Multiple Sclerosis: is strongly related to poor Vitamin D receptors – umbrella review Oct 2024

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Vitamin D in Multiple Sclerosis: A Comprehensive Umbrella Review

The Journal of Nutrition Available online 5 October 2024 https://doi.org/10.1016/j.tjnut.2024.10.004 PDF behind paywall

Background
Multiple sclerosis (MS) is an inflammatory neuro-immune disease with a multifaceted etiology and long-lasting adverse effects. Several studies have explored the role of 25-hydroxyvitamin D (25(OH)D) serum levels, vitamin D receptor (VDR) gene polymorphisms, and vitamin D supplementation (VDS) in individuals with MS.

Objective
The aim of this study was to evaluate the relationship of MS with 25(OH)D serum levels, VDR gene polymorphisms, and VDS.

Methods
We assessed relevant papers published in PubMed, Scopus, and Web of Science from the inception up to February 24, 2024. Meta-analyses that investigated the link of 25(OH)D serum levels, VDR gene polymorphisms including Apal (rs7975232), BsmI (rs1544410), Taql (rs731236) and Fokl (rs10735810), and VDS with the risk and clinical manifestations of MS were included. The methodological quality of selected papers was assessed by the Assessment of Multiple Systematic Reviews version 2 (AMSTAR 2). The statistical analysis of this umbrella review was carried out using RStudio version 2023.03.1 and R version 4.3.2, simultaneously.

Results
23 out of 304 records were entered into this umbrella review with a pooled sample size of 37,567 participants. Eleven papers were rated as high quality, one was moderate quality, one was low quality, and ten were critically low quality. The homozygote model of FokI (FF+ff vs. Ff) was significantly associated with an 8% reduction of MS risk (OR: 0.92, 95% CI: 0.86, 0.98; I2= 0%, P>0.99).

Conclusion
According to existing clinical evidence, the risk of MS may be associated with VDR gene polymorphism. Further studies are needed to explore the association of MS and vitamin D.

Introduction
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is prevalent throughout the world. MS is primarily an inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to damage of myelin and axons [1]. It is one of the most common neurological diseases that lead to disability in young adults [2]. Environmental factors and genetics play crucial roles in disease incidence [3]. Environmental factors such as duration and intensity of sunlight exposure, birth latitude, and serum vitamin D (VD) level correlate with MS incidence 4, 5, 6.
VD is an environmental factor with immunomodulatory and anti-inflammatory effects 7, 8. Besides its role in proliferation, differentiation, and immunomodulation, VD has also been shown to play a role in the development and function of the brain 8, 9. VD deficiency has been proposed to be associated with MS through multiple mechanisms, including lower 25-hydroxyvitamin (25(OH)D) levels in MS patients [10]. Evidence from extensive prospective epidemiologic studies suggests that individuals with lower VD levels have a significantly higher risk of developing MS compared with those with levels between 99.2 and 152.9 nmol/L 10, 11. Also, low blood levels of 25(OH)D have been reported in 50 to 70% of MS patients 12, 13, 14. Although VD supplementation (VDS) may not benefit MS [15], Hiremath et al. found that high-dose ergocalciferol supplementation significantly elevated 25(OH)D levels in MS patients. Also, high-dose VDS can increase VD serum levels more than low-dose supplementation [16]. However, Feige’s findings indicate that mega-dose VDS may mimic progressive MS symptoms, including fatigue, muscle weakness, and urinary dysfunction. Mechanistically, these symptoms are reported to be caused by hypercalcemia disrupting normal cellular functions and energy metabolisms, affecting muscle contraction and nerve function, and leading to increased urine production and potential kidney damage, resulting in urinary frequency, urgency, and other dysfunctions, respectively [17].
VD exerts its effects in cells through the VD receptor (VDR), a nuclear transcription factor to which it binds via the carboxyl-terminal ligand-binding domain. The VDR molecule belongs to a large class of nuclear receptors, including thyroid, steroid, and retinoic acid receptors 18, 19. VDR gene polymorphisms can influence the binding efficiency of VD to its receptor, which in turn affects the expression of various genes regulated by VD. These genes are involved in immune modulation and inflammatory responses 20, 21. VDR polymorphisms can affect neurological functions by influencing the re-myelination process and neural plasticity, which are crucial in MS [20]. Immunologically, these polymorphisms can modulate the activity of immune cells, potentially affecting the body’s response to infections and autoimmune conditions [21]. The human VDR gene is located on chromosome 12q13.11, and a series of restriction fragment length polymorphisms (RFLP) in the human VDR gene have been reported, containing BsmI (rs1544410), ApaI (rs7975232), FokI (rs2228570), and TaqI (rs731236) restriction sites [22]. It has been shown that ApaI, BsmI, and TaqI are in strong linkage disequilibrium (LD) near the 3′ untranslated region (UTR) of the VDR gene between exons 8 and 9 [23]. The 3′-UTR of the VDR gene is involved in gene expression regulation by regulating mRNA stability and expression level [24]. Taql and Bsml recessive alleles have been associated with acute and chronic inflammatory diseases and may influence individual responses to VDS 25, 26. Moreover, Maternal FokI FF genotype has been associated with a lower risk of both maternal and neonatal VD deficiency [27]. Several studies have investigated the association between MS and single nucleotide polymorphisms (SNPs) in the VDR gene. Particularly, studies have evaluated associations between common SNPs of the VDR gene (TaqI, ApaI, FokI, and BsmI polymorphisms) and MS. While some studies found these SNPs to be associated with MS 28, 29, 30, others failed to find such associations 31, 32, 33. Polymorphisms in the VDR gene, such as TaqI, ApaI, and FokI, have been associated with MS risk. These polymorphisms may alter the receptor’s finction, impacting the immune system’s ability to regulate inflammation and repair processes 20, 21. For example, the TaqI polymorphism has been linked to better functional recovery in MS patients undergoing rehabilitation [20].
Since VD findings are still controversial, we designed this umbrella review. In this review, we evaluate different aspects of VD in MS. We consider serum level, supplementation, and gene polymorphisms of VDR.

