Skip to main content

Fok I and Bsm I gene polymorphism of vitamin D receptor and essential hypertension: a mechanistic link


The vitamin D receptor (VDR) gene serves as a good candidate gene for susceptibility to essential hypertension. The gene regulates the renin angiotensin system by influencing blood pressure regulation. Around 3% of the human genome is regulated by the vitamin D endocrine system. Several studies have reported mixed results with respect to relationship of VDR gene and hypertension. Observational evidence supports the concept that vitamin D plays a role in the pathogenesis of cardiovascular disease and arterial hypertension which is further supported by meta-analysis and case control studies reporting how VDR polymorphism leads to the onset and development of hypertension. In this review, we summarize the existing literature on the link between VDR and hypertension, including mechanistic studies, observational data, and clinical trials showing relationship of vitamin D level and hypertension with a focus on recent findings related to genetic studies that showed the relationship of VDR gene polymorphism with vitamin D level in hypertensive and normotensive groups. As a result, determining the association of VDR polymorphisms with essential hypertension is expected to aid in the risk assessment for the condition.


Hypertension is a global public health problem with high morbidity and mortality. According to the World Health Organization, one in every three adults worldwide has high blood pressure (BP), which accounts for approximately half of all deaths from cardiac disease and stroke [1]. Hypertension is expected to be 60% more prevalent worldwide by 2025, affecting 1.56 billion people [2]. It is predicted that over 90% of patients with high BP have primary hypertension [3]. Primary hypertension is a polygenic disease caused by the interaction of genetic and environmental factors [4]. Although primary hypertension cannot be cured, it can be managed with appropriate therapy (including lifestyle modifications and medications) [5].

Multiple factors that control BP contribute to developing primary hypertension. The two primary factors include problems in either hormonal (natriuretic hormone, renin-angiotensin-aldosterone system [RAAS]) mechanisms or disturbances in electrolytes (sodium, chloride, potassium). Natriuretic hormone causes an increase in sodium concentrations in cells, which causes BP to rise. The RAAS regulates sodium, potassium, and blood volume, which in turn regulates arterial BP. Angiotensin II and aldosterone are two hormones involved in the RAAS. Angiotensin II causes blood vessel narrowing, increases the release of chemicals that raise BP, and increases aldosterone production. Aldosterone maintains sodium and water levels in the blood. As a result, there is more blood, which puts more pressure on the heart and raises BP [3]. Meanwhile, evidence suggests that genetic factors may play an important role in the development of primary hypertension [1]. It has been estimated that the heritability of hypertension ranges from 31 to 68%. Genome-wide association studies (GWAS) in several multinational cohorts have identified a large number of single nucleotide polymorphisms (SNPs) associated with hypertension [6].

Prospective studies showed that subjects with low vitamin D level was three times more likely to have hypertension than those with high vitamin D concentrations and also suggested that vitamin D receptor (VDR) polymorphism is associated with hypertension [7]. Since the VDR is widely distributed in vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes, the role of vitamin D and VDR in hypertension has received extensive attention [1].

Vitamin D and vitamin D receptor

Vitamin D is a group of fat-soluble molecules, and the most important of which are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). A large amount of vitamin D is converted to vitamin D3 from 7-dehydrocholesterol after exposure to ultraviolet B in the skin. Furthermore, just 10 to 20% of vitamin D comes from the diet as vitamin D2 or vitamin D3 [8]. Foods rich in vitamin D are mainly cod-liver oil, fish, animal liver, eggs, and fortified milk [1].

After entering the body, vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D (25(OH)D, calcidiol), which is the major circulating form of vitamin D and is used to assess overall vitamin D status. The kidney converts 25(OH)D to its bioactive form, 1,25-dihydroxyvitamin D (1,25(OH)2D3, calcitriol), which has much stronger specificity with VDR and is responsible for the majority of vitamin D metabolic actions [9].

