Psoriasis is an immune-mediated inflammatory disease with a global prevalence of 2-3% (1,2). Chronic plaque or psoriasis vulgaris (PsV), the most common subtype, is a multifactorial condition involving complex genetic, immunologic and environmental interactions (1,2). Genetic studies have identified numerous PsV risk loci, primarily associated with immune pathways, inflammatory cascades and epidermal homeostasis, underscoring its polygenic yet partially elucidated genetic nature (3,4).

Vitamin D (VitD) has attracted attention in psoriasis research due to its pleiotropic effects on key psoriatic elements (5-9). Recent data further support a broader cutaneous VitD-related metabolome that may influence skin homeostasis and inflammation (10). VitD promotes keratinocyte differentiation while inhibiting proliferation, thereby counteracting the epidermal hyperplasia of psoriatic plaques (5,6). It also enhances skin barrier integrity by regulating cornified-envelope proteins, such as involucrin and loricrin, lipid synthesis and tight junction components, including claudins (5,7). Beyond its epidermal actions, VitD exerts anti-inflammatory and immunomodulatory effects, including the suppression of plasmacytoid dendritic cells (central initiators of psoriatic inflammation) and inhibition of the T helper (Th)-1/Th17 axis, downregulating associated cytokines (e.g., TNF-α, IFN-γ, IL-1, IL-2, IL-6, IL-8, IL-12, IL-17, IL-22 and IL-23) (5,6). In addition, VitD interferes with major psoriasis-related pathways, including NF-κB and JAK/STAT signaling, and also exerts anti-angiogenic activity, thereby mitigating neovascularization in psoriatic lesions (Fig. 1) (5,8,9).

Previous studies have reported a potential link between VitD deficiency and psoriasis, demonstrating inverse associations between serum VitD levels and disease risk or severity (5,11,12). In addition, altered VitD receptor (VDR) expression has been observed in psoriatic skin (5,7). From a therapeutic perspective, phototherapy, widely used in psoriasis management, may partly exert its effects by elevating serum VitD levels and/or upregulating VDR expression in lesional skin (5,13,14). Furthermore, VitD-based interventions have been shown to be beneficial in psoriasis. Although oral supplementation remains controversial across studies, topical VitD analogs are established treatment modalities (5).

Since the nuclear VDR is the main mediator of most biological actions of active 1,25-dihydroxy VitD₃ (5), the VDR gene has been investigated in relation to psoriasis (15). Located on chromosome 12q13.11, the VDR gene is highly polymorphic containing numerous single-nucleotide polymorphisms (SNPs) that may alter VDR expression or function (16-18). Among the most widely studied VDR variants are FokI (rs2228570; exon 2; +30920 C>T), near the start codon and BsmI (rs1544410; intron 8; + 63980 G>A) and TaqI (rs731236; exon 9; +65058 T > C) both in the 3'-untranslated region (3'-UTR) (16-18). FokI involves a T-to-C substitution that alters the translation initiation site (ATG to ACG), creating two VDR isoforms of different length (427 vs. 424 amino acids) and transcriptional capacity (17,18). The shorter isoform (associated with the C allele) is more transcriptionally active (16-19), potentially enhancing downstream VitD/VDR signaling. FokI is thus a VDR SNP that exhibits a functional impact on protein activity. By contrast, the 3'-UTR non-functional BsmI (G-to-A substitution) and TaqI (T-to-C transition) variants do not alter the protein structure but may influence VDR gene expression and protein levels by affecting mRNA stability, splicing patterns or through linkage disequilibrium (LD) with other functional polymorphisms within the VDR locus (16-19). Particularly for TaqI, its location within a CpG island, where allele-dependent methylation patterns (TT absent, TC partial and CC complete) have been described, could further modulate VDR expression in ethnic-, disease- or tissue/cell-specific contexts (17,19,20).

A number of studies have suggested potential associations between these VDR variants and psoriasis. However, the results have been inconsistent, even within certain populations, possibly due to ethnic genetic or epigenetic variation and/or differences in psoriasis clinical spectrum among cohorts, emphasizing the need for ethnically and clinically stratified research. In addition, associations between these VDR SNPs and psoriasis-related clinical features remain understudied and may benefit from phenotype stratification (15,16,21-23).

To the best of our knowledge, the impact of VDR FokI, BsmI and TaqI on psoriasis has not yet been studied in the Greek population. Given the ethnic variability in genetic polymorphisms (18) and the clinical diversity of psoriasis across studies, this study aimed to investigate the role of three common VDR gene variants, namely FokI (rs2228570), BsmI (rs1544410) and TaqI (rs731236), in PsV susceptibility and clinical phenotype in a Caucasian Greek cohort (Fig. 2).

In this study, the role of three common VDR variants (FokI, BsmI and TaqI) in PsV susceptibility and clinical phenotype was evaluated in a Caucasian Greek cohort. The case-control analysis supported an association between BsmI and PsV susceptibility in the recessive and allelic models, whereas no associations were observed for FokI or TaqI. Subgroup comparisons further indicated associations with major disease-related clinical traits, including age at onset, nail or joint involvement and familial clustering.

