Introduction

Essential hypertension (EH) is still a global health problem. In 2025, it was estimated that 1.56 billion people globally would have EH [1]. Those populations with EH have a higher risk of coronary artery disease, cerebrovascular disease, and heart failure [2]. Recently, genetic polymorphism of Vitamin D receptor (VDR) has been linked to EH development in 30–50% cases [3]. Beyond essential hypertension (EH), VDR gene polymorphisms have also been linked to other common diseases such as osteoporosis [4], type 2 diabetes mellitus [5], and various autoimmune conditions, including multiple sclerosis [6] and systemic lupus erythematosus [7]. BsmI, FokI, ApaI, and TaqI polymorphisms have demonstrated varying degrees of association with these diseases due to their influence on vitamin D metabolism, immune modulation, and cellular differentiation [8]. However, the specific role of VDR polymorphisms in EH has not been fully elucidated, which justifies our focused analysis on EH in this study. Additionally, in cardiovascular metabolism, 1,25-dihydroxyvitamin D (1,25 [OH]2 D) binds to the VDR, a transcription factor in the aortic endothelium, and smooth muscle vascular cells to exercise its biological effects on myocardiocytes [9–11].

The most investigated polymorphisms of VDR are FokI (rs2228570, C>T) and BsmI (rs1544410, G>A). FokI polymorphisms are made up of a T to C transition that changes the start codon and the length of the vitamin VDR protein. Compared to the polymorphic form that contains the variant C (allele F), the variant T (allele f) in FokI, produce the longer total protein with 427 amino acids which have a lower level of biological activity. VDR with the FokI CC genotype (FF) that has shorter a total protein of 424 amino acids resulting in higher VDR protein activity when compared to VDR with the CT (Ff) or TT (ff) genotypes [12–16]. This is because CC are more likely to be found in the VDR gene. The truncated protein, namely the 424 amino acid protein, found in individuals with the FF genotype is believed to contribute to the onset of EH by enhancing the production of renin and angiotensin II. Therefore, dominant homozygous (FF) and heterozygous (Ff) have a 2.2-fold increased chance of developing EH compared to recessive homozygous (ff) [17].

The BsmI polymorphisms is an A to G nucleotide substitution that can be found in intron 8 and has an effect on the stability of the transcript [18]. These polymorphisms have been linked with an increased likelihood of developing EH [18]. Therefore, BsmI GG genotype (BB) might also contribute to EH. Conversely, the ApaI and BsmI polymorphisms, traditionally recognized for their involvement in modulating messenger ribonucleic acid (mRNA) stability and protein translation of VDR, were postulated to exert an influence on vitamin D functionality, consequently affecting plasma renin activity and blood pressure levels [19, 20].

The polymorphisms chosen for this study (BsmI, FokI, ApaI, and TaqI) are the most commonly studied and clinically relevant variants in the VDR gene [21]. Previous study has identified these polymorphisms as the genetic variants associated with blood pressure regulation through mechanisms involving the renin-angiotensin system (RAS) and vascular function [21]. Other polymorphism, such as Tru9I (rs757343), has been studied in relation to vitamin D metabolism, but evidence for their direct involvement in EH is still limited [22]. Additionally, polymorphisms such as Cdx2 (rs11568820) are known to affect the VDR gene promoter region, but they are more commonly associated with conditions like bone density or inflammatory diseases rather than EH [23]. Given the existing evidence and the higher prevalence of studies on these polymorphisms, we focused our analysis on the BsmI, FokI, ApaI, and TaqI variants.

Previous meta-analysis of 7 studies had investigate association between VDR gene polymorphism and susceptibility of EH [21]. Results showed that AA genotype (bb) frequency was decreased in EH patients compared with healthy controls indicating that AA genotype (bb) reduce susceptibility to EH [21]. Meanwhile, this meta-analysis did not find significant correlation between FokI polymorphism and susceptibility to EH [21]. Emerging evidences revealed other single nucleotide polymorphism (SNP) that may play role in increasing the susceptibility of EH along with additional studies that may modify previous results [24]. In accordance with the consensus for updating systematic review [25], our aim is to elucidate the relationship between VDR gene polymorphisms and the risk of EH.

Methods

Results

Initial search strategy identified 2370 records from database searching with 2 additional records from manual search (S1 Table). Results were imported to Endnote X9 and with duplicates removed, there were 2174 records left for review. Title and abstracts were reviewed based on inclusion and exclusion criteria and resulting 30 reports. There were 30 full text paper to be reviewed. There were 17 reports excluded because of 4 conference abstracts, 1 commentary paper, 4 reviews, 6 studies with no genotype frequency on hypertensive group, and 2 studies of pregnant patients. There were 13 reports that included in this systematic review with additional 7 reports from previous systematic review [21] and 2 studies from manual searching. Finally, a total of 22 reports representing 22 studies will be used in this systematic review (Fig 1).