VDR is a nuclear receptor protein that has a high affinity and specificity for binding to vitamin D3 (a form of vitamin D). When occupied by vitamin D3, VDR is phosphorylated, resulting in a change in surface conformation. The activated VDR then binds to the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D-responsive elements in the gene promoter region [10]. Activated VDR/RXR regulates the transcription of genes encoding proteins that perform traditional and nontraditional D3 functions such as maintaining musculoskeletal health, calcium homeostasis, normal BP, and cardiovascular function by recruiting complexes of either coactivators or corepressors [11]. Surprisingly, liganded 1,25(OH)2D3-VDR can interact directly with cyclic adenosine monophosphate (cAMP) dependent response element (CRE) binding protein (CREB), blunting its binding to CRE. These activities appear to be carried out in the absence of liganded-VDR heterodimerization with RXR. As a result, the expression of specific target genes will be regulated, facilitating the synthesis of vitamin D-regulated proteins (Fig. 1) [12, 13].

Fig. 1
figure 1

Mechanism of action of vitamin D (VD) by binding through its receptor. UVB, ultraviolet B; OHase, hydroxylase; 25(OH)D, 25-hydroxyvitamin D; VDR, vitamin D receptor; RXR: retinoid X receptor; VDRE, vitamin D responsive elements. Created with BioRender (Toronto, Canada;

Human VDR is encoded by a single gene on chromosome 12 at 12q12–14. By modulating the expression of target genes, this protein mediates the pleiotropic effects of 1,25(OH)2D3 [14]. 1,25(OH)2D3 is a negative endocrine-regulating hormone in the RAAS that acts by inhibiting renin messenger RNA (mRNA) expression regardless of calcium metabolism, which is involved in bone function. Biological activities of vitamin D are mediated by binding to the VDR, where SNPs can cause changes in arterial BP and contribute to the onset of hypertension [15]. In recent decades, it has been found VDR exists in almost all human cells and modulates about 3% of human genes by activating a transcription of target gene. So, more and more attention has been paid to the role of vitamin D in non-skeletal diseases, including diabetes mellitus, autoimmune disease, hypertension, and cardiovascular disease (CVD).

Mechanistic links of vitamin D receptor with hypertension

The genes that control vitamin D levels are thought to be responsible for 30 to 50% of BP fluctuations [13]. Identifying the genes that control vitamin D levels in essential hypertension may thus provide a better factor in determining the disease molecular pathogenesis.

The RAAS is critical in the physiologic regulation of sodium and potassium balance, intravascular volume, and BP [16]. It is now well established that excessive RAAS activity increases the risk of cardiovascular disease, which can be reduced by inhibiting or blocking the RAAS [17].

Renin-angiotensin-aldosterone system

Increased activation of the RAAS, which is a key regulator of electrolyte and volume homeostasis, contributes to the development of arterial hypertension. Renin is primarily produced by the kidney’s juxtaglomerular cells and stimulates the production of angiotensin II and aldosterone, both of which increase BP directly through vasoconstriction and indirectly through salt and water retention and other mechanisms [18].

Low vitamin D status has been linked to clinical outcomes that have previously been linked to excess RAAS activity, such as hypertension, inflammation, and CVD [19]. Animal studies and human genetic association studies have provided mechanistic support for these observations; however, conflicting data exist, and large-scale studies are needed to confirm the effect of vitamin D therapy on the RAAS and RAAS-mediated clinical outcomes.

Animal studies have shown that the 1,25(OH)2D3-VDR complex negatively regulates renin expression and that this vitamin D-induced reduction in RAAS activity can prevent adverse vascular outcomes to the same extent as pharmacologic angiotensin receptor antagonism [20]. In VDR and 1α-hydroxylase knockout mice, inappropriate, increased RAAS activation has been reported. Importantly, VDR and 1α-hydroxylase knockout mice developed arterial hypertension and myocardial hypertrophy, even after calcium homeostasis was restored; however, blocking the RAAS with angiotensin-converting enzyme inhibitors normalized BP and cardiac abnormalities [21, 22]. Furthermore, in 1α-hydroxylase knockout mice, increased RAAS activation, arterial hypertension, and myocardial abnormalities could be successfully treated with 1,25(OH)2D3 [22].

