Prostate cancer (PCa) is the fifth most common cause of death worldwide and the second most common cancer in men [1, 2]. As well as it remains the second leading cause of cancer death worldwide and the most frequently diagnosed type of cancer in men [3]. It was reported that 1,414,259 men were diagnosed with PCa and 375,304 died of PCa worldwide in 2020 [4]. In Morocco, PCa is the most common cancer in men aged over 50, with a proportion of 12.4% after lung cancer, according to the cancer registry [5]. It remains the most important cancer in terms of incidence and mortality, it represents the leading cause of cancer mortality in men aged over 70 [6]. Genetic factors and many other risk factors are associated with a higher risk of developing PCa [7]. Alcohol consumption and smoking are considered well-established environmental risk factors for this cancer [8]. The causality of PCa is still not well explained, although genetic polymorphisms may play an important role in the genesis of this disease.

Vitamin D, the active form of which is 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], has been indicated as an important prohormone involved in the risk of PCa and in several actions, including its antiangiogenic, antiproliferative, and apoptotic effects [9, 10]. Previous studies have discovered that normal and malignant prostate cells contain vitamin D receptors (VDR) that initiate the antiproliferative action of 1,25(OH)₂D₃ [11, 12]. Thus VDR, coded by the VDR gene located on chromosome 12q13.1 has been considered as a ligand-dependent transcription factor [13, 14]. It has also been shown that serum levels of 1,25(OH)₂D₃ can affect the proliferation and differentiation of prostate tumor cells [15, 16]. VDR has been studied in relation to the pathogenesis of PCa. High VDR expression in clinical PCa samples is linked to a lower risk of fatal cancer. This suggests that the vitamin D pathway plays an anti-oncogenic role in the progression of PCa [17]. Consequently, any modification of the VDR can cause an increase in the incidence of PCa [18], the VDR gene includes several allelic variations that have been epidemiologically associated with the etiology of PCa [19]. The most common single nucleotide polymorphisms (SNPs), including BsmI and TaqI, have been identified as impacting the expression and function of VDR protein, which has been linked to PCa [20–22]. VDR genetic polymorphisms have also been linked to PCa progression [23]. Environmental and physiological factors are also involved in the metabolism of the vitamin D, including levels of exposure to ultraviolet light, skin color, and genes involved in the synthesis and metabolism of vitamin D, which may be involved in the risk of PCa [24, 25].

Genetic variety is crucial for promoting the development of more sophisticated genes, safeguarding existing populations, advancing evolutionary processes, and enabling adaptation to changing conditions in the natural environment [26, 27]. Conversely, the identification of gene polymorphisms is crucial in the process of detecting and treatment of diseases [28, 29]. On the other hand, determination of gene polymorphism is important in characterizing of various populations [30] in order to define genotypes of individuals and their associations with immune system, resistance, or susceptibility to cancers [31]. Genetic studies have analysed the relationship between PCa risk and VDR polymorphisms [22, 32, 33], several of which have suggested statistically remarkable associations [22, 33], and others have detected the absence of association [21]. Others have reported an association between VDR SNPs and prostate-specific antigen (PSA) level, Gleason score, and consequently PCa risk in men [20]. Additionally, polymorphisms in the 3' untranslated region (UTR), including the ApaI and TaqI sites, have been shown to affect gene transcription and mRNA stability [18]. It is assumed that the differential carriage of these SNPs has an effect on the transcriptional activity of the VDR and on the risk of cancer. Which normally manifests itself following the activation of target genes via the vitamin D responsive element (VDRE) when the active metabolite 1,25(OH)₂D₃ binds to the VDR. Although numerous studies have explored the relationship between VDR gene polymorphisms and PCa risk, the findings have been inconsistent across different populations [20–22]. While some studies have reported significant associations between ApaI, BsmI, and TaqI polymorphisms and PCa, others have found no correlation [23]. Moreover, most of these studies have been conducted in European and Asian populations, with limited data available on African and North African populations, including Morocco. Additionally, while previous research has largely focused on the association between VDR polymorphisms and PCa risk, few studies have investigated their potential impact on clinicopathological features such as PSA levels, tumor stage, Gleason score, and smoking status. Our research addresses this knowledge gap by providing the first comprehensive analysis of VDR gene polymorphisms (ApaI, BsmI, and TaqI) in Moroccan men with PCa, assessing not only their potential role in cancer susceptibility but also their associations with clinicopathological characteristics.

This case-control study aimed to evaluate the association between the investigated VDR polymorphisms (BsmI, ApaI, TaqI) in PCa patients in the Moroccan population in association to clinicopathological features.

Our results show that the average age was 69.8 ± 9.08 and 69.4 ± 9.01 years in PCa patients and control subjects, respectively. Additionally, the average PSA level among cancer patients was significantly higher compared to that in the controls (1.8 ± 1.4 ng/mL), p = 0.037 (Table 2).

Table 3 presents the genotypes and their frequencies according to the Hardy-Weinberg equation of the alleles of the polymorphisms of the VDR gene digested by (BsmI, ApaI, TaqI) enzymes in participants with PCa and in controls. A significant association was observed between the ApaI and TaqI polymorphisms and the risk of PCa (p = 0.045 and p = 0.029, respectively), while no association was found for the BsmI polymorphism (p = 0.927).

The BB genotype of BsmI SNP was present in 16% of PCa patients compared to 30% of healthy controls, whereas the bb genotype was found in 46% of PCa patients and 42% of controls. The estimated OR for PCa occurrence compared to controls for the BsmI polymorphism was 0.952 (95% CI: 0.226–4.01, p = 0.947).