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Fig 1. PRISMA 2020 flow diagram for updated systematic reviews which included searches of databases, registers and other sources.

https://doi.org/10.1371/journal.pone.0314886.g001

This systematic review identified 13 case-control studies [39–57], 2 cross sectional studies [58, 59], and 1 cohort study [60] from a total of 13 countries (Table 1). There were 17 studies reporting about FokI polymorphism [39, 41, 42, 44, 45, 47–55, 57, 58, 60], 9 studies reporting about BsmI polymorphism [41, 42, 47–49, 51, 53, 54, 60], 7 studies reporting ApaI polymorphism [41, 42, 47, 48, 51, 54, 57], 8 studies reporting TaqI polymorphism [40–42, 46–49, 54], and 2 studies reporting other SNPs (CYP24A1 rs2762939,CYP2R1 rs1993116 and rs10741657; CYP24A1 rs4809957 and rs6068816) [43, 56]. Additionally, 1 study report only the recessive model for BsmI polymorphism and TaqI polymorphism.[59] Genotyping methods for detecting polymorphism were varied from 11 studies using PCR with Taqman [40, 43, 45, 47, 48, 50, 52, 56–59], 10 studies using PCR with restriction fragment length polymorphism (RFLP) [39, 41, 42, 44, 49, 51, 53–55, 60], or 1 study using PCR with amplification refractory mutation system (ARMS) [46]. Population age from all studies were varied between 25 to more than 100 years old. Glocke, et al. [50] and Gussago et al. [54] include patients with more than 90 and 100 years old in case group, respectively. Other comorbidities beside EH were diabetes from 3 studies [40, 48, 52], dyslipidemia from 2 studies [45, 48], stroke from 1 study [42], obesity and metabolic syndrome from 2 studies [48, 59]. There were 15 studies with case group include hypertensive patients defined by SBP ≥ 140 and/or DBP ≥ 90 mmHg [39, 41, 43, 44, 47–49, 51, 52, 55–60]. Meanwhile, there were 7 studies with case group include hypertensive patients from all stages [40, 42, 45, 46, 50, 53, 54]. The distribution frequency of all genotype in the control group from all studies were consistent with HWE (p > 0.05).

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Table 1. Characteristic of included studies.

https://doi.org/10.1371/journal.pone.0314886.t001

Risk of essential hypertension in patients with BsmI polymorphism

We conducted an evaluation of nine studies that reported on the susceptibility to EH in patients with the BsmI polymorphism (Figs 2 and S10–S12) [41, 42, 47–49, 51, 53, 54, 60]. Additionally, one study focused solely on a recessive model for the BsmI polymorphism [59]. The recessive model indicated a reduced risk of EH in patients who were recessive homozygous (bb) for BsmI (OR: 0.81; 95%CI, 0.69 to 0.94, p = 0.007; I² = 35%, p = 0.13) (Fig 2). However, no significant results were found for the allele, additive, and dominant models (S10–S12 Figs). A fixed effect model (FEM) was employed for all analyses as there was no significant statistical heterogeneity. Subgroup analyses of all models based on the continent of origin also yielded no significant findings (S13–S16 Figs). Sensitivity analysis using a leave-one-out approach for the allele, additive, and dominant models showed no change in the pooled results (S17 Fig). Conversely, the leave-one-out analysis for the recessive model revealed a shift to non-significance upon the exclusion of the study by Wang et al. [60].

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Fig 2. Forest plot for recessive model (Genotype bb vs Genotype BB + Bb) of BsmI polymorphism in risk of hypertension.

The solid squares denote the odds ratios, with the horizontal lines indicating the 95% confidence intervals and the diamond denotes the pooled effect size. SD, standard deviation; IV, inverse variance; CI, confidence interval; df, degrees of freedom; Chi2,chi-squared statistic; p, p-value; I2, I-squared heterogeneity statistic; Z, Z statistic.

https://doi.org/10.1371/journal.pone.0314886.g002

Risk of essential hypertension in patients with other single nucleotide polymorphisms

Other SNPs were reported in only two studies [43, 56]. Ye et al. [56] examined the role of CYP2R1 rs1993116 and rs10741657, and CYP24A1 rs4809957 and rs6068816 in EH susceptibility. They found a significantly lower SBP in treated EH patients with the TT genotype of rs1993116 and rs10741657 (p = 0.002). For adjusted additive and dominant models, there was a significant reduction in EH risk associated with rs1993116, resulting in an OR of 0.788 (95%CI, 0.644–0.963; p = 0.02) and 0.719 (95%CI, 0.545–0.949; p = 0.02), respectively. The results for rs10741657 were also significant, with an OR of 0.805 (95% CI, 0.66–0.983; p = 0.033) for the additive model and 0.733 (95% CI, 0.556–0.966; p = 0.028) for the dominant model. There were no significant associations between CYP24A1 rs4809957 and rs6068816 with EH susceptibility.