Human studies have supported this theory, demonstrating that low circulating vitamin D concentration are associated with higher plasma renin activity and angiotensin II concentrations [23, 24], and that vitamin D deficiency is associated with higher RAAS activity, which can be reduced with vitamin D3 therapy intervention [20, 25]. Extrapolating from these findings, vitamin D therapy may help to lower RAAS activity and improve complications associated with excess RAAS activity, such as hypertension, insulin resistance, and nephropathy [26].

Cyclic adenosine monophosphate protein kinase a signaling pathway

cAMP has long been recognized as a significant intracellular signal that stimulates renin production in juxtaglomerular cells. It is well established that cAMP signals through CRE located in target gene promoters, which interact in homodimeric or heterodimeric forms with members of the activating transcriptional factor/CREB/CRE modulator (CREM)/basic leucine zipper domain transcription factor family. Intracellular cAMP is synthesized from ATP by adenylate cyclase, which is activated by membrane receptors; cAMP binds to the regulatory subunit of protein kinase A, releasing the catalytic subunit, which enters the nucleus and phosphorylates CREB at serine 133 or CREM at serine 117, resulting in the recruitment of ubiquitous coactivators cyclic binding protein and p300 to promote gene transcription [27].

The discovery that liganded VDR suppresses renin expression in the presence of 1,25(OH)2D3 by binding to the transcription factor CREB sheds light on the molecular effects of vitamin D on the RAAS. CREB can no longer stimulate renin transcription by binding to CRE in the renin gene promoter region, so renin transcription is inhibited [27]. In patients with arterial hypertension, renin activity was found to be inversely related to 1,25(OH)2D3 levels [28]. Importantly, reduced renin and angiotensin II levels were observed in several, but not all, studies that investigated RAAS activity after treatment with 1,25(OH)2D3 (Fig. 2) [12, 29]. As a result, more research is needed to determine the clinical significance of vitamin D.

Fig. 2
figure 2

Proposed mechanism for action of vitamin D on renin expression. 1,25(OH)2D3, 1,25-dihydroxyvitamin D; Gαs, Gs protein α subunit; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; VDR, vitamin D receptor; PKA, protein kinase A; P, phosphate; CREB, cyclic adenosine monophosphate dependent response element binding protein; CRE, cyclic adenosine monophosphate response element; CBP, cyclic adenosine monophosphate binding protein; Pol, polymerase. Created with BioRender (Toronto, Canada; Adapted from Legarth et al. [12] according to the Creative Commons Attribution License

Increasing molecular and clinical evidence suggests that vitamin D deficiency contributes to insulin resistance, which is thought to play a role in the pathogenesis of arterial hypertension. Furthermore, the renoprotective effects of vitamin, such as decreased podocyte loss and hypertrophy or suppression of mesangial cell proliferation, may prevent the development of arterial hypertension in the course of renal failure [30].

Vitamin D receptor polymorphisms

All the mechanisms discussed play a role in developing hypertension as well as polymorphism in the VDR gene which binds to high-affinity receptors mediates the biological activities of 1,25(OH)2D3, and polymorphisms in the gene encoding the VDR appear to predispose the onset of hypertension [31, 32].

The expression and nuclear activation of the VDR are required for vitamin D effects. Several genetic variations in the VDR have been discovered. DNA sequence variations, which occur frequently in the population, are referred to as “polymorphisms” and can have biological effects. To see whether there is a linkage between VDR polymorphisms and diseases, epidemiological studies are performed. In these studies, the presence of a variation of the gene is studied in a case and control group [33]. Since the discovery of VDR polymorphism a number of papers have been published studying VDR gene and the position of different SNPs and their role in various diseases (Table 1, Fig. 3) [15, 34,35,36,37,38,39,40,41].

