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Review

Genetic Polymorphisms in Cytochrome P450 Enzymes Involved in Vitamin D Metabolism and the Vitamin D Receptor: Their Clinical Relevance

by
Yazun Jarrar
1,
Ghayda’ Alhammadin
2 and
Su-Jun Lee
3,*
1
Department of Basic Medical Sciences, Faculty of Medicine, Al-Balqa Applied University, Al-Salt 19117, Jordan
2
Department of Pharmaceutical Science, College of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan
3
Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan 50834, Republic of Korea
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2025, 15(4), 128; https://doi.org/10.3390/jpm15040128
Submission received: 4 March 2025 / Revised: 22 March 2025 / Accepted: 25 March 2025 / Published: 27 March 2025
(This article belongs to the Special Issue New Approaches in Pharmacogenomics)
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Abstract

:
Individual variations in the active form of vitamin D (Vit.D) arise from a combination of dietary intake, sun exposure, and genetic factors, making it complex and challenging to maintain optimal levels. Among Vit.D-related genes, variations in CYP2R1 and CYP27B1 influence Vit.D synthesis, CYP24A1 regulates its inactivation, and the Vit.D receptor (VDR) mediates Vit.D signaling. These genetic variations contribute to substantial differences in Vit.D concentrations and associated clinical effects. However, there has been a lack of comprehensive, simultaneous exploration of these key genes and their clinical implications. This review provides a systematic analysis of genetic variants in Vit.D-related P450 genes identified in human clinical studies, along with in silico predictions of their functional consequences. Since multiple genes seem to influence the body’s response to Vit.D, studying just one genetic variant may not fully explain Vit.D deficiency. A comprehensive evaluation of all Vit.D-related genes could offer valuable insights for advancing personalized medicine in Vit.D management. This study provides a foundation for developing a more personalized approach to Vit.D supplementation and regulation, guided by genetic information.

1. Introduction

Vitamin D (Vit.D) plays a critical role in calcium absorption and homeostasis and has been extensively studied in the context of bone density and skeletal health. However, emerging evidence has expanded its relevance to a broader range of physiological and pathological processes, including diabetes, hypertension, cardiovascular disease, autoimmune disorders, cancer, and depression [1]. Inter-individual variation in circulating 25-hydroxyVit.D (25-OH Vit.D) levels exceeds a 30-fold range [2], driven by multiple factors such as sun exposure, dietary intake, age, sex, pharmacological interactions, disease status, and genetic predisposition [3]. Among these, genetic factors contribute significantly to variability in 25-OH Vit.D levels, accounting for an estimated 23–83% of the observed differences [4,5]. Notably, genes involved in Vit.D metabolism, including those regulating its biosynthesis and clearance, have been identified as major determinants of inter-individual variation [6]. For instance, polymorphisms in CYP27B1 and CYP2R1 have been implicated in calcium-related disorders such as Vit.D-dependent rickets type 1 (VDDR1) [7,8,9]. Furthermore, genetic variants in CYP2R1, CYP24A1, and Vit.D receptors (VDRs) have been associated with altered circulating 25-OH Vit.D concentrations in a gene-dependent manner [4,10]. Specifically, mutations in CYP24A1 have been linked to dysregulated Vit.D metabolism and hypercalcemia [11]. The biological impact of genetic variants is highly diverse, ranging from complete loss-of-function mutations that abolish enzymatic activity to neutral polymorphisms with no discernible effect on gene function or expression [12]. Functional consequences of genetic variants include amino acid substitutions leading to altered protein function, premature stop codons resulting in truncated proteins, splicing variants that modify mRNA length and stability, frame-shift mutations caused by nucleotide insertions or deletions leading to premature termination codons, and regulatory variants that influence gene expression levels [13]. A comprehensive understanding of the functional consequences of these genetic variants remains limited, making it challenging for clinicians and patients to accurately address Vit.D deficiency based on genotyping a limited set of variants, often relying on assumptions or statistical predictions. To ensure optimal Vit.D levels, it is more reliable and clinically beneficial to genotype for well-characterized functional variants or those previously validated in human studies. Importantly, Vit.D deficiency may result from non-genetic factors such as drug interactions, hepatic or renal impairment, or insufficient sun exposure, leading to potential misclassification as a genetic disorder [6]. Conversely, mutations in genes involved in Vit.D biosynthesis may obscure the phenotypic manifestation of other genetic variants associated with Vit.D deficiency, complicating accurate diagnosis due to overlapping environmental or clinical factors, as well as interactions with other Vit.D-related genetic variants. This uncertainty has led to reported hesitancy among both clinicians and patients regarding the clinical utility of genotyping in this context [14]. In this review, we examine the functional roles of Vit.D-related genetic variants that have been experimentally characterized. Furthermore, we summarize the genetic variants that exhibit strong associations with human diseases and emphasize the need for further investigation into uncharacterized variants through in silico analyses and functional validation studies.

2. Vitamin D

Vit.D is an essential fat-soluble secosteroid required for maintaining calcium and phosphate homeostasis, thereby ensuring proper bone mineralization, muscle function, and various cellular processes. First identified by McCollum et al. in 1922, Vit.D was hypothesized to facilitate calcium deposition, and subsequent studies demonstrated its role in preventing rickets, a metabolic disorder characterized by defective bone mineralization due to impaired calcium and phosphate metabolism [15]. It was later established that both sunlight exposure and dietary sources, such as cod liver oil, could prevent and treat rickets by increasing Vit.D levels [16]. Genetic mutations affecting Vit.D metabolism, as well as dietary deficiencies, have been identified as primary contributors to this disorder [17]. Vit.D exists in two primary forms: Vit.D3 (cholecalciferol), primarily derived from animal sources, and Vit.D2 (ergocalciferol), obtained from plant and fungal sources. In 1924, Steenbock and colleagues at the University of Wisconsin demonstrated that irradiating yeast enhanced its Vit.D2 content, leading to the fortification of milk as a strategy to prevent rickets [18]. Structurally, Vit.D is classified as a secosteroid, sharing a core four-ring backbone typical of steroidal compounds, with a characteristic broken ring structure (Figure 1). Both Vit.D2 and Vit.D3 are biologically inactive and require sequential hydroxylation, first at the 25th carbon in the liver and then at the 1st carbon in the kidneys, to produce the active hormone calcitriol (1,25-dihydroxyVit.D). Calcitriol plays a pivotal role in regulating calcium and phosphate metabolism, thereby contributing to skeletal integrity, immune function, and various physiological processes [19].

3. The Metabolism and Bioactivity of Vit.D

Humans obtain Vit.D through two primary sources: endogenous synthesis of Vit.D3 in the skin upon exposure to ultraviolet B (UVB) radiation and exogenous intake from dietary sources, fortified foods, and supplements. Cutaneous synthesis accounts for approximately 90% of total Vit.D production, while dietary sources, including egg yolks, oily fish, shiitake mushrooms, organ meats, and liver, contribute to the remaining fraction [20]. Upon exposure to UVB radiation (wavelength 290–315 nm), the precursor molecule 7-dehydrocholesterol (7-DHC), present in the epidermal cells, undergoes photochemical conversion to pre-Vit.D3. Subsequent thermal isomerization results in the formation of Vit.D3. Similarly, Vit.D2 is derived from plant and fungal sources through a comparable process. However, both Vit.D3 and Vit.D2 are biologically inactive and require enzymatic activation through sequential hydroxylation. As illustrated in Figure 2, the first hydroxylation occurs in the liver, where the enzyme CYP2R1 catalyzes the conversion of Vit.D into 25-hydroxyVit.D [25(OH)D], also referred to as calcidiol. This metabolite, the primary circulating form of Vit.D, has a half-life of approximately two weeks and serves as a biomarker for assessing Vit.D status [21]. The second hydroxylation step occurs predominantly in the kidneys, where the enzyme CYP27B1 catalyzes the conversion of 25(OH)D into its biologically active form, 1,25-dihydroxyVit.D [1,25(OH)2D], also known as calcitriol. This conversion is tightly regulated by parathyroid hormone (PTH) in response to serum calcium and phosphate levels, as well as other mediators such as growth hormone (GH) [22]. Beyond renal hydroxylation, extra-renal tissues—including keratinocytes, osteoblasts, lymph nodes, placenta, colon, and alveolar macrophages—express CYP27B1, enabling local conversion of 25(OH)D into 1,25(OH)2D. This suggests an autocrine–paracrine role for calcitriol in various physiological processes [21]. In murine models, CYP2R1 knockout results in a significant (>50%) reduction in circulating 25(OH)D levels, although complete depletion does not occur, indicating the presence of alternative metabolic pathways. In humans, mutations in CYP2R1 and CYP27B1 have been implicated in hereditary rickets, further underscoring their critical role in Vit.D metabolism [23]. Additionally, CYP3A4, an enzyme primarily involved in xenobiotic metabolism, contributes to Vit.D catabolism by hydroxylating calcitriol, thereby reducing its biological activity and facilitating its degradation. This enzymatic regulation plays a crucial role in maintaining the balance between active and inactive forms of Vit.D, particularly in extra-renal tissues [24]. Furthermore, CYP27A1, a mitochondrial enzyme predominantly expressed in the liver, hydroxylates 25(OH)D at the 24-position, leading to the formation of 24,25-dihydroxyVit.D, an inactive metabolite. This catabolic pathway serves as a protective mechanism against Vit.D toxicity and plays a key role in calcium homeostasis [25].