For BsmI, carriers of the AA genotype exhibited a 42.3% reduced risk of PsV compared with G-allele carriers (GA/GG). The allelic model further supported this pattern, demonstrating a protective effect of the A allele against PsV. The BsmI variant has already been associated with psoriasis, but findings vary by ethnicity (21,23,26,27). The present results align with case-control studies and meta-analyses indicating a protective role of the A allele and/or AA genotype in Caucasian and Asian populations (21,23,27). In this context, a Japanese study reported increased PsV risk for the GG genotype, while the A allele and AA genotype appeared protective (27). Two meta-analyses supported this trend, demonstrating an inverse association between the A allele and PsV risk in overall populations, although significance was lost after correction and in Asian populations, despite undefined psoriasis subtypes and precluded intra-European evaluation (21,23). However, additional studies have found no association or even opposite effects (15,22,28).

In this context, the present data suggest that among the studied VDR variants, BsmI may represent a PsV susceptibility-related marker in the Greek population. From a biological perspective, this 3' non-coding variant may be associated with regulation of VDR expression (i.e., via altered mRNA stability and/or LD with functional polymorphisms), rather than receptor structural changes (16-19). Altered VDR expression may, in turn, affect VitD/VDR-mediated signaling relevant to PsV pathogenesis, given the roles of VitD in key processes involved in psoriatic inflammation, including keratinocyte proliferation/differentiation, epidermal barrier function and immune responses (5-9). However, further research is needed to determine whether rs1544410 itself has regulatory effects or reflects other functional variants, particularly given population and/or ethnic differences in LD architecture (18).

Both FokI and TaqI showed no impact on PsV susceptibility in the present cohort. Although findings vary among populations (15,21-23,28), a number of studies in Caucasian, Asian and North African (Egyptian) groups have similarly reported no association between these variants and PsV risk (21,29-34). Divergent results across studies may reflect differences in ethnic or population genetic backgrounds, including LD structure, as well as in epigenetic variation, environmental exposures or methodological factors such as study design, sample size or psoriasis subtype composition (18).

Intra-patient analyses indicated additional phenotype-specific associations. Among PsV cases, FokI appeared to be associated with age at disease onset under the dominant and allelic models. In the dominant model (TT + TC vs. CC), T-allele carriers (TT/TC) exhibited a nearly 2.6-fold increased risk of early-onset PsV (<40 years). This was further supported by the allelic model (T vs. C), indicating that the FokI T allele may predispose to earlier disease onset. Although age-at-onset effects of VDR SNPs have been explored (33-42), only one study has shown an association between the BsmI GG genotype and early-onset disease (<40 years) in a Caucasian (Turkish) cohort of mixed psoriasis subtypes (n=102) (37).

FokI was also associated with familial psoriasis under the recessive model (TT vs. TC + CC). Patients with PsV carrying the TT genotype were nearly 6.8 times more likely to report an affected first- to third-degree relative compared with C-allele carriers (TC/CC), suggesting that FokI may play a role in heritable patterns of psoriasis. Although not directly comparable, a study in a Caucasian (British) PsV cohort (n=205) found that the FokI C allele combined with a promoter variant reduced the risk of non-familial (sporadic) psoriasis (34). Since that effect was haplotype-dependent, the present finding may represent one of the first single-variant indications that FokI itself could contribute to familial clustering of psoriasis.

Notably, the FokI TT genotype in this cohort seemed to be associated with both early-onset PsV and familial disease, features that frequently co-occur clinically, as early-onset psoriasis tends to cluster in families (43). Mechanistically, FokI (T-to-C substitution) alters the translation initiation site (ATG to ACG), resulting in a longer, less active VDR isoform in T allele carriers (16-19), which may impair downstream VitD/VDR-mediated effects on skin homeostasis and immune responses. Thus, compromised VitD/VDR signaling in TT homozygotes may reflect a genetic overlap, potentially involving FokI, which could contribute to both familial aggregation and early disease onset. This aligns with the known clinical tendency of early-onset PsV to cluster in families (43), but requires further validation.

Significant associations were also observed for nail psoriasis with both BsmI and TaqI under the dominant and allelic models. In the dominant model, carriers of the BsmI A allele (AA/GA) and the TaqI C allele (CC/CT) exhibited a ~2.8- and ~3.1-fold increased risk of nail involvement, respectively. The allelic models also indicated higher risk of nail disease for both the BsmI A and TaqI C alleles. This contrasts with an Asian (Korean) PsV cohort (n=104) in which neither variant was associated with nail psoriasis (40).

TaqI was further associated with PsA comorbidity under the allelic model (C vs. T), indicating that the C allele may protect against joint disease in this cohort. Although relevant data are limited (40,44,45), a Caucasian (Turkish) study (n=51) has similarly shown an association between the TaqI T allele and increased PsA risk (44). These findings suggest that TaqI may influence extra-cutaneous manifestations of PsV, modulating the overall disease burden beyond the skin.