Table 1 Association studies of known SNPs of VDR gene with chronic disease
Fig. 3
figure 3

Structure of vitamin D receptor gene and position of known polymorphisms. Asterisks indicate that these polymorphisms are in the coding sequence. UTR, untranslated region. Created with BioRender (Toronto, Canada; Adapted from Uitterlinden et al. [15] with permission from Elseiver

Among the many described SNPs of VDR, two diallelic polymorphisms have been reported to affect VDR molecular signaling, namely Fok I (C > T, rs2228750) within the first coding exon, and Bsm I (A > G, rs1544410) lying in the last intron [33]. The VDR Fok I-F mutated allele has been shown to increase VDR protein transcriptional activity, while the Bsm I-B mutated allele affects VDR mRNA stability leading to a reduction of VDR protein amount in tissues. It has been shown that these genetic changes in the VDR can significantly reduce the effectiveness of vitamin D action [33]; thus, contributing to the development of several cardiovascular diseases, in particular, the Bsm I-B allele has been strongly associated with hypertension [42, 43]. The purpose of this review is to summarize the vast amount of information regarding VDR polymorphisms and essential hypertension and discuss its possible role as diagnostic tools.

Fok I polymorphism and essential hypertension

One of the most studied SNP of the VDR gene is Fok I (rs2228570). This polymorphism, which consisted of a T to C change in exon 2, was described in the early 1990s. Because the change occurs within a start codon (ATG), when the C variant is present, an alternate start site is used, resulting in a protein of a different size [33]. Fok I polymorphism can generate truncated proteins and is associated with increased risk for hypertension [15, 44, 45]. Fok I polymorphism is caused by a thymine-to-cytosine transition, which leads to a translational frameshift characterized by an extension of the open reading frame to the next initiation codon (ATG), resulting in the synthesis of a truncated 424-amino acid protein. In the 427-amino acid protein, ATG-encoded methionine (M1 form) was present in the f allele, whereas ACG-encoded methionine (M4 form) was present in the F allele [46]. The truncated protein in individuals with the FF genotype is thought to promote the development of essential hypertension by increasing the production of renin and angiotensin II (Fig. 4) [47, 48]. The transcriptional activity of the truncated protein is suggested to be higher than that of the full-length protein. Moreover, the increased responsiveness of the truncated protein to 1,25(OH)2D3 might alter the function of VDR and vitamin D in cells and tissues [49]. Low levels of 25(OH)D combined with Fok I polymorphism have been associated with increased plasmatic renin activity [12]. This suggests that 1,25(OH)2D3 can downregulate renin expression in humans, and increase cardiovascular and metabolic disease risk [50].

Fig. 4
figure 4

Proposed mechanism of vitamin D receptor (VDR; Fok I) polymorphism in susceptibility to essential hypertension. 1,25(OH)2D3, 1,25-dihydroxyvitamin D; SNP, single nucleotide polymorphism; UTR, untranslated region. Adapted from Nunes et al. [47] with permission from Oxford University Press

Regarding the role of SNP Fok I in other diseases, Liu et al. [51] analyzed its association with psoriasis but the results were not significant for Caucasians and East Asians. In contrast, Alizadeh et al. [52] found no significant association between SNP Fok I and coronary artery disease (CAD) based on a general analysis in Caucasians and East Asians. Recently, Shi et al. [53] observed no relation between this SNP and susceptibility to polycystic ovary syndrome. However, Liu et al. [54] showed that Fok I is a susceptibility factor for ovarian cancer. Further, Zhao et al. [55] found an increased risk of intervertebral disc degeneration in Hispanics and Asians with the f allele and Lu et al. [56] suggested that Fok I protects against CAD. Cao et al. [57] found that homozygosis is associated with an increased risk of tuberculosis, particularly in East and Southeast Asia, and Jiao et al. [58] observed that the F allele is associated with a decreased risk of diabetic retinopathy in Chinese subjects. However, Tizaoui et al. [35] in their study reported that Fok I VDR polymorphisms is associated with rheumatoid arthritis risk. Liu et al. [34] reported that Fok I (rs2228570) polymorphisms increase susceptibility to gestational diabetes mellitus in Asian and African population. Another study conducted by Caccamo et al. [40] suggested an association between gestational hypertension and the VDR FF haplotype. In accordance with previous study Abouzid et al. [38] reported that Fok I SNP TT genotype was associated with a higher incidence of heart failure and hypertension.