4. Vit.D Receptor

Vit.D-binding protein (VDBP), a member of the albumin superfamily, plays a crucial role in the transport and distribution of Vit.D metabolites. Approximately 85% of circulating 25-hydroxyVit.D [25(OH)D] and 1,25-dihydroxyVit.D [1,25(OH)2D] are bound to VDBP, facilitating their delivery to target tissues. However, studies have shown that the absence of VDBP does not necessarily result in Vit.D deficiency unless dietary intake is severely restricted, suggesting the presence of compensatory mechanisms for Vit.D homeostasis [26]. The biological actions of Vit.D are mediated through the activation of the cytosolic Vit.D receptor (VDR), a ligand-dependent transcription factor belonging to the nuclear receptor superfamily. Acting as a hormone, 1,25(OH)2D binds to VDR and translocates into the nucleus of target cells, where it regulates gene transcription. The ubiquitous expression of VDR across various tissues underscores the extensive physiological functions of Vit.D. It is estimated that 1,25(OH)2D directly or indirectly modulates the expression of approximately 1250 genes by binding to VDR and interacting with Vit.D response elements (VDREs) in promoter regions, thereby activating or repressing transcription [27]. Structurally, VDR shares common features with other nuclear receptors, including a DNA-binding domain, a ligand-binding domain, a highly conserved N-terminal domain of 23 amino acids, and a flexible hinge region. Upon activation, VDR typically forms a heterodimer with one of the three retinoid X receptor (RXR) isoforms (α, β, or γ), enhancing its transcriptional activity [28]. Given its pivotal role in gene regulation, dysregulation of VDR signaling has been implicated in a range of pathological conditions, including rickets, psoriasis, renal osteodystrophy, and several autoimmune disorders such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease [29,30].

5. Biological Functions of Vit.D

Vit.D exerts a broad range of well-documented biological functions. The active metabolite, 1,25-dihydroxyVit.D [1,25(OH)2D], works in concert with parathyroid hormone (PTH) and calcitonin to regulate calcium and phosphorus homeostasis. This regulation is achieved through enhanced intestinal absorption of these minerals, stimulation of osteoclastic bone resorption, and reduced renal excretion, thereby maintaining skeletal integrity and bone mineralization. Beyond its classical role in calcium–phosphorus metabolism, the widespread expression of VDR in various cell types—including keratinocytes, lymphocytes, pancreatic β-cells, and cells of the pituitary and parathyroid glands—suggests additional biological functions for Vit.D [31]. Vit.D is a key regulator of cellular proliferation and differentiation, influencing multiple cell-specific processes such as cell cycle progression, apoptosis, and differentiation. Notably, 1,25(OH)2D has been implicated in cell cycle arrest at the G0-G1 phase, thereby exerting antiproliferative effects [32]. In one study, the Vit.D analog EB1089 was shown to induce the expression of differentiation-associated epithelial genes, promoting differentiation and reversing the malignant phenotype of squamous cell carcinoma. Additionally, EB1089 inhibited the insulin-like growth factor 1 (IGF-1) signaling pathway, thereby inducing apoptosis in breast cancer cells [32]. Vit.D also functions as a potent immunomodulatory hormone. Several clinical studies have demonstrated that 1,25(OH)2D exerts immunoregulatory effects on both innate and adaptive immune responses, which can be attributed to VDR expression in immune cells and their ability to metabolize Vit.D [33]. Vit.D deficiency has been associated with an increased risk of immune-mediated disorders, including psoriasis, rheumatoid arthritis, type 1 diabetes, sepsis, multiple sclerosis, tuberculosis, and respiratory tract infections [34]. In response to bacterial, viral, or fungal infections, inflammatory cytokines such as interferon-γ and Toll-like receptor activation stimulate macrophages and monocytes to upregulate CYP27B1 expression. This leads to the local conversion of 25(OH)D to its active form, 1,25(OH)2D, which subsequently induces the synthesis of cathelicidin, an endogenous antimicrobial peptide that disrupts microbial membranes and enhances host defense mechanisms [35]. Furthermore, 1,25(OH)2D modulates the function of antigen-presenting cells, such as dendritic cells, by promoting the secretion of immunosuppressive cytokines, thereby contributing to immune tolerance [36]. Several studies have also demonstrated that 1,25(OH)2D directly influences B-cell function in a manner similar to its effects on T cells. Resting B cells exhibit low VDR expression, which increases upon activation. In its active state, 1,25(OH)2D inhibits the differentiation of plasma and memory B cells, induces apoptosis in activated B cells, and promotes the secretion of anti-inflammatory cytokines, thereby modulating humoral immunity [37].

6. Vit.D Deficiency and Its Link to Human Diseases

Due to its long half-life and relatively stable serum concentration, independent of PTH fluctuations, the serum level of 25-hydroxyVit.D [25(OH)D] is widely used as a reliable biomarker for assessing whole-body Vit.D status. According to the National Institutes of Health (NIH) and the Office of Dietary Supplements, optimal serum 25(OH)D levels are defined as >20 ng/mL (50 nmol/L), while Vit.D deficiency is diagnosed when serum 25(OH)D levels fall below 12 ng/mL (30 nmol/L) [38]. Vit.D deficiency may arise due to inadequate dietary intake, insufficient sun exposure, malabsorption disorders, or conditions that impair the metabolic activation of Vit.D. Furthermore, several factors influence the risk of Vit.D deficiency, including age, lifestyle, ethnicity, breastfeeding status, geographic latitude, skin pigmentation, and genetic polymorphisms in Vit.D-related genes [39]. Across various regions of the world, Vit.D deficiency remains highly prevalent. Epidemiological studies indicate that more than 20% of the population in India, Pakistan, Afghanistan, Jordan, and Tunisia exhibit serum 25(OH)D levels below 12 ng/mL (30 nmol/L) [40]. A survey revealed that 50% of pregnant women in the United Arab Emirates, 59% of healthy schoolchildren in Saudi Arabia, and 83% of women in Nigeria are Vit.D deficient [41]. A cohort study conducted in Jordan involving 3,007 participants reported that 40.17% were Vit.D deficient, 27.7% had insufficient levels, 17.02% had adequate levels, and only 15.11% had optimal Vit.D levels [42]. Despite high levels of sunlight exposure in both summer and winter, Vit.D deficiency is widespread across Africa and the Middle East. This paradox may be attributed to factors such as sun-avoidant behaviors, traditional clothing that limits skin exposure, dietary restrictions influenced by cultural practices, and genetic variations in Vit.D metabolism [41]. Vit.D deficiency has been strongly associated with various adverse health outcomes, including increased all-cause mortality. A meta-analysis conducted in 2017, encompassing over 17,000 participants, demonstrated a significant correlation between low 25(OH)D levels and elevated mortality risk [43]. Additionally, critically ill patients with sepsis often present with low Vit.D levels. Administration of a single intravenous bolus dose of 400,000 IU of cholecalciferol in the early stages of sepsis has been shown to reduce pro-inflammatory interleukin levels while increasing cathelicidin, an antimicrobial peptide with endotoxin-neutralizing properties [44]. Emerging evidence also suggests that Vit.D deficiency is associated with pregnancy complications such as preeclampsia, low birth weight, and gestational diabetes. Rostami et al. recommend a maintenance dose of 400–600 IU/day of Vit.D supplementation during pregnancy when serum 25(OH)D levels are below 40 ng/mL [45]. Moreover, numerous clinical studies have identified a link between Vit.D deficiency and cardiovascular disorders, including coronary artery disease, cardiomyopathy, and hypertension [46]. It is well established that seasonal influenza outbreaks predominantly occur in winter. One proposed explanation is the seasonal fluctuation in serum 25(OH)D levels due to variations in UV light exposure [47]. Several studies have substantiated this hypothesis, demonstrating that Vit.D deficiency increases susceptibility to acute viral respiratory tract infections in both children and adults [48]. According to data from the National Health and Nutrition Examination Survey (NHANES) in the United States, which included 14,108 participants, individuals with serum 25(OH)D levels below 30 ng/mL had a 58% higher risk of developing acute respiratory infections than those with higher Vit.D levels [48]. Respiratory viruses cause cellular and tissue damage upon entry into the respiratory epithelium, triggering both innate and adaptive immune responses that lead to inflammation and, in severe cases, sepsis, which may be life-threatening [49]. A meta-analysis of 25 randomized controlled trials demonstrated that Vit.D3 or D2 supplementation significantly reduces the risk of acute respiratory infections [50].

7. Genetic Variants in Genes Related to Vit.D Metabolism and Signaling

Genetic variants can influence gene regulation, transcription, and protein structure and function, depending on their location within the gene [51]. These variations play a crucial role in explaining inter-individual differences in various phenotypes, including susceptibility to Vit.D deficiency [52]. In this review, we focus on key genes involved in Vit.D metabolism, including Vit.D-activating enzymes CYP2R1 and CYP27B1, the Vit.D-inactivating enzyme CYP24A1, and the VDR.

