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. 2023 May 19;26(4):316–322. doi: 10.1097/MCO.0000000000000945

Impact of vitamin D receptor polymorphisms in selected metabolic disorders

Martyna Fronczek a, Tadeusz Osadnik a, Maciej Banach b
PMCID: PMC10256311  PMID: 37144463

Purpose of review

Vitamin D (vitD) can regulate metabolic pathways in adipose tissue and pancreatic β cells by interacting with its vitamin D receptor (VDR). The aim of this study was to review original publications published in the last months and verify the relationship between genetic variants in the VDR gene and type 2 diabetes (T2D), metabolic syndrome (MetS), overweight, and obesity.

Recent findings

The recent studies concern genetic variants located in the coding and noncoding regions of the VDR gene. Some of the described genetic variants may affect VDR expression or posttranslational processing altered functionality or vitD binding capacity of VDR. Nevertheless, the data collected in recent months on the assessment of the relationship between VDR genetic variants and the risk of T2D, MetS, overweight, and obesity still do not give a clear answer to whether they have a direct impact on these metabolic disorders.

Summary

Analysis of the potential association between VDR genetic variants and parameters such as glycemia, body mass index, body fat, and lipid levels improves the current understanding of the pathogenesis of T2D, MetS, overweight, and obesity. A thorough understanding of this relationship may provide important information for individuals with pathogenic variants and enable the implementation of appropriate prevention against the development of these disorders.

Keywords: metabolic syndrome, obesity, type 2 diabetes, vitamin D receptor

INTRODUCTION

Vitamin D (vitD) is a fat-soluble vitamin and is characterized by a steroid structure. VitD is converted in the hydroxylation process in the liver with the participation of hydroxylases [mainly by 25-hydroxylase CYP2R1) to 25-hydroxyvitamin D (25(OH)D] [1,2,3▪]. Second hydroxylation to the biologically active form 1,25(OH)2D, that is, calcitriol, is mediated by renal 1α-hydroxylase [2]. The vitD genomic response is induced through the binding of calcitriol to the cytosolic vitamin D receptor (VDR), which functions as a nuclear receptor and transcription factor. The calcitriol and VDR bind to the retinoid X receptor and the complex enter the nucleus, where it recognizes and binds to the vitamin D response element in the promoter region of genes, whose expression is dependent on vitD [4,5]. In this way, vitamin D can regulate the metabolism, proliferation, differentiation, or apoptosis of numerous cells, including adipocytes or pancreatic beta cells (Fig. 1) [5]. 

FIGURE 1.

FIGURE 1

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Effect of vitamin D and its receptor on adipocytes and pancreatic beta cells. 25(OH)2D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-hydroxyvitamin D; VDR, vitamin D receptor; RXR, retinoid X receptor; VDRE, vitamin D response element (created with BioRender.com).

Box 1.

Box 1

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no caption available

VitD is excreted mainly in the form of 24,25(OH)2D and 1,24,25(OH)3D in the bile, which is formed by the inactivation of 25(OH)D and 1,25(OH)2D by vitD 24-hydroxylase [3▪,4].

Previous studies indicate that genes encoding proteins related to the synthesis, distribution, and metabolism pathway of vitD, may participate in vitD deficiency (VDD) and in the pathomechanism of metabolic disorders or cardiovascular diseases [6–8].

The aim of this study was to review original publications published in the last months and verify the relationship between genetic variants in the vitamin D receptor and metabolic disorders such as type 2 diabetes, metabolic syndrome, overweight, and obesity.

RECENT FINDINGS

Association of vitamin D receptor polymorphisms with type 2 diabetes and glycemic status

Type 2 diabetes (T2D) is a complex and chronic disease that affects the quality of life of patients and the incidence of other diseases [9]. The VDR gene is expressed in pancreatic cells and disrupting its signaling pathway may affect insulin secretion [10,11]. Previous studies provide evidence of the association of VDR polymorphisms as potential genetic factors that may increase the risk of developing T2D. Unfortunately, these results are still inconsistent and show discrepancies [12▪▪].