Of note, while the BsmI A allele seemed to be protective in the present case-control setting, it was associated with nail involvement among PsV cases. This pattern may indicate phenotype-modifying effects after disease onset. Although the functional impact of VDR variants on VitD signaling remains unclear, both BsmI and TaqI may exert tissue- and/or cell-specific regulatory effects on VDR expression (18,19), potentially influencing phenotype-specific inflammatory cascades involved in nail psoriasis. In addition, as the TaqI C allele creates a CpG site prone to DNA methylation (17,19,20), the present findings suggest that, in addition to genetic variation, epigenetic modifications at this locus may underlie tissue-specific inflammation, with possible implications for both nail and joint disease.

Furthermore, the TaqI C allele in this cohort was associated with both psoriatic onychia and arthritis, two clinically related features, but with inverse effect patterns. While nail involvement often predicts increased arthritis risk (1,46), the C allele appeared to be protective against PsA while predisposing to nail disease. These divergent effects within the nail-joint axis may arise from distinct genetic and/or epigenetic drivers, including differences in the genetic architecture of cutaneous vs. joint disease (1,47) and in allele-dependent TaqI methylation (17,19,20), potentially resulting in tissue-specific VitD/VDR signaling. As methylation status varies by ethnicity, disease state or tissue type (17,19,48), TaqI may exert phenotype-specific effects driven by context-dependent epigenetic regulation. This warrants further investigation within the nail-joint spectrum of psoriatic disease.

Key strengths of the present study include the focus on a single ethnic group (Greek subjects) and a specific psoriasis subtype (PsV), reducing genetic and phenotypic heterogeneity. The relatively large control group (n=812; 1:4 case-control ratio) is also an advantage compared with commonly used 1:1 or 1:2 designs in genetic association studies (15,22,23,28). In addition, the inclusion of several clinical traits, beyond case-control comparisons, provides insights into whether VDR variation may contribute to PsV phenotype. The FDR correction for multiple testing further improves the reliability of the results.

However, certain limitations require consideration. First, the PsV sample (n=203) is relatively modest for detecting subtle effects. Second, although the single-center, ethnically and clinically uniform design enhances internal validity, it may limit the generalizability of the present findings to other psoriasis subtypes or populations with different genetic, epigenetic or environmental backgrounds. In addition, while cases and controls were matched on age, sex and ethnicity, the population controls lacked detailed clinical and exposure data, preventing detection of psoriasis status or potential confounders. However, given the national psoriasis prevalence in Greece (~2.2%) (2,49), the expected number of psoriasis cases among 812 controls is low, reducing, but not eliminating, the risk of misclassification. Furthermore, only three VDR SNPs were analyzed, without investigating rare variants or haplotypes. Finally, VitD-related confounders (VitD serum levels, dietary or supplemental intake, sun exposure), which could influence VDR activity, were not assessed.

While VDR has not emerged as a psoriasis susceptibility locus in genome-wide association studies (GWAS) (3), several lines of evidence still support its biological relevance, including the role of the VitD/VDR axis in key psoriatic components, altered VDR expression in psoriatic skin, the widespread use of topical VitD analogs in psoriasis treatment, variable but suggestive associations for FokI, BsmI and TaqI in prior studies and the potential epigenetic regulation at the TaqI CpG site (5-9,15-17,19-23). Emerging data also indicate additional cutaneous VitD-related bioactive metabolites, some with alternative receptor targets, underscoring the broader secosteroid network in the skin (10). By design, GWAS, which apply stringent significance thresholds and often treat psoriasis as a single trait across diverse clinical and ethnic backgrounds, could miss variants with small-to-moderate or indirect effects influenced by LD patterns and/or ethnic-, disease subtype- or epigenetic-related factors (19,50,51). Thus, the associations observed in the present genetically and clinically uniform cohort could reflect ethnic- and/or phenotype-specific VDR effects that may be too weak to be captured in GWAS (19).

In conclusion, to the best of our knowledge, this was the first study to explore VDR FokI (rs2228570), BsmI (rs1544410) and TaqI (rs731236) variants in association with PsV in a Greek population. The present results showed that BsmI may contribute to disease susceptibility, while all three polymorphisms may influence major clinical traits, including age at onset, nail or joint involvement and familial clustering of PsV.

Although the functional consequences of these variants are not fully elucidated, VDR genetic variation and epigenetic modification may alter receptor activity or expression levels, potentially modulating key processes disrupted in psoriasis. In this regard, the present findings suggest that common VDR variants may exert small, context-dependent effects that could play a role in PsV initiation and phenotypic expression. Thus, the VDR locus may represent a potential biomarker for personalized risk stratification and clinical profiling in PsV. Further prospective studies in larger Caucasian cohorts, integrating both genotypic and phenotypic data, are needed to validate these findings and further elucidate the complex genetic basis of PsV, particularly its links to VitD/VDR signaling and its potential clinical implications.