7.1. VDR Genetic Variants

The VDR gene, located on chromosome 12q13.11, encodes the Vit.D receptor, a nuclear transcription factor that mediates the biological effects of 1,25(OH)2D. Upon activation, VDR heterodimerizes with the retinoid X receptor RXR, forming the VDR/RXR complex, which binds to VDREs in the promoter regions of target genes, thereby regulating their transcription [51].
Single-nucleotide polymorphisms (SNPs) in the VDR gene have been implicated in reduced Vit.D activity and are associated with various diseases. Among these, the rs7975232 (ApaI), rs2228570 (FokI), rs731236 (TaqI), and rs1544410 (BsmI) polymorphisms are the most extensively studied [51]. ApaI (rs7975232) and BsmI (rs1544410) are located within intron 8 of the VDR gene, while FokI (rs2228570) and TaqI (rs731236) are situated in exon 2 and exon 9, respectively. The rs2228570 and rs731236 polymorphisms may influence translation and alter VDR protein structure, whereas rs7975232 and rs1544410 have been associated with mRNA stability and reduced gene expression, ultimately leading to decreased VDR activity and impaired Vit.D function [52].
Numerous studies across different populations have explored the relationship between VDR polymorphisms and rheumatoid arthritis (RA). A meta-analysis of 21 studies published before February 2020 found that the rs2228570 polymorphism exhibited a protective effect against RA in both European and Asian populations, whereas rs731236 conferred a lower risk of RA among Africans and Arabs. However, rs1544410 was not significantly associated with RA risk in any population [53]. Another meta-analysis, including 17 studies, examined the association between VDR polymorphisms and asthma susceptibility. This study identified a statistically significant link between the wild-type rs2228570 and homozygous rs731236 genotypes and asthma susceptibility. Furthermore, the study suggested that ethnic background influences asthma risk, with higher susceptibility observed among American, Asian, and African populations [54].
Several studies have also investigated the role of VDR polymorphisms in tuberculosis (TB) susceptibility across diverse ethnic groups. A systematic review of six studies conducted in the Iranian population reported that rs731236 was significantly associated with increased TB risk across all genetic models, while rs1544410 was linked to an elevated TB risk only in the dominant genotype model. Conversely, rs2228570 and rs7975232 did not show significant associations with TB progression in this population [55]. In addition, a meta-analysis of nine genetic studies published before 2017 examined the association between VDR polymorphisms (rs11568820, rs2228570, rs731236, and rs1544410) and resistance to enveloped viral infections, including Respiratory Syncytial Virus (RSV), Hepatitis B virus (HBV), and Dengue virus. The findings indicated that rs2228570 was consistently associated with increased susceptibility to RSV infection, and a global pattern was observed between RSV incidence and the distribution of rs2228570 alleles, suggesting its potential role as a genetic marker contributing to RSV transmission [54].
In the context of COVID-19, a study conducted in Iran genotyped eight VDR polymorphisms (rs7975232, rs1544410, rs731236, rs2228570, rs757343, rs739837, and rs11568820) in 500 hospitalized patients using the PCR-RFLP method. The study reported that rs7975232 was associated with shortness of breath; rs2228570 with high fever and hypertension; rs1544410 with chronic kidney disease; and rs757343 with hypertension, vomiting, and respiratory distress in mild to moderately ill patients [56]. A separate study in Turkey examined the relationship between VDR polymorphisms (rs2228570, rs7975232, rs731236, and rs1544410) and COVID-19 prognosis using genetic data from 297 COVID-19 patients in the Marmara University Medical Genetics Biobank. The study found that 83% of participants had Vit.D deficiency, with 40.7% exhibiting severe deficiency. Notably, 62.8% of ICU-admitted patients carried the TT genotype of rs731236, highlighting a potential link between this variant and severe COVID-19 outcomes [57]. More recently, Alhammadin et al. (2023) investigated the relationship between VDR gene variants (rs7975232, rs2228570, and rs731236) and COVID-19 severity as well as long-COVID symptoms in 100 Jordanian patients. While rs7975232 and rs2228570 were not significantly associated with disease severity, rs731236 was significantly linked to milder disease courses, with the wild-type genotype associated with mild illness and the heterozygous genotype predominantly found in asymptomatic individuals. Regarding long-COVID symptoms, the heterozygous rs7975232 and wild-type rs731236 genotypes were associated with persistent fatigue and muscle pain, while the homozygous rs731236 genotype was strongly correlated with prolonged respiratory distress [58].

7.2. Genetic Variants in Genes Related to Vit.D Metabolism

The CYP2R1 gene plays a pivotal role in the Vit.D metabolic pathway. Located on chromosome 11p15.2, this gene spans approximately 15.5 kb and encodes a 501-amino-acid enzyme, 25-hydroxylase, which catalyzes a rate-limiting step in the hepatic conversion of pre-Vit.D into its bioactive form, 25(OH)D [18]. Notably, polymorphisms in CYP2R1, such as rs10741657, rs12794714, and rs10766197, have been implicated in modulating 25(OH)D concentrations, likely through alterations in gene expression or enzymatic activity [59]. Several studies have investigated the functional impact of these polymorphisms. A meta-analysis involving 52,417 healthy participants demonstrated that the rs10741657 variant is significantly associated with lower 25(OH)D levels and an increased risk of Vit.D deficiency under a dominant model (GG + AG vs. AA), particularly among European and Asian populations (OR = 1.42, 95% CI = 1.11–1.83, P = 0.006) [60]. Additionally, a cross-sectional study of 180 patients in Virginia reported that carriers of the rs10741657 risk allele exhibited a 3.7-fold higher likelihood of Vit.D insufficiency [61]. Another study in individuals with metabolic syndrome identified the G/G homozygous genotype of rs10741657 as being associated with reduced serum Vit.D3 levels [62].
The CYP27A1 gene, located on chromosome 2q35, spans approximately 18.6 kb and consists of nine exons and eight introns [63]. Together with CYP2R1 and CYP3A4, CYP27A1 encodes enzymes involved in the 25-hydroxylation of Vit.D in the liver, a critical step in the biosynthesis of 25(OH)D [7]. Although CYP2R1 exhibits high affinity and specificity for Vit.D, CYP27A1 and CYP3A4 demonstrate broader substrate specificity but a lower affinity for Vit.D metabolism [64]. Among the studied CYP27A1 polymorphisms, rs17470271 and rs933994 have been evaluated for their role in Vit.D metabolism [65]. However, their clinical significance remains unclear. A study on pulmonary tuberculosis in a Chinese cohort found no significant association between these variants and Vit.D-related outcomes, suggesting that CYP27A1 genetic variability alone may not be a primary determinant of Vit.D status [66]. Furthermore, recent research suggests that CYP27A1 polymorphisms may exert a weaker influence on circulating 25(OH)D levels compared to polymorphisms in CYP2R1 [67].
The CYP27B1 gene, located on chromosome 12q14.1, encodes 1-alpha-hydroxylase, a mitochondrial cytochrome P450 enzyme of 508 amino acids, which catalyzes the final activation step of Vit.D by converting 25(OH)D to its biologically active form calcitriol [68]. This hydroxylation occurs primarily in the kidneys and is crucial for Vit.D–mediated calcium homeostasis and immune regulation. The CYP27B1 gene consists of nine exons and encodes an enzyme integral to renal Vit.D activation [69]. Several key CYP27B1 polymorphisms, including rs10877012 and rs4646536, have been linked to altered Vit.D levels and associated health outcomes [70]. In a Canadian cohort, rare variants such as rs118204009 (G/A), rs118204011 (C/T), and rs118204012 (A/G) were found to correlate with lower Vit.D levels and conditions such as VDDT1 rickets. Specifically, individuals homozygous for the rs118204012 (AA) genotype exhibited a significantly increased risk of Vit.D insufficiency, particularly among males [71].
Further research has explored the association between CYP27B1 polymorphisms and autoimmune diseases. The rs10877012 polymorphism has been reported to influence serum calcidiol levels, potentially modulating immune responses in disorders such as multiple sclerosis, RA, and systemic lupus erythematosus. This suggests that genetic variations in CYP27B1 may impact Vit.D metabolism and immune function, indicating the gene’s role in disease susceptibility and Vit.D homeostasis [72]. Additionally, a study on Iranian populations revealed a significant association between the rs4646536 variant and Vit.D deficiency, with carriers displaying a markedly higher risk of Vit.D insufficiency [70].