Meanwhile, Varakantham et al. reported that patients with the CYP24A1 rs2762939 CC variant had a significantly higher risk of EH in males (OR: 3.141; 95% CI, 1.164 to 8.478; p = 0.024) and an inverse association in females (OR: 0.398; 95% CI, 0.172 to 0.920; p = 0.031) [43].

The complete summary for the risk of essential hypertension across different polymorphisms (FokI, BsmI, ApaI, and TaqI) and genetic models are available in Table 2.

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Table 2. Summary of essential hypertension risk in patients with FokI, BsmI, ApaI, and TaqI polymorphism.

https://doi.org/10.1371/journal.pone.0314886.t002

Discussions

In this review, we examined the association between various VDR polymorphisms and EH risk. No significant association was found between the FokI polymorphism and EH risk, a result that remained unchanged after sensitivity analysis, suggesting no study had a disproportionate influence on the overall effect-size estimate. Furthermore, considering that ethnicity and age are important factors in studying EH, as indicated by previous research, we conducted additional related analyses [61]. The subgroup analysis indicated that continent of origin did not influence the results. However, meta-regression revealed that age and sex significantly affected the findings. The impact of the FokI polymorphism on EH risk varied according to sex, with the recessive homozygous (ff) genotype associated with a higher risk of EH in females but a lower risk in males. Additionally, younger individuals with the ff genotype had a higher EH risk, while older individuals had a lower risk. Methodological quality, assessed by NOS score, also significantly influenced EH risk, with higher quality studies indicating a higher risk for those with the ff genotype. Meanwhile, our meta-analysis of the BsmI polymorphism indicated that, in the recessive model analysis, individuals with the recessive homozygous (bb) genotype exhibited a lower risk of EH. This polymorphism involves a nucleotide substitution (A to G in intron 8) that affects transcript stability, reducing VDR protein levels and potentially increasing RAS activity and blood pressure [61].

Three of the four single nucleotide polymorphisms (SNPs) occur within intron sections (the TaqI, ApaI, and BsmI variants), whereas the FokI variant is the only one that alters the codon. The BsmI and TaqI polymorphisms do not alter the structure of the VDR protein; however, they can affect the stability and/or translation efficiency of RNA [62]. Previous studies have reported associations between VDR gene polymorphisms and plasma renin activity [63]. Consequently, the influence of these VDR polymorphisms on EH risk has been investigated and confirmed by previous meta-analyses [21, 24]. According to Nunes et al. [24], the recessive homozygous (ff) genotype of the FokI polymorphism was associated with a lower risk of EH in the global population analysis. This effect was also evident in the Asian subgroups. However, their meta-analysis was based on small studies, comprising only six pooled studies, with evidence for the Asian subgroups derived from only two studies. Other polymorphisms were not examined in that review [24]. Meanwhile, another meta-analysis conducted by Zhu et al. [21] reported differing results, indicating no significant association between the FokI polymorphism and EH risk. However, they found that the BsmI polymorphism might increase EH risk. Their analysis showed that individuals with the homozygous dominant (BB) genotype, corresponding to the GG genotype, had a higher risk of EH compared to those with the homozygous recessive (bb) genotype, corresponding to the AA genotype [21]. Therefore, the substitution from A to G may indeed increase EH risk, a finding that is consistent with our meta-analysis.

The previous two meta-analyses did not undertake a comprehensive evaluation of the genetic interplay involving age, sex, and population origin in relation to EH risk. In our study, we found that age and sex significantly influence the association between the FokI polymorphism and EH risk. These findings may elucidate the existing discrepancies and inconsistent results concerning the FokI polymorphism’s effect on EH risk. Therefore, it is crucial that future studies take age and sex into account when assessing the impact of the FokI polymorphism on EH risk. Conversely, our analysis of the BsmI polymorphism reveals a more consistent association with EH risk, which appears to be independent of age.