Section snippets
Method
Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) recommendations were utilized for reporting screening and selection evaluation phases [34]. The protocol of present umbrella review was registered in PROSPERO (ID: CRD42024521541).

Study selection
The current umbrella review includes meta-analyses and systematic reviews that were published between 2012 and 2024. As illustrated in Figure 1, in the initial advanced search, 304 selected papers were retrieved, from which 82 papers were omitted due to duplication. In the title/abstract screening phase, 189 papers were excluded. Afterward, the full texts of the remaining papers were evaluated, of which 10 papers were omitted based on reasons including three systematic reviews 39, 40, 41, three…

Discussion
Our umbrella review comprehensively assessed the association between VD status and MS through an analysis of published meta-analyses and systematic reviews from 2012 to 2024. These papers collectively examined a total of 39,567 participants and focused on three main areas: serum levels of VD, VDS, and gene polymorphisms related to the VDR, specifically ApaI, BsmI, FokI, and TaqI.
The production, absorption, and utilization of VD in the body are influenced by a number of variables that affect its…

Conclusion
This study conducted a comprehensive assessment of the relationship between vitamin D and MS, highlighting the slight genetic impact of VDR mutations and possible advantages for certain subgroups. Nevertheless, it does not consistently recommend the use of VDS in the management of MS because of variations in research methods and study differences. The results emphasize the need for further systematic research to more accurately determine the function of VD in MS….

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VitaminDWiki - 14 studies in both categories Multiple Sclerosis and Vitamin D Receptor

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VitaminDWiki - The risk of 50+ diseases at least double with poor Vitamin D Receptor

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VitaminDWiki - Vitamin D Receptor activation can be increased in 16+ ways

Resveratrol,  Omega-3,  Magnesium,  Zinc,   Quercetin,   non-daily Vit D,  Curcumin,   Berberine,  intense exercise, Butyrate   Sulforaphane   Ginger,   Essential oils, etc  Note: The founder of VitaminDWiki uses 10 of the 16 known VDR activators