7.3. Genetic Variants in Vit.D-Inactivation Gene

The CYP24A1 gene, located on chromosome 20q13.2, encodes 24-hydroxylase, a mitochondrial enzyme essential for the inactivation of Vit.D [73]. This enzyme catalyzes the 24-hydroxylationof 1,25(OH)2D, converting it into calcitroic acid, an inactive metabolite that is subsequently excreted, thereby tightly regulating Vit.D homeostasis [74]. CYP24A1 is highly expressed in the kidney and plays a crucial role in increasing the solubility of Vit.D metabolites for renal clearance [75,76]. Several SNPs in CYP24A1, including rs2248137, rs2296241, and rs927650, have been associated with circulating Vit.D levels and disease susceptibility [77,78]. One study reported a significant association between the rs2248137 variant and multiple sclerosis risk, showing that MS patients carrying the CC genotype had significantly lower 25(OH)D levels compared to individuals with the GG or CG genotypes [64]. In addition, CYP24A1 polymorphisms have been implicated in non-alcoholic fatty liver disease (NAFLD) and Vit.D deficiency. A study identified a strong correlation between the rs2296241 and rs2248359 variants and reduced serum Vit.D levels, suggesting that genetic variations in CYP24A1 may contribute to impaired Vit.D metabolism in patients with NAFLD [79]. Further research has explored the role of CYP24A1 variants in differentiated thyroid cancer (DTC). A study in a German cohort found that specific CYP24A1 haplotypes, such as rs2248137C/rs2296241G, were significantly associated with lower circulating 1,25(OH)2D₃ levels in DTC patients compared to healthy controls [80]. These findings suggest that genetic variants in CYP24A1 may contribute to alterations in Vit.D metabolism, hence influencing the risk and progression of certain diseases.

8. In Silico Analysis of Genetic Variants Related to Vit.D Metabolism and Signaling

We conducted an in silico evaluation, which refers to computational simulations and bioinformatics tools used to analyze biological data of nonsynonymous genetic variants in key human Vit.D-related genes—CYP2R1, CYP27B1, CYP24A1, and VDR—identified in the clinical variant database of GenBank (https://www.ncbi.nlm.nih.gov/clinvar/ accessed on August 2024). The analyzed genetic variants, using in silico tools, are genetic variants with unknown or uncertain functionality on human Vit.D deficiency. The analysis utilized widely adopted computational prediction tools, PolyPhen-2 and Sorting Intolerant From Tolerant (SIFT), to assess the potential functional impact of these variants. PolyPhen-2 predicts the potential impact of amino acid substitutions by analyzing sequence conservation and structural changes within the protein. It assigns scores based on the likelihood of a variant affecting protein function [81]. Similarly, SIFT evaluates evolutionary conservation, determining whether an amino acid substitution is likely to be tolerated or damaging based on sequence homology and amino acid properties [82].
The results for CYP2R1, CYP27B1, CYP24A1, and VDR variants are summarized in Table 1, Table 2, Table 3 and Table 4, respectively. Notably, the functional consequences of many of these variants remain uncharacterized in vitro and clinically. The in silico assessment of CYP2R1 nonsynonymous variants (Table 1) revealed a broad spectrum of predicted functional effects. Variants such as Pro36Leu (107C>T), Pro41Thr (121C>A), Ile332Thr (995T>C), Leu300Arg (899T>G), Gly450Arg (1348G>C), and Arg248Ser (744A>C) were predicted to be deleterious by both tools. PolyPhen-2 assigned scores approaching or equal to 1.0, suggesting a high likelihood of pathogenicity, while SIFT classified them as “not tolerated.” These substitutions likely disrupt protein structure or function, as they occur at residues critical for enzymatic activity or stability. Conversely, several variants were consistently predicted to be benign. For instance, Glu8Lys (22G>A), Arg67Lys (200G>A), and Thr402Ile (1205C>T) were classified as having minimal or no impact on protein function by both tools. However, discrepancies between prediction tools were observed for certain variants. For example, Leu193Met was classified as “damaging” by PolyPhen-2(score 0.963) but deemed “tolerated” by SIFT. These inconsistencies likely arise from differences in the computational algorithms and training parameters used by each tool [83]. When conflicting results occur, researchers can consider additional factors such as population-specific allele frequencies and functional assays.
Although in silico tools offer useful predictions about the possible effects of genetic variants, care should be taken when interpreting their findings. Discrepancies between these tools indicate the need for experimental validation to confirm functional effects.
Similarly, the analysis of CYP27B1 variants (Table 2) showed that among the 100 examined variants, Arg14Cys (40C>T), Arg389Cys (1165C>T), Arg459Leu (1376G>T), and Arg335Pro (1004G>C) were consistently classified as deleterious by both PolyPhen-2 (high pathogenicity scores) and SIFT (“not tolerated”). These variants are predominantly located at conserved residues, frequently involving polar or charged amino acids essential for CYP27B1 stability and enzymatic function. In contrast, substitutions such as Pro112Leu (335C>T), Ala129Thr (385G>A), and Gly208Val (623G>T) were predicted to be benign, suggesting negligible effects on protein function.
The evaluation of CYP24A1 variants (Table 3) indicated diverse functional consequences. For example, Met1Ile (3G>T) was predicted to be damaging by PolyPhen-2 (score 0.931) and “not tolerated” by SIFT (score 0.30), indicating a likely deleterious effect. Similarly, Gly102Arg (304G>C) was classified as highly damaging by both tools, with a PolyPhen-2score of 1.0 and a SIFT score of 1, suggesting a severe impact on protein function. Conversely, Ser8Gly (22A>G) was predicted to be benign, with a PolyPhen-2 score of 0.104 and a SIFT score of 0.70, implying minimal disruption. Variants such as Asp84Asn (250G>A) and Val218Leu (652G>T) were similarly classified as benign. However, conflicting predictions were observed for Ala12Pro (34G>C), which was considered “damaging” by PolyPhen-2 (score 0.612) but “tolerated” by SIFT (score 0.70).
Finally, the analysis of VDR variants (Table 4) identified several substitutions classified as deleterious, with PolyPhen-2 scores nearing 1.0 and “not tolerated” designations by SIFT, indicating a high probability of functional impairment. Notable examples include Arg22Trp (64C>T), Arg54Trp (160C>T), and Val346Met (1036G>A). In contrast, Met4Val (10A>G) and Ala6Val (17C>T) were consistently classified as benign, with low PolyPhen-2 scores and “tolerated” designations in SIFT, suggesting minimal functional consequences.

9. Genetic Variants Identified in Human Clinical Studies

Table 5 summarizes genetic variants in Vit.D-metabolizing genes that have been associated with various diseases in human studies. Notably, the majority of disease-associated mutations in Vit.D -related genes are nonsense SNPs, which introduce premature stop codons, leading to truncated, non-functional proteins that impair Vit.D metabolism and function. Among these variants, the CYP2R1 promoter variant rs10741657 has been linked to reduced circulating 25-hydroxyVit.D levels, increasing susceptibility to Vit.D deficiency, particularly in White European populations. In the CYP27B1 gene, missense variants have been implicated in various forms of VDDR. The rs118204009 variant, which results in an arginine-to-histidine (Arg389His) substitution, has been clinically associated with VDDR1A, causing impaired calcium homeostasis and bone mineralization, as supported by both functional studies and in silico predictions (Table 2). Similarly, the rs118204011 variant, causing a leucine-to-phenylalanine (Leu343Phe) substitution, is linked to VDDR1 and altered enzymatic function. Meanwhile, the rs118204012 variant, which replaces glutamic acid with glycine (Glu189Gly), has been associated with VDDR1A, although in silico analysis suggests it may have a benign impact on protein function (Table 2).

10. Conclusions

Vit.D deficiency and its associated disorders are widespread, affecting populations across various regions globally. Both genetic and non-genetic factors contribute to individual variability in Vit.D metabolism, signaling, and response. Our in silico analysis of genetic variants in Vit.D-related genes with unknown functionality demonstrates that numerous variants significantly impact the key proteins involved in Vit.D activation, inactivation, and signaling mechanisms. These findings may indicate the polygenic nature of Vit.D response, suggesting that analyzing a single genetic variant may not fully explain the phenotypic variability observed in Vit.D deficiency. In this review, we have systematically compiled and examined genetic variants associated with Vit.D synthesis, metabolism, and signaling, integrating in silico functional predictions with clinically studied human variants. This comprehensive approach provides a more detailed understanding of the molecular basis of Vit.D function. A comprehensive analysis of all Vit.D-related genes is essential for advancing personalized medicine in the context of Vit.D deficiency. The development of a specialized diagnostic panel incorporating key genetic variants with significant functional impact on Vit.D metabolism and activity would be invaluable for precise risk assessment and the implementation of personalized treatment strategies. Such advancements could pave the way for targeted interventions to mitigate the adverse health effects associated with Vit.D deficiency.

11. Strengths and Limitations

This review highlights its strong points. It offers a thorough review of the literature on genetic polymorphisms linked to Vit.D and their possible effects on biochemical and metabolic parameters. Finding these genetic variations can aid in the development of individualized treatment plans for patients with Vit.D deficiency, making the review clinically relevant.
It is important to recognize the limitations of this review. Because studies that report significant associations are more likely to be published, potential publication bias may be an issue. Furthermore, there is a lack of thorough information on some ethnic groups, such as Middle Eastern populations. Lastly, a lot of research does not completely take into consideration confounding variables like diet, exercise, and sun exposure, all of which can influence Vit.D levels.

Author Contributions

Conceptualization, S.-J.L. and Y.J.; methodology, S.-J.L. and Y.J.; software, Y.J. and G.A.; data curation, Y.J. and G.A.; writing—original draft preparation, Y.J. and G.A.; writing—review and editing, S.-J.L.; supervision, S.-J.L. All authors have read and agreed to the published version of the manuscript.

Funding

The article was supported by grants from the National Research Foundation of Korea, funded by the Korean government (NRF-2020R1I1A3073778), and the National Research Foundation of Korea, funded by Korea (MIST) (2018R1A5A2021242).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are available with the corresponding author upon request.