In a study Xu et al. individuals with the A/A genotype of the rs2189480 polymorphism (G>A,C,T) of the VDR gene had a lower chance of developing T2D compared to participants with the G/A and G/G genotypes [13,14▪]. This polymorphism occurs in intron 4 and may affect the function of regulatory T cells that influence inflammatory activity. Presumably, by regulating the inflammatory response, this variant may have a protective effect on the development of T2D [14▪].

The second tested variant rs739837 (G>C/T) [15] is in the 3′ untranslated region (3’UTR) of the VDR gene and may affect the posttranscriptional regulation of the VDR. It is suggested that by affecting the stability and transcription of mRNA, VDR may increase the risk of developing T2D. In a study by Xu et al. individuals living with overweight or obesity with C/C and G/C genotypes of this polymorphism had a higher risk of developing T2D. Additionally, participants with higher body mass index (BMI) and the C allele also had higher fasting plasma glucose levels. It is suggested that genetic variants in the VDR gene may affect the insulin signaling pathway and lead to insulin resistance [14▪]. A published meta-analysis by Zeng et al. indicated that the T allele, T/T, and G/T genotypes in this polymorphism were associated with an increased risk of T2D [16▪]. And another study showed that individuals with T/T and G/T genotypes were more likely to T2D develop [17▪].

Another polymorphism of the VDR gene is the rs3847987 variant (C>A) [18]. It was found in a Chinese population study, that this variant was not associated with T2D but participants with A/A and C/A genotypes with hypertriglyceridemia were more likely to have T2D [17▪].

The most frequently analyzed polymorphism was rs7975232 in intron 8 (C>A). rs7975232 which may affect the stability of VDR mRNA, and translation of VDR [19–21]. This polymorphism may be associated with a reduced risk of T2D in North American countries and the Caucasian population and may increase the risk of T2D in a mixed population [12▪▪]. Another study indicates that the T allele of the rs7975232 is associated with the onset of T2D, while the G allele can be regarded as a protective allele [22]. On the other hand, other studies have not shown a relationship between rs7975232 genotypes and T2D [23–25].

Other rs1544410 polymorphism (C>A,G,T) is located in intron 8 near the 3′ end. Due to its location, its strong linkage disequilibrium with a polyadenosine microsatellite repeat in the 3′UTR and may affect the VDR translational activity [26,27]. A study by Liu et al. indicates that it may be associated with a reduced risk of T2D in Asians [12▪▪]. Another study indicates that the G allele of the rs1544410 may be associated with T2D in individuals with healthy periodontium [28]. Maulood et al. found a significantly higher fasting blood glucose value in patients with rs1544410 G/A and A/A genotypes and a higher triglyceride value in diabetic patients with the G/A genotype. Ultimately, they found no significant relationship between rs1544410 and T2D risk [24]. Also, a UK study found no significant correlation between rs1544410 and T2D risk [29]. In Malaysian patients, rs1544410 polymorphism was not associated with T2D, but in contrast, was an association between rs1544410 and the development of insulin resistance in T2D patients with poor glycemic control. Researchers suggest that the A/A genotype may protect against insulin resistance (95% lower insulin resistance likelihood) [30].