In the mid-2000s, an in vitro study demonstrated that the transcriptional activity of VDR with Fok I-F SNP was lower than that of TFIIB factor (an RNA polymerase II-specific transcript) with Fok I-F SNP. Thus, the Fok I polymorphism appears to be functional, and the 424 aa VDR variant appears to be slightly more active than the 427 aa variants in terms of transactivation capacity as a transcription factor. Some promoter regions of vitamin D target genes may be more sensitive to this VDR genotype-dependent difference in activity than others [59]. Due to the importance of the association between hypertension and Fok I polymorphism, we performed a review to find out whether this SNP of VDR gene plays a protective role in hypertension or should be considered as a risk factor for the onset of the disease.

Bsm I polymorphism and essential hypertension

Bsm I is a nucleotide substitution from A to G found in intron 8 that affects transcript stability. It is in linkage disequilibrium with other polymorphisms, and its association with certain diseases is most likely the result of this phenomenon (Fig. 5) [60].

Fig. 5
figure 5

Proposed mechanism of vitamin D receptor (VDR; Bsm I) polymorphism in susceptibility to essential hypertension

A previous GWAS reported that the SNP Bsm I (rs1544410) in the VDR gene is associated with hypertension in Spanish population, systolic BP (SBP) with Bsm I (rs1544410) CC genotype was higher than TC or TT genotypes in men but not in women [61]. On the contrary, in a Korean study, Bsm I T allele carriers had higher SBP, higher diastolic BP (DBP), and higher prevalence of hypertension than CC carriers [62]. Recently, a prospective cohort of American men found suggestive evidence for associations of VDR Bsm I and Fok I polymorphisms with hypertension risk [32].

Regarding the role of SNP Bsm I in other diseases, Abouzid et al. [38] analyzed its association with CVDs and reported that GA Bsm I genotypes had an increased risk of obesity and also found that AA Bsm I genotype can be protective against CVD. Recently, Nugroho et al. [63] reported no association of this SNP with diabetic kidney disease. However, Nam et al. [37] reported that Bsm I polymorphism VDR gene were associated with obesity in Korean patients with type 2 diabetes mellitus. Further Liu et al. [34] found that VDR Bsm I (rs1544410) polymorphism was associated with gestational diabetes mellitus in Asian and African population [34].

This review identified and analyzed studies that investigated the relationship of VDR (Fok I and Bsm I) polymorphisms with essential hypertension. Swapna et al. [31] examined the relationship between Fok I polymorphism and essential hypertension in South Indian population. A total of 480 subjects were included in the study, with 280 hypertensive subjects and 200 healthy controls ranging in age from 35 to 60 years. They observed a significant association of Fok I polymorphism with essential hypertension. They also observed a significant difference in the frequencies of genotypes and alleles at the VDR locus. The FF, ff, Ff exhibited frequencies of 53.6, 10.7, and 35.7%, respectively, in hypertensive individuals, and 34, 15, and 51%, respectively, in healthy normotensive subjects. The risk of hypertension was calculated from the odds ratio (OR). Notably, men and women with the FF genotype had a higher risk of hypertension (men: OR, 2.020; 95% confidence interval [CI], 1.228–3.322; women: OR, 2.467; 95% CI, 1.246–4.4881) and in individuals with a positive family history of hypertension (OR, 2.011; 95% CI, 1.119–3.616), smoking (OR, 3.686; 95% CI, 1.414–9.611), and alcohol consumption (OR, 2.239; 95% CI, 0.983–5.096) [31].