The ApaI polymorphism showed a significant association, with the aa genotype being less frequent in PCa patients (14%) compared to controls (26%), and an OR of 5.33 (95% CI: 1.16–24.6, p = 0.024). Similarly, for the TaqI polymorphism, the tt genotype was present in 14% of PCa patients and 19% of controls, and the Tt genotype was 45% among the cases and 27% in the control group, with an OR of 4.63 (95% CI: 1.09–19.7, p = 0.031).

Table 4 illustrates the association between patient demographic and behavioral parameters with VDR genotypes. A significant relationship was found between the ApaI polymorphism and smoking status in PCa patients (p = 0.023). However, no SNPs showed associations with alcohol consumption in PCa patients.

Further analysis examined the correlation between VDR genotypes and clinicopathological features in PCa patients (Table 5). A significant association was observed between the BsmI SNP and PSA levels (p = 0.045), where 67% of cases had PSA levels higher than 10 ng/mL, including 31 (46.3%) with the bb genotype. The Gleason score was significantly associated with the ApaI polymorphism (p = 0.049), as 31 (42.5%) of the study population had a Gleason score > 7, with 48.4% of them carrying the Aa and Tt genotypes. A total of 21 patients presented with advanced pathological stage T (T3 and T4), distributed respectively 8% and 13%, and most of them carried the TT genotype. The TaqI polymorphism was significantly associated with pathological T stage (p = 0.042), with most patients carrying the TT genotype. Additionally, a strong association (p = 0.013) was found between surgical history and the TaqI SNP, with the majority (38.5%) of patients carrying the TT genotype.

Vitamin D deficiency is common in the general population worldwide. The metabolically active form 1,25(OH)₂D₃ of vitamin D exerts its actions through interaction with the VDR. Severe vitamin D deficiency with a 25(OH)D concentration below < 30 nmol/L (or 12 ng/mL) dramatically increases the risk of excess mortality [37]. Moreover, a low vitamin D status is associated with an increased risk of various cancers, including PCa [37]. It was the anticancer effects of vitamin D that drew attention to investigate the VDR gene polymorphism. Studies on the relationship between VDR mutations and PCa conducted in several populations have yielded conflicting results, ranging from statistically significant associations to no correlation [32, 38–40]. Many other studies have linked common genetic variations in the VDR gene (ApaI, BsmI, FokI, and TaqI) to increased risk of PCa. VDR SNPs at the 3' end of the gene were associated with a 3- or 4-fold increased risk of PCa in two preliminary studies [40]. ApaI, BsmI, FokI, and TaqI polymorphisms could influence VDR expression by altering mRNA stability; they are located in the 3' UTR region of the VDR gene with strong linkage disequilibrium, which explains why they are sometimes studied together in haplotype analysis [41, 42].

Our research revealed significant associations between the ApaI and TaqI polymorphisms of the VDR gene and the risk of PCa (p = 0.024; OR = 5.33; 95% CI: 1.16–24.6), (p = 0.031; OR = 4.63; 95% CI: 1.09–19.7), on the other hand, the BsmI polymorphism does not show any significant association. This finding is compatible with a number of previous research conducted in a population of African men, which found that PCa risk was strongly correlated with the TaqI (rs731236) and ApaI (rs7975232) SNPs (p < 0.05) [43]. Also the BsmI SNP is associated with the PSA level (p < 0.05) which also agrees with our results (p = 0.045), which is consistent with a study showing that decreased vitamin D status correlates with PSA levels in men with PCa [44], and that there is no correlation between the two parameters in healthy men [45]. Similarly, a recent meta-analysis revealed that TaqI polymorphism of VDR in the Asian population may be related to PCa risk [46]. Nevertheless, a meta-analysis of 17 studies investigating TaqI, BsmI, poly-A, and FokI polymorphisms in exon 2 concluded that none of these variants was likely to be a significant predictor of cancer risk of the prostate [47]. These associations suggest that these two polymorphisms (ApaI and TaqI of the VDR gene) may play a role in the genetic predisposition to PCa. More specifically, the Aa genotype of the ApaI polymorphism and the Tt genotype of the TaqI polymorphism were more frequent in patients with PCa, with significant OR, suggesting an increased risk of cancer associated with these genotypes, located in exon 9, which encodes the ligand-binding domain of VDR. These observations are consistent with other studies that have also suggested links between VDR gene polymorphisms and PCa risk [48]. However, other work has revealed no correlation between these SNPs and cancer risk of prostate [49, 50].

Our results found associations between BsmI and TaqI polymorphisms with clinical features of PCa, such as PSA level, Gleason score, and pathological T stage. These associations suggest that VDR gene polymorphisms may have an influence on the progression and clinical presentation of PCa. The strong association between TaqI polymorphism and patients’ surgical history is also notable (p = 0.013), this could indicate that this polymorphism is linked to a clinical course that requires surgical intervention. Additionally, ApaI polymorphism was significantly associated with tumor Gleason score (p = 0.049), which is an indicator of PCa severity. The significant association (p = 0.023) between the ApaI polymorphism and smokers within the PCa group raises interesting questions about the interaction between genetic and environmental factors in the development of PCa. This highlights the importance of considering behavioral risk factors in conjunction with genetic variations.

Nevertheless, this investigation is subject to numerous limitations. The small sample size is one of the main limitations, which could have impacted the statistical power of our findings. Furthermore, the study’s focus on genetic profiling of VDR polymorphisms, while informative, did not delve deeply into the underlying biological mechanisms. Additional mechanistic research is required to explore how these polymorphisms affect VDR expression and its downstream effects in PCa cells.