Acknowledgments

The authors would like to thank Al-Balqa Applied (Jordan) and Inje University (South Korea) for supporting this research.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

25-OH Vit.D25-Hydroxyvitamin D
7-DHC7-Dehydrocholesterol
CYPCytochrome P450 Enzyme
GHGrowth Hormone
MSMultiple Sclerosis
PTHParathyroid Hormone
RARheumatoid Arthritis
RXRRetinoid X Receptor
SNPSingle-Nucleotide Polymorphism
VDDR1Vitamin D-Dependent Rickets Type 1
VDRVitamin D Receptor
VDREVitamin D Response Element
Vit.DVitamin D

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Jpm 15 00128 g001
Figure 1. The structure of vitamin D2 and vitamin D3. The structures were obtained from the NCBI database (https://pubchem.ncbi.nlm.nih.gov/).
Figure 1. The structure of vitamin D2 and vitamin D3. The structures were obtained from the NCBI database (https://pubchem.ncbi.nlm.nih.gov/).
Jpm 15 00128 g001
Jpm 15 00128 g002
Figure 2. The metabolism and activation pathway of vitamin D. Vitamin D can be obtained from the diet or synthesized in the skin from 7-dehydrocholesterol upon UVB sunlight exposure. In the liver, vitamin D is converted to 25-hydroxyvitamin D [25(OH)D], the major circulating form, via CYP2R1. This is transported in the blood bound to vitamin D-binding protein (DBP) and further hydroxylated in the kidney by CYP27B1 to form 1,25-dihydroxyvitamin D [1,25(OH)2D], the active form. Active vitamin D binds to the vitamin D receptor (VDR) to regulate calcium and phosphate homeostasis and mediate various cellular effects. Excess vitamin D is inactivated by CYP24A1, which converts it into the metabolites 1,24,25(OH)3D for excretion.
Figure 2. The metabolism and activation pathway of vitamin D. Vitamin D can be obtained from the diet or synthesized in the skin from 7-dehydrocholesterol upon UVB sunlight exposure. In the liver, vitamin D is converted to 25-hydroxyvitamin D [25(OH)D], the major circulating form, via CYP2R1. This is transported in the blood bound to vitamin D-binding protein (DBP) and further hydroxylated in the kidney by CYP27B1 to form 1,25-dihydroxyvitamin D [1,25(OH)2D], the active form. Active vitamin D binds to the vitamin D receptor (VDR) to regulate calcium and phosphate homeostasis and mediate various cellular effects. Excess vitamin D is inactivated by CYP24A1, which converts it into the metabolites 1,24,25(OH)3D for excretion.
Jpm 15 00128 g002
Table 1. Genetic variants in CYP2R1 gene and their functionality prediction using in silico tools.
Table 1. Genetic variants in CYP2R1 gene and their functionality prediction using in silico tools.
Genetic Variant
ID		LocationAmino Acid
Substitution		PolyPhenSIFT
15929394T>CTrp2ArgBenign0Not tolerated0.07
217963714G>CTrp5SerBenign0Not tolerated0.21
191955817G>CArg6ThrBenign0Tolerated0.36
139924522G>AGlu8LysBenign0.018Tolerated0.36
79288829G>CGly10AlaBenign0.001Tolerated0.50
208475740C>GLeu14ValBenign0.295Tolerated0.30
141473069C>APhe23LeuBenign0Tolerated0.07
327060677G>CGly26AlaBenign0Tolerated0.29
1059990107C>TPro36LeuDamaging0.945Not tolerated1
1939745112G>AGly38SerBenign0.07Tolerated0
2414155121C>APro41ThrDamaging1Not tolerated1
2332099163C>GLeu55ValDamaging0.86Tolerated0.07
1950230169G>TAla57SerBenign0Tolerated0.14
1368104200G>AArg67LysBenign0Tolerated0
2533332203A>CLys68ThrBenign0.042Tolerated0
847396235T>ALeu79IleBenign0.036Not tolerated1
1345679253T>CSer85ProBenign0Tolerated0
1912325272G>AGly91AspDamaging0.94Not tolerated1
2134296T>CLeu99ProDamaging1Not tolerated1
960805310G>AGlu104LysDamaging0.984Not tolerated1
2068341325A>GArg109GlyDamaging1Not tolerated1
1000400352A>GMet118ValBenign0.43Tolerated0
957411421G>AVal141IleBenign0.003Tolerated0
934633467C>GSer156CysDamaging0.454Not tolerated1
2374820497A>GAsn166SerBenign0.001Tolerated0
835914515A>GTyr172CysBenign0.07Tolerated0
1304683551C>TThr184MetDamaging0.777Not tolerated1
1310664577C>ALeu193MetDamaging0.963Tolerated0
2060962577C>GLeu193ValBenign0.002Tolerated0
2172123582C>GIle194MetDamaging0.558Not tolerated1
2067369661G>AAla221ThrBenign0.294Tolerated0
1918882744A>CArg248SerBenign0.17Tolerated0
1996774806A>GLys269ArgBenign0.034Tolerated0
2281495850A>GMet284ValBenign0.077Tolerated0
418154851T>CMet284ThrBenign0.059Not tolerated1
218799852G>AMet284IleBenign0.00Tolerated0
1435363859G>AGly287SerBenign0.00Tolerated0
2470790899T>GLeu300ArgDamaging1Not tolerated1
1356309913G>AGly305SerBenign0.166Tolerated0
936742950A>GAsn317SerDamaging0.864Tolerated0
429315995T>CIle332ThrDamaging0.999Not tolerated1
10593021011G>TGln337HisBenign0.002Tolerated0
17147461054T>ATrp352ArgDamaging0.876Not tolerated1
4293161126C>TPro376SerDamaging1Not tolerated1
21607641142A>GHis381ArgDamaging0.725Tolerated0
20673111147A>GThr383AlaDamaging0.909Tolerated0
30795761148C>TThr383IleDamaging0.998Tolerated0
30795771151C>GSer384CysDamaging0.999Not tolerated1
10089031166T>AVal389GluDamaging0.999Not tolerated1
22887201178C>TSer393PheBenign0.11Tolerated0
9308981181T>CIle394ThrDamaging1Not tolerated1
22608931196C>GThr399ArgDamaging0.511Tolerated0
13025221198G>CVal400LeuDamaging0.662Tolerated0
24161701205C>TThr402IleBenign0.20Tolerated0
20929371232A>GGlu411GlyDamaging0.992Tolerated0
21938721280A>GAsp427GlyDamaging0.984Not tolerated1
22631461291T>CTyr431HisBenign0.001Tolerated0
29646761298C>GAla433GlyBenign0.005Tolerated0
25544041303A>GLys435GluDamaging0.593Tolerated0
30167921322T>CPhe441SerDamaging1Not tolerated1
10259901348G>CGly450ArgDamaging1Not tolerated1
21380931351G>AGlu451LysDamaging0.994Not tolerated1
13855101363C>TArg455TrpDamaging1Not tolerated1
13916351364G>AArg455GlnDamaging1Not tolerated1
13343161394T>GLeu465TrpDamaging1Not tolerated1
22333391397T>CLeu466ProDamaging1Not tolerated1
30795781424A>GHis475ArgBenign0Tolerated0.50
25805401427A>TGlu476ValBenign0Not tolerated0.50
21273121436C>APro479GlnDamaging1Tolerated0
32706071478C>GPro493ArgDamaging0.986Tolerated0
PolyPhen provides a probability score for how damaging a variant is, with higher values indicating more likelihood of pathogenicity, while SIFT predicts whether a substitution is “tolerated” or “not tolerated”, with a focus on protein functionality. The numbering of nucleotides is based on the DNA sequence of the CYP2R1 transcript NM_024514.5.
Table 2. Genetic variants in CYP27B1 gene and their functionality prediction using in silico tools.
Table 2. Genetic variants in CYP27B1 gene and their functionality prediction using in silico tools.
Genetic Variant
ID		LocationAmino Acid
Substitution		PolyPhenSIFT
31000440C>T.Arg14CysDamaging0.996Not tolerated0.73
93461641G>AArg14HisDamaging0.989Not tolerated0.73
307944749T>ATrp17ArgBenign0Tolerated0.23
1943189148G>AAla50ThrBenign0Tolerated0.09
1715471163A>GLys55GluDamaging1Not tolerated0.91
1467327164A>TLys55MetDamaging0.996Not tolerated0.91
1457495170G>TGly57ValDamaging0.996Tolerated0.09
2301172200A>GGln67ArgBenign0.016Tolerated0.09
1975900230T>CLeu77ProBenign0.016Tolerated0.09
3079444286G>AGlu96LysBenign0.085Tolerated0.09
380287305G>AGly102GluBenign0.014Tolerated0.09
2180339310C>TArg104TrpBenign0.004Tolerated0.09
1960647311G>AArg104GlnBenign0.175Tolerated0.09
1658320G>AArg107HisDamaging1Not tolerated0.91
1923855328T>CPhe110LeuBenign0Tolerated0.09
