Multiple sclerosis is a demyelinating neurodegenerative autoimmune illness. Motor dysfunction, autonomic symptoms, and psychbehavioral aspects of MS include gait difficulties, paresthesia, visual issues, vertigo, incontinence, sexual problems, pain, cognitive dysfunctions, emotional disturbances, and depression. MS biomarkers and gene variants certainly may be able to help identify various stages of MS and build personalized treatment plan [30, 31].

This study aimed to investigate the association between the VDR c.1056A > G and c.1025-49C > A SNVs and susceptibility to MS in a group of Egyptian population which is an important point provides insights into the potential role of vitamin D in preventing inflammatory disorders and its impact on clinical outcomes. The findings of the study could have implications for the treatment and prevention of MS in Egypt. Our results revealed that there was an increase in the G allele in the MS group, which was suggested to be the risky allele; however, this difference did not reach statistical significance in VDR c.1056A > G (rs731236). On the other hand, in VDR c.1025-49C > A (rs7975232), the variant allelic distribution of the A allele, which was supposed to be the risky allele, was increased in the MS group but did not reach statistical significance. The genotype distribution in both variants showed no significant relation to MS pathogenesis. Most of the published work agreed with part of our data and disagreed with others.

Regarding the VDR c.1056A > G genotype distribution analysis, in agreement with our results, Mazrouei-Arani et al. (2022) conducted a study on 101 MS patients and 101 healthy subjects in the Iranian population, and Moosavi et al. (2021) conducted a study on 160 MS patients and 162 healthy personnel and found that the genotype frequency of VDRc.1056A > G did not differ between the patients and controls (P = 0.348 and P = 0.092, respectively) [1, 18]. Additionally, Hassab et al. (2019) and Zayed et al. (2019) (in which 50 and 63 Egyptian MS patients were recruited, respectively) revealed no statistically significant association between MS and VDRc.1056A > G (P = 0.945 and P = 0.845, respectively) [22, 32].

In other studies, conducted on the Turkish population, there was nostatistically significant difference between 167 MS patients and 146 healthy controls, and between 70 MS patients and 70 healthy controls, respectively [33, 34]. Additionally, Zhang et al. (2018) conducted a meta-analysis which included 24 case–control studies with a total of 4013 cases and 4218 controls and found that the association between the VDRc.1056A > G variant and MS was not significant under dominant, recessive genotypes, and allele contrast (P = 0.078, P = 0.314, and P = 0.127, respectively) in overall populations [35]. Similarly, Imani et al. (2019) conducted a meta-analysis with a total of 30 case–control studies and detected no significant association across different genotype models [18].

In contrast to our findings, Al-Temaimi et al. (2015) found that the genotype distribution of Kuwaiti VDR c.1056A > G in 50 MS patients was significantly different from that of 50 healthy controls (P = 0.0008) [21].

In addition, Mohammadi et al. (2020) discovered a statistically significant negative relationship between the VDR c.1056A > G variant and risk of MS in the homozygote A/A genetic model (OR = 0.28, 95% CI: 0.08–0.9; P = 0.04) [36]. Additionally, Abdollahzadeh et al. (2018) found that the homozygote G/G genotype carriers for the VDR c.1056A > G variant have a predisposition to MS (OR = 2.18, 95% CI = 1.05–4.52) [37]. Furthermore, Zhang et al. (2019) conducted a meta-analysis, which included 27 case–control studies with 4879 MS patients and 5402 controls and observed that the G/G genotype is associated with the risk of MS (OR = 0.76, 95% CI = 0.62–0.94) [38].

Concerning the allelic distribution, similar to our findings, Mohammadi et al. (2020) conducted a meta-analysis which showed that in allelic comparison, no statistical association between allele G and risk of MS was found in 1206 Iranian patients (P = 0.07) [36].

However, Moosavi et al. (2021) found that the G allele was more prominent in 160 MS patients than in the 162 control individuals, increasing the risk of disease susceptibility by 1.6 times (OR = 1.6, P = 0.0232) [1]. According to Abdollahzadeh et al. (2018), the G allele had a positive correlation with MS (OR = 1.98, 95% CI = 1.36–2.87; P = 0.003), while the A allele had a negative association (OR = 0.51, 95% CI = 0.39–0.73; P = 0.003) [36]. Additionally, Al-Temaimi et al. (2015) demonstrated that the G allele was associated with MS risk (OR = 1.7, 95% CI = 1.2–2.4; P = 0.003) [21].

Regarding the VDR c.1025-49C > A genotype distribution analysis, in agreement with our results, many studies and meta-analyses done on Turkish and Iranian populations have agreed with our results, showing no evidence of an association between VDR c.1025-49C > A and MS risk [17, 35, 37, 38].

In contrast to our findings, a statistical analysis of a study done by Mazrouei-Arani et al. (2022) revealed a significant association between VDR c.1025-49C > A genotypes and MS disease (P = 0.05), showing that MS patients had an A/A genotype 2.54 times higher than the CC genotype (OR = 2.54, P = 0.029) [18].

Upon evaluating the genotypes by Cetinel et al. (2021), a statistically significant correlation was found with VDRc.1025-49C > A A/A, C/C, and A/C (P < 0.01, 0.01, and P < 0.01, respectively) in the SPMS group and with VDR:c.1025-49C > A A/A and A/C genotypes (P = 0.01 and 0.04, respectively) in the PPMS group, but no significant difference was found in the genotypes within the RRMS group [16].

In a meta-analysis study conducted on 1206 cases and 1402 controls, a statistically significant association was also found between the VDR c.1025-49C > A homozygote genetic model of A/A and G/G and the risk of MS (OR = 3.48, 95% CI = 1.7–6.9; P = 0.00) [36]. Additionally, Zhang et al. (2019) performed a meta-analysis revealed a significant association between the VDRc.1025-49C > A variant and MS risk in Asians in the recessive model C/C genotype (OR = 0.66, 95% CI = 0.53–0.82; P = 0.0002) [37].

Regarding the allelic distribution, like our findings, Imani et al. (2019) meta-analysis showed no statistically significant difference in allelic discrimination [17].

However, Mohammadi et al. (2020) meta-analysis showed a statistically significant relationship between the A allele and decreased risk of MS in Iran (OR = 0.54, 95% CI = 0.37–0.79, P = 0.00) [36]. Additionally, Hassab et al. (2019) study detected a statistically significant association between the A allele and MS cases (OR = 2.47, 95% CI = 1.25–4.88, P = 0.008) [22]. Furthermore Zhang et al. (2018) conducted a meta-analysis which observed that the A allele was associated with MS risk in Asian populations (OR = 1.267, 95% CI = 1.074–1.496; P = 0.005) [35].

The contradictory results of the studies may be because; small sample sizes, differences in ethnicities, extensive geographic variation, interactions with other genetic or environmental factors, and/or clinical heterogeneity.

The significance of this manuscript is that it presents a research study that looks into the relationship between VDR gene variants and MS in the Egyptian population. The study analyzes genetic data using TaqMan Real-Time Polymerase Chain Reaction (PCR) which is accurate method and provides insights into the potential role of vitamin D in preventing inflammatory disorders and its impact on clinical outcomes. The findings of the study could have implications for the treatment and prevention of MS in Egypt. The research adds to the body of knowledge on the subject and may help guide future research and clinical practice. It is recommended that the results obtained by this study be studied on a wider scale with a larger sample size, taking into consideration the presence of different ethnicities. It is also advised that other single nucleotide variants (SNVs) of the vitamin D receptor (VDR) affecting multiple sclerosis (MS) should be studied. This will help in clarifying the genetic role in the development of MS and achieving more accurate results.