In accordance with the results of previous study, another study was undertaken by Prasad et al. [13] in southeast population of India to determine the status of Fok I VDR gene polymorphism along with vitamin D levels and BP in patients with essential hypertension. A total of 400 subjects were included in the study, with 200 hypertensive subjects (SBP ≥140 mmHg and DBP ≥90 mmHg) and 200 healthy controls ranging in age from 25 to 60 years. They observed a significant association of SBP with vitamin D levels. A reduced level of vitamin D was observed in essential hypertension patients. Risk of hypertension was calculated from ORs. The ff genotype was found to be 8.06 times more likely to have essential hypertension than FF genotypes (OR, 8.06; 95% CI, 3.71–17.47; P = 0.0001).

Glocke et al. [64] conducted a study to compare the prevalence of Fok I polymorphism in 101 elderly (> 90 years) and 208 young subjects (< 90 years) of both sexes (Caucasians of German descent). A negative effect of Fok I polymorphism on DBP was observed in the elderly group (P < 0.05), especially in those with the ff genotype because they had a lower mean BP of 70 ± 2.12 mmHg than those with FF genotype (82.9 ± 3.10 mmHg) and Ff genotype (76.17 ± 2.69 mmHg) [64]. The prevalence of hypertension was lower in subjects with ff and Ff genotypes than in those with FF genotype; however, the difference was not statistically significant. The lifespan of the subjects can also be affected by this polymorphism [13].

Wang et al. [32] conducted a prospective study in 1211 Caucasian American men with a minimum and maximum follow-up period of 15.2 and 27.4 years, respectively. In this study, 695 subjects were diagnosed with hypertension. The prevalence of Fok I and Bsm I polymorphism was investigated in 885 subjects and 998 subjects, respectively, and the majority of hypertensive patients had a polymorphism of the VDR gene. The association of Fok I polymorphism with the risk for hypertension was found only in the recessive model. The ff genotype in model 2 had a multivariate hazard ratio (HR) of 1.32 (95% CI, 1.03–1.70) for the incidence of hypertension. The correlation between 25(OH)D level and the risk for hypertension was higher in subjects with the ff genotype than in those with the Ff and FF genotypes. They also observed bB or BB genotype of the VDR Bsm I polymorphism were linked to an increased risk of hypertension. The bB and BB genotype in model 2 had a multivariable HR of 1.27 (95% CI, 1.04–1.55) and 1.19 (95% CI, 0.90–1.56), respectively, for incidence of hypertension. Combined bB and BB genotypes, the HR was 1.25 (95% CI, 1.04–1.51) found only in the recessive model. There was no significant interaction between circulating vitamin D metabolites and VDR gene polymorphisms in relation to hypertension risk [32].

Cottone et al. [60] conducted a study in 71 patients with essential hypertension and 72 control subjects of both sexes, aged 18 to 75 years, in Italy. The frequencies of FF, Ff, and ff genotypes in hypertensive patients were 50.7, 42.3, and 7.0%, respectively, and in control subjects were 40.3, 50.0, and 9.7%, respectively. The allelic frequencies of F and f were 71.8 and 28.2%, respectively, in hypertensive patients, and 65.3 and 34.7%, respectively, in normotensive individuals. The DBP was different for all three genotypes of Fok I polymorphism (P = 0.018). Patients with the ff genotype had a higher DBP than those with the Ff genotype (P = 0.002). A negative correlation was observed between 25(OH)D levels and pulse BP, and this correlation was statistically significant in patients with the Ff genotype (r = − 0.474, P = 0.035) and between 25(OH)D and 24-hour SBP in patients with Bb Bsm I genotypes (r = − 0.397, P = 0.020). The frequencies of BB, bb, and Bb genotypes in hypertensive patients were 22.5, 57.8, and 19.7%, respectively, and 20.8, 52.8, and 26.4%, respectively, in control subjects. In hypertensive patients, the allelic frequencies of B and b were 51.5 and 48.5%, respectively, and 47.2 and 52.8%, respectively, in normotensive individuals. There was no link found between a particular genotype or allele and hypertension. A link between polymorphism and plasma renin activity was also not found [60].