VDR genetic variant rs2228570 (aka rs10735810, A>C,G,T) is a variant in exon 2 [31,32]. rs2228570 affects vitD function and alters the binding efficiency of vitD to VDR, which may result in impaired insulin function and lead to T2D [12▪▪]. This polymorphism affects the formation of a longer or shorter variant of the VDR [31]. rs2228570 is characterized by the presence of two ATG start codons separated by six nucleotides. The synthesis of a longer variant of the VDR (f-VDR, 427 aa) with lower activity is conditioned by the occurrence of the A allele (f allele). In the case of substitution with the F allele, only one start codon is observed, resulting in a shorter VDR protein (F-VDR, 424 aa) [19,20,33–35]. Depending on the formed VDR, a different ability to induce the transcription of vitD-dependent genes is observed [33,36]. In a study by Liu et al., rs2228570 was associated with a significantly reduced risk of T2D in African and Asian countries [12▪▪]. Also, other studies conducted on Pakistani [37] and Jordanian [38] individuals demonstrate the potential relationship of this VDR polymorphism with susceptibility to T2D. Another published paper indicates that individuals with T2D and the C allele of rs2228570 may have an increased risk of periodontitis [28]. In contrast, some investigations show no significant association between rs2228570 and T2D [23,29] or glycemic status [23,39]. Also, a study in Malaysian patients with T2D with good or poor glycemic control indicated that rs2228570 was not associated with T2D. However, it was shown that healthy volunteers with the C/T genotype had lower BMI compared to the C/C and T/T genotypes (92% lower obesity likelihood). In addition, individuals with T2D with poor glycemic control were characterized by a higher BMI compared to individuals with good glycemic control with T2D and healthy volunteers (mean BMI (kg/m2): 29.4 ± 5.9 vs. 27.9 ± 5.2 and 26.4 ± 4.5, P = 0.007). This observation suggests that the rs2228570 polymorphism may be related to the development of obesity in non-T2D subjects [30].

Another rs731236 polymorphism is the A>G substitution in exon 9. This polymorphism is located near the exon-intron border and therefore may potentially affect the mRNA stability of the VDR gene [20]. A study in a small group of patients with T2D indicates that the T allele of rs731236 may be associated with T2D [22]. Another indicates that rs731236 is not related to glycemic status [23,25,39] but may be related to vitD insufficiency in the South African population [39].

Association of vitamin D receptor polymorphisms with metabolic syndrome

The presence of obesity together with two of the three additional diagnostic criteria (elevated blood pressure, impaired carbohydrate metabolism, or elevated nonhigh-density lipoprotein cholesterol) is referred to as metabolic syndrome (MetS). The development of obesity and MetS components significantly increases the risk of cardiovascular events [40]. In addition, VDD may be associated with, among others, increased levels of nonlipid biomarkers of cardiovascular risk, such as high sensitivity C-reactive protein, cystatin-C, creatinine, uric acid, or hemoglobin A1c (HbA1c) [41]. Additionally, it has also been shown that vitD supplementation has no effect on the level of adiponectin and leptin, which are related to the regulation of the body's energy management [42]. Moreover, the level of 25(OH)D and mutations in the genes encoding the proteins of the vitD synthesis and metabolism pathway do not relate to telomere length [43]. 1,25(OH)2D by its VDR plays an important role in the regulation of many metabolic pathways. VDR is expressed in β-Langerhans cells, muscle cells, liver cells, and adipocytes [5]. Fat storage decreases with obesity, and visceral fat accumulation may have an adverse effect on insulin signaling. Some studies suggest that genetic variants of the VDR gene and obesity may affect the risk of T2D [5,14▪]. The effect of vitD on MetS, its components, and the influence of VDR genetic variants has not yet been well documented. Studies indicate that polymorphisms of the VDR gene may affect insulin resistance, BMI, and high-density lipoprotein cholesterol (HDL-C) levels.

A cross-sectional study of pregnant women with and without MetS showed no significant association between the individual components of MetS and rs2228570. Alzaim et al. indicate that the F allele and FF genotype could be protective and the f allele ff genotype may have a risk role for MetS among pregnant Arab women [44].

In a study of Brazilian adolescents aged 10–19, rs7975232 was not associated with an increased risk of developing MetS, but the C/C genotype in the recessive model was significantly associated with arterial hypertension. In the case of the remaining VDR polymorphisms, no significant associations with MetS components and VDD were observed. The researchers indicate the importance of searching for genetic markers related to vitD metabolism in children and adolescents living with overweight or obesity. Identification of genetic markers will make it possible to identify the risk of developing MetS at an early age, and this will contribute to faster diagnosis of this disease and will allow a more effective fight against its progression [45].