In parallel to the BsmI polymorphism, the Taq-I polymorphism, situated within exon 9 but with both exerting influence on the 3’ untranslated region (3’UTR) of the VDR gene, assumes a pivotal role in modulating VDR gene expression. Specifically, it operates by regulating mRNA stability and protein translation efficiency [19]. The 3’UTR constitutes a locus for epigenetic phenomena, notably CpG island methylation, which demonstrates susceptibility to alterations contingent upon racial factors and the presence of polymorphisms within this gene region [20]. While these genetic variants do not induce alterations in the amino acid sequence of the resultant protein, they possess the capacity to modify the sequence within this regulatory segment of the gene, thereby exerting influence on gene expression and subsequent protein synthesis. Empirical evidence suggests that Bsm-I, Apa-I, and Taq-I exhibit linkage disequilibrium, with particularly robust linkage observed between Bsm-I and Taq-I [59]. This phenomenon implies that over time, restricted recombination within a specific gene locus fosters the emergence of polymorphisms intricately associated with one another, thereby potentially elucidating their concomitant effects across diverse biological processes [12]. Consequently, the linkage disequilibrium observed between the Bsm-I and Taq-I polymorphisms may be construed as a genetic determinant contributing, albeit partially, to the observed association of both variants with heightened blood pressure levels and susceptibility to EH [59]. In contrast to the available evidence, however, this meta-analysis did not uncover any significant association between the ApaI and TaqI polymorphisms and EH risk. This discrepancy could be attributed to the noted partial contribution of both polymorphisms towards EH susceptibility compared to the primary determinant, namely the BsmI polymorphism.

The differential association between VDR polymorphisms and EH risk could be attributed to the distinct biological functions of each polymorphism. For example, the BsmI polymorphism involves a nucleotide substitution in intron 8 that influences transcript stability, potentially reducing VDR protein expression [18]. This reduction may lead to increased RAS activity, contributing to elevated blood pressure and hypertension risk [19, 20]. Conversely, other polymorphisms like TaqI and ApaI, while located in similar non-coding regions, may not exert as pronounced an effect on gene expression. Studies have shown that TaqI and ApaI polymorphisms, though associated with VDR mRNA stability, have less influence on downstream pathways that regulate blood pressure compared to BsmI [47, 54]. Moreover, the linkage disequilibrium observed between BsmI and TaqI suggests that these polymorphisms may exert combined effects, yet BsmI appears to play a more dominant role in modulating the VDR’s influence on hypertension. This could explain why BsmI shows a stronger and more consistent association with EH risk in our analysis, while TaqI and ApaI do not. Additionally, FokI is unique in that it directly alters the structure of the VDR protein, leading to functional changes in receptor activity, but its impact on EH risk appears to be more dependent on population characteristics such as age and sex, as demonstrated in our meta-regression analysis.

Our study builds upon prior reviews, such as those conducted by Zhu et al. [21] and Nunes et al. [24], which examined the relationship between VDR polymorphisms and EH. We included additional studies published since these reviews and employed updated meta-regression techniques to assess the impact of age, sex, and study quality. This comprehensive approach allows for a more accurate understanding of the associations between VDR polymorphisms and EH risk.

Our meta-analysis encountered several limitations. Significant heterogeneity was observed in the results pertaining to the FokI and TaqI polymorphisms, likely stemming from variations across studies rather than sampling errors. The primary sources of heterogeneity were methodological quality, age, and sex differences among the studies, as indicated by meta-regression analysis. Despite conducting additional analyses by exclusively including studies with the same design, the heterogeneity persisted. Furthermore, potential publication bias may have affected our results, as smaller studies with null or negative findings are less likely to be published, which could have inflated the associations observed for certain polymorphisms. Although we used funnel plots and Egger’s test to assess publication bias, the limited number of studies included in some analyses might have hindered our ability to detect bias accurately.

Another limitation arises from the variability in study designs, including differences in population demographics, genotyping methods, and diagnostic criteria for essential hypertension. This variability could have contributed to the inconsistent findings across studies, particularly for the ApaI and TaqI polymorphisms. Additionally, the scarcity of data prevented us from fully assessing the impact of sex on the BsmI polymorphism. Similarly, we were unable to investigate the influence of methodological quality, sex, and age on the ApaI and TaqI polymorphisms due to the limited number of available studies.

Further research is needed to explore the role of other environmental and genetic factors that may interact with VDR polymorphisms to influence EH risk. For instance, vitamin D levels, sun exposure, dietary intake, and lifestyle factors such as physical activity and smoking could modify the effects of these polymorphisms on hypertension [64]. Additionally, epigenetic mechanisms, including DNA methylation and histone modifications, may further influence how VDR gene expression affects blood pressure regulation [65]. Future studies should also consider investigating the combined impact of other polymorphisms, such as those in the RAS, on EH risk. Larger multi-ethnic cohort studies with standardized genotyping methods will be essential for validating these associations and identifying potential gene-environment interactions that may contribute to the development of hypertension. Such studies will help elucidate the broader genetic landscape underlying EH and improve personalized approaches to prevention and treatment.

Conclusions

FokI polymorphism’s impact on EH risk is influenced by sex, age, and study quality, with the recessive homozygous (ff) genotype associated with lower EH risk in males and older individuals. Conversely, BsmI polymorphism is independently associated with EH risk, with recessive homozygotes having lower risk. No significant association was found between ApaI and TaqI polymorphisms and EH risk.

Supporting information