In another study, Errouagui et al. [65] examined 177 hypertensive (aged 45.47 to 68.41 years) and 222 normotensive subjects (aged 34.67 to 64.59 years) of both sexes in Morocco, and found a strong association between Fok I polymorphism and hypertension in codominant, dominant, and recessive genetic models, whereas no association was observed between Bsm I polymorphism and hypertension in all genetic models. The ff genotype was significantly less common in hypertensive patients than in controls (OR, 0.24; 95% CI, 0.10–0.58; P = 0.002). The average vitamin D concentrations in subjects with the FF, Ff, and ff genotypes were 28.06 ± 10.57, 29.04 ± 11.97, and 26.40 ± 19.15 ng/mL, respectively. However, the differences in vitamin D concentrations between subjects with FF and Ff were not statistically significant [65].

Jia et al. [66] studied 2409 hypertensive and 3063 normotensive people from a community-based epidemiological survey in Jiangsu Province, China. The majority of the population was Han. After controlling for confounding factors (sex, age, body mass index, total cholesterol, triglycerides, high-density lipoprotein and low-density lipoprotein cholesterol, and smoking), the correlation of Fok I polymorphism with lower risk of hypertension in men was significant. For the additive, dominant, and recessive models, the ORs (95% CI) were 0.828 (0.74–0.927, P = 0.001), 0.75 (0.631–0.89, P = 0.001), and 0.816 (0.67–0.995, P = 0.044), respectively. The Ff/ff genotype was associated with lower BP than the FF genotype (P = 0.002) [66].

Gussago et al. [67] conducted another study on 70-year-old subjects and centenarians of both sexes in northern Italy. The frequencies of the FF, Ff, and ff genotypes in centenarians were 47.4, 42.1, and 10.5%, respectively, with F being the most common allele (68.4%). In the control group, the frequencies of the FF, Ff, and ff genotypes were 48.4, 38.7, and 12.9%, respectively, with F being the most common allele (67.8%). Furthermore, the FF genotype was associated with a higher prevalence of hypertension than the Ff and ff genotypes (P = 0.015) [67].

A meta-analysis conducted by Nunes et al. [47] in Brazil reported a significant association of Fok I polymorphism with hypertension. F and f allele frequencies were 55.9 and 44.1% in hypertensive patients, respectively, and 54.3 and 44.7% in control subjects [47]. However, a meta-analysis conducted in Chinese population by Zhu et al. [43] found no correlation of Fok I polymorphism with susceptibility to hypertension. They also observed that Bsm I polymorphism was associated with susceptibility to hypertension. The frequency of VDR Bsm I AA genotype decreased in hypertension patients compared with healthy controls. The population carrying VDR Bsm I AA genotype (OR, 0.69; 95% CI, 0.54–0.89; P = 0.005) had lower susceptibility to hypertension relative to those carrying GA or GG genotype (OR, 1.32; 95% CI, 1.05–1.68; P = 0.02). The frequency of A allele was higher in the case group than that of control group (OR, 0.83; 95% CI, 0.69–0.99; P = 0.04) [43]. In accordance with findings in Chinese population, a preliminary study conducted by Abouzid et al. [38] reported Fok I TT genotype was associated with a higher incidence of hypertension whereas they did not observe a significant association between hypertension and Bsm I polymorphism.