Jin et al. showed that rs731236, rs7975232, rs2228570, and rs1544410 were not associated with the risk of developing MetS. However, an association was shown between hypertriglyceridemia and rs7975232. T/T genotype had lower triglyceride levels than G/G and G/T genotypes (mean triglyceride (mmol/l): 1.29 ± 0.63 vs. 1.78 ± 1.59, P < 0.01). Also, lower levels of HDL-C were noted in rs1544410 (A/A+G/A vs. G/G mean HDL-C (mmol/l): 1.28 ± 0.29 vs. 1.42 ± 0.34, P < 0.05) and in rs731236 variant (C/C+T/C vs. T/T mean HDL-C (mmol/l): 1.27 ± 0.29 vs. 1.42 ± 0.34, P < 0.05) [46].

Interesting results were provided by a study conducted on a group of healthy women from Southeast Asia. The genetic risk assessment (GRS) in the study was constructed based on five SNPs associated with vitD concentration (vitamin D-GRS): rs12785878 (DHCR7), rs12794714 (CYP2R1), rs6013897 (CYP24A1), rs2282679 (VDBP) and rs1801725 (CASR). In the conducted analyses, no significant relationship was observed between D-GRS and 25(OH)D, glucose, HbA1c, BMI, total cholesterol, HDL-C, low-density lipoprotein cholesterol, and triglycerides. Significantly higher body fat percentage values were observed in participants who followed a high-carbohydrate diet (mean intake 319 g/day) and carried > 2 VDD risk alleles to individuals with ≤ 2 risk alleles [mean log body fat percentage (%): 1.60 ± 0.04 vs. 1.53 ± 0.11, P = 0.016] [47▪▪].

Published results in recent years indicate that VDR genetic variants may be associated with MetS components such as abdominal obesity, BMI ≥30, prediabetes, diabetes, elevated non-HDL cholesterol level, high normal blood pressure, or hypertension. Further research with a much larger sample size is needed to verify this relationship.

Association of vitamin D receptor polymorphisms with overweight and obesity

Adipose tissue stores vitD in the organism, which affects its release and prevents the uncontrolled conversion of 25(OH)D to 1,25(OH)2D. On the other hand, vitD itself regulates metabolic pathways in adipose tissue, including adipogenesis, adipocyte apoptosis, and lipid metabolism by interacting with its receptor. It has been reported that VitD regulates the expression of many genes (i.e., interleukin 6, interleukin 1, peroxisome proliferator-activated receptor γ, NADPH oxidase, adipocyte-binding protein 2, or transcription nuclear factor 2) which may affect metabolic processes. Adipose tissue itself also affects the expression of enzymes that metabolize vitD. Conversion of 25(OH)D to 1,25(OH)2D in adipose tissue may be conditioned by the degree and type of obesity. It has been reported that abdominal subcutaneous adipose tissue (SAT) has less potential to synthesize 1,25(OH)2D than visceral adipose tissue (VAT) [3▪,5]. In addition, it was shown that 1,25(OH)2D3 stimulation significantly increased the expression of the VDR gene in the adipose tissue of individuals with BMI >40 kg/m2 compared to the tissue of individuals with BMI <25 kg/m2. Higher expression of the VDR gene was found in visceral preadipocytes of individuals living with obesity compared to lean individuals [48]. On the other hand, findings suggest that genetic variants within the VDR gene may significantly impact the development of obesity [49,50].

In an Iranian study on the relationship between the rs731236, rs7975232, and rs1544410 polymorphisms of the VDR gene and the risk of obesity, it was shown that the rs7975232 A allele and the A/A genotype may be predictors of obesity. Significantly higher BMI (mean BMI (kg/m2): 31.6 ± 7.7 vs. 28.6 ± 6.6, P = 0.022) and fasting blood glucose (mean fasting blood glucose (mg/dL): 114.6 ± 32.4 vs. 103.7 ± 29.4, P = 0.003) concentrations were observed in individuals with the A/A genotype [51]. Perhaps, rs7975232 polymorphism may predict an increased risk of obesity and could help identify new strategies to treat this metabolic disorder. The study conducted by Khattab et al. showed no significant relationship between rs1544410 and BMI or bioelectrical impedance parameters [26].