1705730335C>TPro112LeuBenign0Tolerated0.09
2191011346C>GHis116AspDamaging1Not tolerated0.91
2092360350G>AArg117HisDamaging1Not tolerated0.91
1950321358C>TArg120CysDamaging1Not tolerated0.91
432037373G>AGly125ArgDamaging1Not tolerated0.91
1659374G>AGly125GluDamaging1Not tolerated0.91
722611385G>AAla129ThrDamaging0.576Tolerated0.09
1339453386C>TAla129ValDamaging0.998Tolerated0.09
1016722413G>TArg138LeuDamaging1Not tolerated1
1067732428C>TPro143LeuDamaging0.585Tolerated0
310002437T>ALeu146HisDamaging1Not tolerated1
2514871448G>AAla150ThrBenign0.295Tolerated0
3079445461A>TTyr154PheBenign0.190Tolerated0
3270536463G>TAla155SerBenign0Tolerated0
3339156490G>AAsp164AsnDamaging1Not tolerated1
1443676511C>TArg171CysDamaging1Not tolerated1
310001541G>TAla181SerBenign0Tolerated0.27
1345874547G>CVal183LeuDamaging1Not tolerated1
1674566A>GGlu189GlyBenign0.165Tolerated0
3079449571T>CTyr191HisBenign0.253Tolerated0
2152155580G>AGly194ArgBenign0Tolerated0
968805584T>ALeu195GlnDamaging1Not tolerated1
1339454623G>TGly208ValDamaging1Not tolerated1
2336628651C>AAsp217GluBenign0Tolerated0
2187188657G>CGlu219AspBenign0.176Tolerated0
1708812704C>AThr235AsnDamaging1Not tolerated1
2332756707T>CMet236ThrBenign0.025Tolerated0
2116143733C>TLeu245PheBenign0.01Tolerated0
1900220764G>AArg255GlnBenign0Tolerated0
2627673779T>GMet260ArgDamaging1Not tolerated1
2499531781T>GPhe261ValDamaging1Not tolerated1
310000788T>GPhe263CysDamaging1Not tolerated1
309999794A>TGln265LeuDamaging1Not tolerated1
2123967850G>AGlu284LysBenign0.01Tolerated0.09
2911178914A>CGln305ProBenign0Tolerated0
1929411939G>CGlu313AspDamaging1Not tolerated1
1666962C>GThr321ArgDamaging1Not tolerated1
16601004G>CArg335ProDamaging1Not tolerated1
32705371009C>TPro337SerDamaging1Not tolerated1
16731027C>TLeu343PheDamaging1Not tolerated1
23592371052T>GLeu351ArgDamaging1Not tolerated1
33627361052T>CLeu351ProDamaging1Not tolerated1
21914461094C>TSer365PheBenign0Tolerated0
20207011108C>ALeu370MetDamaging1Not tolerated1
13394551160A>CAsn387ThrDamaging0.774Tolerated0
16721165C>GArg389GlyDamaging1Not tolerated1
13242061165C>TArg389CysDamaging1Not tolerated1
16691166G>A.Arg389HisDamaging1Not tolerated1
28062551192G>AGly398SerBenign0.41Tolerated0
10011771198T>GTyr400AspDamaging1Not tolerated1
19361061217C>TThr406MetDamaging1Not tolerated1
13430911232G>ACys411TyrDamaging0.965Not tolerated1
2650951286G>CArg429ProDamaging0.976Tolerated0
27359031294C>TArg432CysDamaging1Not tolerated1
23313801318C>TPro440SerBenign0.025Tolerated0
30794431337T>GLeu446ArgDamaging1Not tolerated1
27223141352G>TGly451ValDamaging1Not tolerated1
8028711357C>TArg453CysDamaging1Not tolerated1
21034401364G>ACys455TyrDamaging1Not tolerated1
10073041376G>AArg459HisDamaging1Not tolerated1
32516011376G>TArg459LeuDamaging1Not tolerated1
28089641382C>AAla461GluDamaging1Not tolerated1
3099961385A>TGlu462ValDamaging1Not tolerated1
8575141474C>TArg492TrpDamaging0.996Tolerated0
21645871499G>ASer500AsnDamaging0.599Tolerated0
3099951505A>GAsn502SerBenign0.238Tolerated0
20990091517T>GLeu506TrpDamaging0.923Tolerated0.09
PolyPhen provides a probability score for how damaging a variant is, with higher values indicating more likelihood of pathogenicity, while SIFT predicts whether a substitution is “tolerated” or “not tolerated”, with a focus on protein functionality. The numbering of nucleotides is based on the DNA sequence of the CYP27B1 transcript NM_000785.4.
Table 3. Genetic variants in CYP24A1 gene and their functionality prediction using in silico tools.
Table 3. Genetic variants in CYP24A1 gene and their functionality prediction using in silico tools.
Genetic Variant
ID		LocationAmino Acid
Substitution		PolyPhenSIFT
6945003G>TMet1IleDamaging0.931Not tolerated0.30
144661222A>GSer8GlyBenign0.104Tolerated0.70
307940334G>CAla12ProDamaging0.612Tolerated0.70
153053837G>AAla13ThrBenign0.008Not tolerated0.30
33883973C>GPro25AlaBenign0.049Not tolerated0.30
327051078A>CArg26SerBenign0.024Not tolerated0.30
338838101C>TThr34MetDamaging0.661Tolerated0.70
2154023116G>TArg39LeuBenign0.208Not tolerated0.30
3079401116G>AArg39GlnBenign0.226Tolerated0.70
2311515134C>APro45GlnBenign0.078Not tolerated0.30
1021961175C>TPro59SerDamaging0.98Not tolerated0.70
338836217A>TIle73PheDamaging0.967Tolerated0.1
1921257250G>AAsp84AsnBenign0.002Tolerated0.1
338833295A>GMet99ValDamaging0.998Tolerated0
897021296T>CMet99ThrDamaging0.996Tolerated0
2124827304G>CGly102ArgDamaging1Not tolerated1
2652423305G>CGly102AlaDamaging1Not tolerated1
1384043313G>CGlu105GlnBenign0.428Tolerated0
1974478320T>CVal107AlaDamaging1Not tolerated1
2398535323A>GHis108ArgDamaging0.997Tolerated0
1988031324C>AHis108GlnDamaging0.991Tolerated0
2490932337T>GCys113GlyBenign0.003Tolerated0
1044874343C>ALeu115MetDamaging0.988Tolerated0
2367135356A>GTyr119CysDamaging1Not tolerated1
338832359G>TArg120LeuDamaging1Not tolerated1
3019023359G>AArg120HisDamaging1Not tolerated1
2101959366G>TGlu122AspDamaging1Not tolerated1
2477504368G>ASer123AsnBenign0.339Tolerated0
897020376C>TPro126SerDamaging1Not tolerated1
2866341382C>TArg128TrpDamaging1Not tolerated1
728557385C>ALeu129MetDamaging0.999Tolerated0
897019397C>GPro133AlaDamaging1Tolerated0
1067888400T>GTrp134GlyDamaging1Not tolerated1
1036471425A>GLys142ArgBenign0.039Tolerated0
2729394437G>AGly146GluDamaging1Not tolerated1
631878443T>CLeu148ProDamaging0.998Not tolerated1
1489324457G>AGlu153LysBenign0Tolerated0
1038891467A>CGln156ProDamaging0.96Tolerated0
285894469C>TArg157TrpDamaging0.999Not tolerated1
1373583469C>GArg157GlyDamaging0.997Not tolerated1
634948470G>AArg157GlnDamaging0.929Tolerated0
895613473T>CVal158AlaBenign0.199Not tolerated1
942179475C>TArg159TrpDamaging1Not tolerated1
29676476G>AArg159GlnDamaging1Not tolerated1
935088505C>APro169ThrDamaging0.565Not tolerated1
1443102533A>GLys178ArgBenign0.008Tolerated0
3079404571G>TAsp191TyrDamaging1Not tolerated1
2185427576G>CGlu192AspBenign0.001Tolerated0
338830577C>ALeu193IleBenign0.036Tolerated0
2495690581G>ACys194TyrDamaging0.956Tolerated0
1358313598G>AVal200IleBenign0Tolerated0
338829604G>CAsp202HisDamaging0.981Not tolerated1
1079881616G>AGlu206LysDamaging0.999Tolerated0
2652422625A>GLys209GluDamaging1Tolerated0
1948727639A>CGlu213AspDamaging0.997Not tolerated1
2067418652G>TVal218LeuBenign0.131Tolerated0
2683548652G>AVal218MetDamaging0.993Not tolerated1
1948222683A>GGln228ArgBenign0.002Not tolerated1
2411429688A>CAsn230HisDamaging0.858Tolerated0
2544280688A>TAsn230TyrDamaging0.948Not tolerated1
338827695G>AGly232GluBenign0.001Tolerated0
898600735G>AMet245IleDamaging0.785Tolerated0
1979274743C>TThr248MetDamaging0.731Not tolerated1
338824776T>CLeu259ProDamaging1Tolerated0.10
1913130788T>CLeu263ProDamaging1Not tolerated0.90
1464834815C>GThr272SerDamaging1Tolerated0
1028372833T>CIle278ThrDamaging1Not tolerated1
2549031856A>GIle286ValBenign0.003Tolerated0
1406180859G>AAsp287AsnBenign0.013Tolerated0
338823861C>AAsp287GluBenign0.085Tolerated0
1015029904C>TLeu302PheDamaging0.996Tolerated0
697520908G>CCys303SerDamaging0.614Tolerated0
1945084928C>TArg310TrpDamaging0.989Tolerated0
2664932948G>TLeu316PheDamaging0.998Tolerated0
29681964G>AGlu322LysDamaging1Not tolerated1
1018075989C>TThr330MetDamaging1Not tolerated1
16471561031G>AArg344HisDamaging1Not tolerated1
