26), no correlation between the VDR BsmI and Koebner phenomenon was observed in our sample. Although, similar to prior studies (22,26), we could not reveal further associations between the studied VDR polymorphisms and other clinical manifestations of vitiligo, our findings underline the need for analyzing VDR variants according to disease-related clinical features in order to identify genetically-based subsets of patients that may benefit from personalized approaches to vitiligo diagnosis or treatment.
This study presents some limitations to consider. Apart from the relatively small sample size (110 cases), our analyses included data only from SEC subjects, thus making the results applicable only to this ethnotic group, especially considering that genetic variability differs within European populations (32-34). Moreover, investigations on other common VDR SNPs, such as the ApaI, as well as haplotype analysis was not conducted, thus limiting the acquisition of further genetic information. Regarding other clinical aspects, i.e., Sutton nevi, the limited data available did not allow us to analyze each feature separately, which might have influenced the results.
In conclusion, the current study provided evidence to support a potential implication of the studied VDR SNPs in the clinical course and treatment decision making of vitiligo. The FokI CC genotype and C allele seemed to play a protective role in early onset of vitiligo (≤30 years), while the TaqI C allele may reduce the risk for future development of leukotrichia. Moreover, no evidence was found to support an association between the VDR BsmI, TaqI, and FokI loci and vitiligo susceptibility in our cohort.
Even with limitations, this study will enrich the evolving field of vitiligo genetics, especially among SEC subjects, providing a reference for subsequent investigations in order to translate all genetically derived data into clinical applications for early diagnosis and individualized, precision treatment of vitiligo. Further research with larger sample sizes is needed to validate our results and elucidate whether the same associations are also eligible in vitiligo patients among other Caucasian populations or diverse ethnotic groups.
Funding
No funding was received.
Availability of data and materials
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
MSK, ND, EN conceived the presented idea, while DI and PS developed the whole theory. MSK designed the experiments and DI, ML, PS prepared the samples and performed the experiments. PS, EN, SM, MS, SG, AT and DR contributed to clinical data and sample collection. KX made the data entry and CD performed the statistical analyses. DI, MSK, PS, ND interpreted the results and designed the figures. PS, DI, AN and LK wrote the manuscript under the supervision of ND and EN, and DAS contributed to the final editing. All the authors discussed the results and contributed to the final manuscript.
Ethics approval and consent to participate
Written informed consent for participation in the study and use of their genetic data was obtained from all participants.
Patient consent for publication
Written informed consent for publication of any associated data was obtained from all participants.
Competing interests
DAS is the Editor-in-Chief for the journal, but had no personal involvement in the reviewing process, or any influence in terms of adjudicating on the final decision, for this article. The other authors declare that they have no competing interests.
Acknowledgments
We would like to thank GENOMED for providing anonymized and de-identified genotyping data of SEC individuals.
Abbreviations:
|
BSA |
body surface area |
|
CI |
confidence interval |
|
EDTA |
Ethylenediaminetetraacetic acid |
|
HWE |
Hardy-Weinberg equilibrium |
|
PCR |
polymerase chain reaction |
|
SD |
standard deviation |
|
SEC |
Southeastern European Caucasian |
|
SNPs |
single-nucleotide polymorphisms |
|
VDR |
vitamin D receptor |
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