In turn in another study, individuals living overweight or obesity with VDR rs739837 C/C or G/C genotypes had a higher risk of developing T2D compared to nonobese individuals with the G/G genotype. A higher fasting plasma glucose level was also observed in individuals with the VDR rs739837 C allele with a BMI above 26.96 kg/m2. The second analyzed variant, rs2189480 had no relation to overweight or obesity [14▪].

The study conducted in a group of adults living with obesity indicates that VDR gene polymorphisms rs731236, rs7975232, rs1544410, and rs2228570 could be associated with some obesity markers. Finally, the analyzed VDR polymorphisms were not associated with changes in body weight and insulin sensitivity in dietary intervention and did not affect the level of transcription in the analyzed SAT of the abdominal cavity. However, higher BMI [A/G+G/G vs. A/A mean BMI (kg/m2): 35.3 ± 0.3 vs. 34.1 ± 0.3, P = 0.007], and fat mass [A/G+G/G vs. A/A mean fat mass (kg): 41.8 ± 0.7 vs. 39.1 ± 0.7, P = 0.006] values were observed in individuals with the rs731236 G allele. Also, higher BMI [C/A+A/A vs. C/C mean BMI (kg/m2): 35.3 ± 0.3 vs. 34.1 ± 0.3, P = 0.023] and fat mass [C/A+A/A vs. C/C mean fat mass (kg): 41.7 ± 0.6 vs. 39.4 ± 0.7, P = 0.028] values were reported among carriers of the rs7975232 A allele. In the case of the rs2228570, individuals living with overweight or obesity with the G allele had significantly higher adipose tissue insulin resistance index (G/G+G/A vs. A/A mean adipose tissue insulin resistance index: 7.8 ± 0.4 vs. 5.6 ± 0.5, P = 0.01) and increased levels of fasting-free fatty acids [G/G+G/A vs. A/A mean fasting-free fatty acid (μmol/l): 637.8 ± 13.4 vs. 547.9 ± 24.7, P = 0.011] [52▪▪].

Published data from the last months indicate divergent observations. Undoubtedly, the aspect limiting the correct interpretation of these publications is the fact that they cover different ethnic origins and differ in the size of the study groups. Analyses should be carried out on a large group of subjects to clearly determine the impact of VDR genetic variants on discussed disorders and diseases. It should be noted that most of the presented papers concern only observational studies (including cross-sectional studies) or meta-analyses. The VDR is being analyzed as a candidate gene whose variants may be associated with T2D, MetS, overweight, or obesity. Research with candidate genes may be limited by selection bias, low genetic coverage, high rate of false positives, and publication bias. At present, none of the presented variants is directly related in human genome-wide association studies (GWAS) to the discussed diseases. The quoted publications suggest that it is still important to look for an explanation of how genetic variants within the VDR gene affect the development of MetS, obesity, and insulin sensitivity. Analysis of the potential relationship between the genetic background of the VDR and such parameters as glycemia, adipose tissue, and lipid disorders improve the current understanding of the pathogenesis of T2D, MetS, overweight, and obesity. Confirmation of the impact of some VDR genetic variants on the parameters associated with these disorders and diseases may allow future personalized therapy for patients and provide information for individuals with pathogenic variants to implement prevention against the development of cardiometabolic disorders.

CONCLUSION

Publications collected in recent months on the assessment of the relationship between VDR genetic variants and the risk of T2D, MetS, overweight, and obesity still do not give a clear answer to whether they directly impact discussed metabolic disorders. It is still important to examine how genetic variants within the VDR gene are related to T2D, overweight, obesity, and MetS.

Acknowledgements

None.

Financial support and sponsorship

The Medical University of Silesia in Katowice and the Medical University of Lodz covered the publication costs.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest

  • ▪▪ of outstanding interest

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