19593931058T>CLeu353ProDamaging1Tolerated0
20811561100G>AArg367GlnBenign0.184Tolerated0
14641801103C>AAla368GluDamaging0.997Tolerated0
3388171121T>CMet374ThrDamaging0.874Not tolerated1
3388161124C>TPro375LeuDamaging1Not tolerated1
20407751139G>ACys380TyrDamaging1Not tolerated1
14551641147G>CGlu383GlnDamaging1Not tolerated1
296791186C>TArg396TrpDamaging1Not tolerated1
9539061187G>AArg396GlnDamaging1Not tolerated1
3388141207G>AVal403IleDamaging0.618Tolerated0
8969431219T>ATyr407AsnDamaging1Not tolerated1
296801226T>CLeu409SerDamaging1Not tolerated1
20777531235G>AGly412GluDamaging1Tolerated0
33627601238C>AThr413LysDamaging0.612Not tolerated1
20059561259A>CGln420ProDamaging0.996Tolerated0
13337371268G>TGly423ValDamaging1Tolerated0
19045761282A>GAsn428AspDamaging0.812Tolerated0
25587441288G>AGlu430LysBenign0.001Tolerated0
25355271298G>TSer433IleDamaging0.601Not tolerated1
13336451310C>APro437HisDamaging1Not tolerated1
9315711315C>TArg439CysDamaging1Not tolerated1
3388131361C>TPro454LeuDamaging1Not tolerated1
13543971366G>CGly456ArgDamaging1Not tolerated1
8969401369G>AVal457IleBenign0.003Tolerated0
19843621387A>GIle463ValBenign0.023Tolerated0
27168551390G>CGly464ArgDamaging1Not tolerated1
10630761394G>AArg465HisDamaging1Not tolerated1
24548351450G>AAsp484AsnBenign0.002Tolerated0
16225341460C>TAla487ValDamaging1Tolerated0
24821641467C>GAsp489GluDamaging0.999Tolerated0
19194791490A>CHis497ProDamaging1Tolerated0
30794021502T>ALeu501GlnDamaging1Not tolerated1
30663411507C>GPro503AlaDamaging1Not tolerated1
21383561508C>TPro503LeuDamaging1Not tolerated1
8955401513C>GArg505GlyDamaging1Not tolerated1
30167671513C>TArg505TrpDamaging1Not tolerated1
8955391518A>TGlu506AspDamaging0.944Tolerated0
14462331518A>CGlu506AspDamaging0.944Tolerated0
19032251519C>ALeu507IleDamaging1Tolerated0
18034231525A>GIle509ValBenign0.002Tolerated0
8955381528G>AAla510ThrDamaging0.921Tolerated0
6974361529C>TAla510ValBenign0.265Tolerated0
23271221535G>ACys512TyrBenign0.015Tolerated0.1
PolyPhen provides a probability score for how damaging a variant is, with higher values indicating more likelihood of pathogenicity, while SIFT predicts whether a substitution is “tolerated” or “not tolerated”, with a focus on protein functionality. The numbering of nucleotides is based on the DNA sequence of the CYP24A1 transcript NM_000782.5.
Table 4. Genetic variants in VDR gene and their functionality prediction using in silico tools.
Table 4. Genetic variants in VDR gene and their functionality prediction using in silico tools.
Genetic Variant
ID		LocationAmino Acid
Substitution		PolyphenSIFT
3088872T>CMet1ThrBenign0.29Not tolerated0.68
32357112T>GMet1ArgDamaging0.97Not tolerated0.68
217484910A>GMet4ValBenign0Tolerated0.42
88235714C>TAla5ValBenign0Tolerated0.47
226149117C>TAla6ValBenign0Tolerated0.47
88235652C>TArg18TrpDamaging0.99Not tolerated0.53
303290153G>AArg18GlnBenign0.01Tolerated0.47
241092158G>AVal20MetBenign0.07Tolerated0.47
95973661C>TPro21SerDamaging0.96Not tolerated0.74
88235464C>TArg22TrpDamaging1Not tolerated1
88099965G>AArg22GlnDamaging0.91Not tolerated1
207261865G>CArg22ProDamaging1Not tolerated1
213732176G>AVal26MetDamaging1Not tolerated1
275911679T>CCys27ArgDamaging1Not tolerated1
95022486A>GAsp29GlyDamaging1Not tolerated1
84846789G>AArg30GlnDamaging0.61Tolerated0
774598G>AGly33AspDamaging1Not tolerated1
333953998G>CGly33AlaDamaging1Not tolerated1
1407165110A>GAsn37SerDamaging0.99Not tolerated1
7753137G>AGly46AspDamaging1Not tolerated1
1954983137G>CGly46AlaDamaging0.99Not tolerated1
7750149G>AArg50GlnDamaging1Not tolerated1
1193364156G>TMet52IleBenign0.11Tolerated0
3004611160C>TArg54TrpDamaging1Not tolerated1
1370955161G>AArg54GlnDamaging0.99Not tolerated1
717364176C>TThr59IleBenign0.22Tolerated0
961739182C>TPro61LeuDamaging0.94Not tolerated1
1957857191G>AGly64GluDamaging0.54Not tolerated1
1425408199C>TArg67CysDamaging0.81Not tolerated1
1009301200G>AArg67HisBenign0.001Tolerated0
1059781212A>GAsp71GlyDamaging0.58Tolerated0
7746218G>AArg73GlnDamaging1Not tolerated1
3148965220C>AArg74SerDamaging0.999Not tolerated1
880998221G>AArg74HisDamaging1Not tolerated1
635013227G>TCys76PheDamaging1Not tolerated1
3188427236G>ACys79TyrDamaging1Not tolerated1
7749239G>AArg80GlnDamaging0.996Not tolerated1
953840257A>GAsp86GlyBenign0.197Not tolerated1
64425259A>GIle87ValDamaging0.72Tolerated0
880997274G>AGlu92LysDamaging1Not tolerated1
2154778310C>TArg104TrpDamaging1Not tolerated1
880996311G>AArg104GlnDamaging0.998Not tolerated1
962188361C>TArg121TrpDamaging0.986Not tolerated0.79
880995362G>AArg121GlnDamaging0.858Tolerated0.21
2175400388C>TArg130CysDamaging0.996Not tolerated1
2007326389G>CArg130ProDamaging0.921Tolerated0
2136689389G>AArg130HisBenign0.001Tolerated0
957488395T>GIle132SerDamaging1Not tolerated1
1517667411C>AAsp137GluBenign0Tolerated0
2115626419A>CHis140ProDamaging0.941Tolerated0
2438523446A>GAsp149GlyBenign0.109Tolerated0
944289460C>TArg154TrpDamaging0.997Not tolerated1
1006650463C>APro155ThrDamaging0.966Tolerated0
1991958473G>AArg158HisBenign0.388Tolerated0.11
1432897519A>TArg173SerBenign0Tolerated0.11
1971286527C>TPro176LeuBenign0Tolerated0.84
1979236541G>AAsp181AsnBenign0Tolerated0.68
1036372542A>GAsp181GlyBenign0.087Tolerated0.68
1056222565C>AHis189AsnBenign0Tolerated0.74
2521491575C>GThr192SerBenign0Tolerated0.63
1387284610A>CAsn204HisDamaging0.703Tolerated0.21
2267460613C>GLeu205ValBenign0.263Tolerated0.21
1508246634T>ASer212ThrBenign0.263Tolerated0.21
3064877670C>TLeu224PheBenign0.011Tolerated0.21
2093377683C>TPro228LeuDamaging0.976Not tolerated0.79
2119717696C>GAsp232GluBenign0.059Tolerated0.11
2162565720G>TLys240AsnDamaging0.81Not tolerated0.84
2179980725T>CIle242ThrDamaging0.989Not tolerated0.84
1958573759C>GAsp253GluBenign0Tolerated0.11
2074580771G>CGlu257AspBenign0.008Tolerated0.11
1407164775C>GGln259GluDamaging1Not tolerated0.89
1516080781G>AVal261IleBenign0.230Tolerated0.11
1162259803T>CIle268ThrDamaging0.984Not tolerated0.89
3064965820C>TArg274CysDamaging1Tolerated0.05
7752821G>TArg274LeuDamaging1Tolerated0.05
915348821G>AArg274HisDamaging0.998Not tolerated0.95
1504399821G>CArg274ProDamaging1Tolerated0.05
2067557824C>TSer275PheBenign0.271Tolerated0.05
2097936845A>GAsp282GlyBenign0.02Tolerated0
2506489856T>CTrp286ArgDamaging1Not tolerated1
1949259869A>GAsn290SerBenign0Tolerated0.21
3339933874G>CAsp292HisBenign0.003Tolerated0.05
1449972886C>TArg296CysBenign0.045Tolerated0.32
308882889G>AVal297IleBenign0Tolerated0.11
2129305901A>GThr301AlaBenign0Tolerated0
1338550910G>AGly304ArgDamaging1Not tolerated1
7754915C>GHis305GlnDamaging0.977Not tolerated1
7755941T>GIle314SerDamaging0.739Not tolerated1
308879945G>TLys315AsnDamaging0.992Not tolerated1
2438524967C>GLeu323ValDamaging0.999Not tolerated1
7748985G>AGlu329LysDamaging1Not tolerated1
2585094985G>CGlu329GlnDamaging1Not tolerated1
11180991015G>AVal339IleBenign0.001Tolerated0
8600011016T>CVal339AlaBenign0.345Not tolerated1
3816031027C>TArg343CysDamaging1Not tolerated1
21353731030C>TPro344SerDamaging0.998Not tolerated1
77591036G>AVal346MetDamaging0.998Not tolerated1
31884251040A>GGln347ArgBenign0.003Tolerated0
10372201045G>AAla349ThrBenign0Tolerated0
3088781048G>AAla350ThrBenign0.001Tolerated0
7273621073G>AArg358HisBenign0.045Not tolerated1
7547321085C>TThr362IleBenign0.009Tolerated0
24296951088T>CLeu363ProDamaging1Not tolerated1
10386351102C>TArg368CysDamaging1Not tolerated1
13425261103G>TArg368LeuBenign0.045Tolerated0
25193981108C>GArg370GlyDamaging0.957Tolerated0
8401991109G>AArg370HisBenign0,028Tolerated0
10407761115C>TPro372LeuBenign0.226Not tolerated0.89
8825751121C>GPro374ArgDamaging1Tolerated0
10386001163C>AAla388AspDamaging0.792Not tolerated1
77561171C>TArg391CysDamaging1Not tolerated1
2646961171C>AArg391SerDamaging1Not tolerated1
21373191172G>AArg391HisDamaging1Not tolerated1
8823091183G>CGlu395GlnBenign0.129Tolerated0
27474881186G>AGlu396LysDamaging0.995Not tolerated1
2646971190A>CHis397ProDamaging0.999Not tolerated1
24441361204C>TArg402CysDamaging1Not tolerated0.63
26831911205G>AArg402HisDamaging1Not tolerated0.63
27922811214C>TSer405PheDamaging0.999Not tolerated0.63
19170951216T>APhe406IleBenign0.026Tolerated0.37
9924651229G>TCys410PheBenign0.041Tolerated0.37
20995341273G>AGlu425LysDamaging0.981Not tolerated0.42
PolyPhen provides a probability score for how damaging a variant is, with higher values indicating more likelihood of pathogenicity, while SIFT predicts whether a substitution is “tolerated” or “not tolerated”, with a focus on protein functionality. The numbering of nucleotides is based on the DNA sequence of the VDR transcript NM_000376.3.
Table 5. Genetic variants found to be associated with vitamin D-related diseases in human studies.
Table 5. Genetic variants found to be associated with vitamin D-related diseases in human studies.
GeneReference
SNP Number		Molecular
Consequences		Clinical Consequences
CYP27B1rs778438734Nonsense(Tyr7X)Associated with an increased risk of vitamin D-dependent rickets type I (VDDR-I) due to the inhibition of active vitamin D synthesis [83].
CYP27B1rs2140398340Nonsense(Trp17X)Associated with an increased risk of VDDR-I due to the inhibition of active vitamin D synthesis [84].
CYP27B1rs760233049Nonsense(Gln121X)Associated with an increased risk of VDDR-I due to the inhibition of active vitamin D synthesis [85].
CYP27B1rs2140397262Nonsense(Gln135X)Associated with an increased risk of VDDR-I due to the inhibition of active vitamin D synthesis [86].
CYP27B1rs118204009Missense(Arg389His)Associated with an increased risk of VDDR-I due to the impaired 1-α-hydroxylase activity and reduced conversion of25-hydroxyvitamin D3 to its active form [87].
CYP27B1rs118204011Missense(Leu343Phe)Associated with an increased risk of VDDR-I due to reduced 1-alpha-hydroxylase activity, leading to vitamin D deficiency [72].
CYP27B1rs118204012Missense(Glu189Gly)A variant of uncertain significance reported to be associated with vitamin D insufficiency [73,88].
CYP2R1rs1306247629Nonsense(Tyr73X)Associated with an increased risk of VDDR-1B due to disrupted CYP2R1 protein, resulting in impaired vitamin D activation [89].
CYP2R1rs1555014321Nonsense(Glu42X)Associated with an increased risk of VDDR-1B due to truncated CYP2R1 protein, resulting in impaired vitamin D 25-hydroxylase activity [90].
CYP2R1rs1848596931Nonsense(Cys98X)Associated with an increased risk of VDDR-1B due to truncated CYP2R1 protein, resulting in impaired vitamin D 25-hydroxylase activity [91].
CYP2R1rs781823033Nonsense(Arg131X)Associated with an increased risk of VDDR-1B due to truncated CYP2R1 protein, leading to impaired vitamin D 25-hydroxylase activity and defective vitamin D metabolism [92].
CYP2R1rs782006425Nonsense(Trp234X)Associated with an increased risk of VDDR-1B due to truncated CYP2R1 protein, resulting in impaired vitamin D 25-hydroxylase activity [92].
CYP2R1rs199883994Nonsense(Arg424X)Associated with an increased risk of VDDR-1B due to truncated CYP2R1 protein, resulting in impaired vitamin D 25-hydroxylase activity [92].
CYP2R1rs10741657Promoter variant (Altered transcription)Associated with decreased 25-hydroxyvitamin D levels and an increased risk of vitamin D deficiency, particularly in homozygous individuals [60].
VDRrs121909792Nonsense(Tyr295X)Associated with hereditary vitamin D-resistant rickets (HVDRR), presenting with rickets, growth retardation, skeletal deformities, and alopecia [93].
VDRrs1185429975Nonsense(Ser187X)Associated with HVDRR, presenting with rickets, hypocalcemia, and alopecia [59].
VDRrs121909795Nonsense(Gln152X)Associated with HVDRR due to impaired binding of 1,25-dihydroxyvitamin D3 [94].
VDRrs980041568Nonsense(Arg73X)Classified as pathogenic and observed in individuals with vitamin D-dependent rickets [95].
VDRrs201106427Nonsense(Arg50X)Classified as pathogenic and observed in individuals with vitamin D-dependent rickets, presenting with alopecia and hypocalcemia [96].
CYP24A1rs6068816Silent (Arg159Arg)Associated with an increased risk of hyperuricemia, particularly in overweight individuals [97].
CYP24A1rs6022999Intron variantAssociated with an increased risk of chronic hepatitis C virus infection due to disruptions in vitamin D metabolism [98].
CYP24A1rs2762943Promoter variant (Altered transcription)Associated with low serum 1,25-dihydroxyvitamin D levels in multiple sclerosis patients [99].
CYP24A1rs4809959Intron variantIncreased risk of chronic systemic lupus erythematosus due to disruptions in vitamin D metabolism [100].
CYP24A1rs17216707Promoter variant (Altered transcription)Associated with impaired vitamin D metabolism in kidney stone disease [101].
CYP24A1rs6013905Intron variantAssociated with impaired vitamin D metabolism in colorectal cancer patients [102].
CYP24A1rs4809957Intron variantAssociated with vitamin D deficiency in type II diabetes [103].
CYP24A1rs17219315Intron variantAssociated with altered vitamin D metabolism and autism in children [104].
CYP24A1rs2296241Silent (Pro289Pro)Associated with an increased risk of hormone-related cancers [104].
All of the variants were selected from the literature and checked with the NCBI-supported public website PheGenI (The Phenotype–Genotype Integrator, ncbi.nlm.nih/gab/phegeni).
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Jarrar, Y.; Alhammadin, G.; Lee, S.-J. Genetic Polymorphisms in Cytochrome P450 Enzymes Involved in Vitamin D Metabolism and the Vitamin D Receptor: Their Clinical Relevance. J. Pers. Med. 2025, 15, 128. https://doi.org/10.3390/jpm15040128

AMA Style

Jarrar Y, Alhammadin G, Lee S-J. Genetic Polymorphisms in Cytochrome P450 Enzymes Involved in Vitamin D Metabolism and the Vitamin D Receptor: Their Clinical Relevance. Journal of Personalized Medicine. 2025; 15(4):128. https://doi.org/10.3390/jpm15040128

Chicago/Turabian Style

Jarrar, Yazun, Ghayda’ Alhammadin, and Su-Jun Lee. 2025. "Genetic Polymorphisms in Cytochrome P450 Enzymes Involved in Vitamin D Metabolism and the Vitamin D Receptor: Their Clinical Relevance" Journal of Personalized Medicine 15, no. 4: 128. https://doi.org/10.3390/jpm15040128

APA Style

Jarrar, Y., Alhammadin, G., & Lee, S.-J. (2025). Genetic Polymorphisms in Cytochrome P450 Enzymes Involved in Vitamin D Metabolism and the Vitamin D Receptor: Their Clinical Relevance. Journal of Personalized Medicine, 15(4), 128. https://doi.org/10.3390/jpm15040128

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