Both of these polymorphisms have been linked to an increased risk of essential hypertension with conflicting results [13, 32, 68]. The Fok I polymorphism affects the length and function of the VDR protein, resulting in truncated protein formation. The inactivation of VDR is caused by a lack or excess of vitamin D and the inactivation of its biologically active form. Bsm I is a nucleotide substitution from A to G in intron 8 that affects transcript stability. It is in linkage disequilibrium with other polymorphisms, and its association with certain diseases is most likely due to this phenomenon. The findings of the studies support the hypothesis that VDR (Fok I and Bsm I) polymorphisms may be associated with susceptibility to essential hypertension. Furthermore, the age and ethnicity of an individual are important factors to consider when studying hypertension. High BP can be caused by the inhibition of renin activity and the subsequent increase in levels of angiotensin II, a potent vasoconstrictor. Surprisingly, 1,25(OH)2D3 levels influences renin expression, resulting in hypertension. However, the number of studies in this area is still limited. Understanding the molecular and functional consequences of VDR polymorphisms is crucial for fully appreciating their significance and understanding their potential clinical implications.

The most notable mechanism linking vitamin D to hypertension is its role as a negative regulator of the RAAS. A meta-analysis study has indicated Fok I polymorphism of the VDR gene results in formation of a truncated protein that evidently increases the synthesis of renin and angiotensin II, thereby promoting the development of hypertension [47]. Enhanced understanding of the genetic differences in hypertensive population may be a further step in developing individualized treatment strategy. More so, it is worth investigating if direct renin inhibitors e.g., Aliskerin (presently second line of drugs) may be better suited and effective in this set of patients.

Over and above, as genetic technology becomes increasingly inexpensive and accessible, Fok I and Bsm I genotyping can be used as a screening tool in at risk population to assess future risk of developing hypertension.


In India, hypertension has consistently been one of the leading causes of morbidity and mortality. Many studies have linked VDR gene polymorphism with essential however some studies have focused on the triangular relationship of vitamin D, VDR polymorphism, and essential hypertension, but the results of these studies were conflicting. As these studies have certain limitations, such as the fact that the individuals included in the study are of various age and ethnicities. These studies do not yield consistent findings regarding the risk of hypertension and its association with the frequency of Fok I and Bsm I genotypes. More research with larger samples is needed after removing confounding factors to determine whether VDR gene polymorphism is protective or a risk factor for the development of essential hypertension.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.


1,25(OH)2D3 :

1,25-Dihydroxyvitamin D


25-Hydroxyvitamin D


Adenylate cyclase


Blood pressure


Coronary artery disease


Cyclic adenosine monophosphate


Cyclic adenosine monophosphate binding protein


Confidence interval


Cyclic adenosine monophosphate response element


Cyclic adenosine monophosphate dependent response element binding protein


Cyclic adenosine monophosphate response element modulator


Cardiovascular disease


Diastolic blood pressure


Diabetes mellitus

s :

Gs protein α subunit


Gestational diabetes mellitus


Gestational hypertension


Genome-wide association studies


Hazard ratio


Messenger RNA




Odds ratio




Protein kinase A




Rheumatoid arthritis


Renin-angiotensin-aldosterone system


Retinoid X receptor


Systolic blood pressure


Single nucleotide polymorphism


untranslated region


Vitamin D receptor


  1. Lin L, Zhang L, Li C, Gai Z, Li Y. Vitamin D and vitamin D receptor: new insights in the treatment of hypertension. Curr Protein Pept Sci. 2019;20:984–95.

    Article  CAS  Google Scholar 

  2. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–23.

    Article  Google Scholar 

  3. Saseen JJ, MacLaughlin EJ. Hypetension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 9th ed. New York: McGraw-Hill; 2014. p. 87–101.

    Google Scholar 

  4. Scriabine A. Hypertension. In: Taylor JB, Triggle DJ, editors. Comprehensive medicinal chemistry II. Amsterdam: Elsevier; 2007. p. 705–28.

    Chapter  Google Scholar 

  5. Bell K, Twiggs J, Olin BR, Date IR. Hypertension: the silent killer: updated JNC-8 guideline recommendations. Ala Pharm Assoc. 2015;334:4222.

    Google Scholar 

  6. Warren HR, Evangelou E, Cabrera CP, Gao H, Ren M, Mifsud B, et al. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat Genet. 2017;49:403–15.

    Article  CAS  Google Scholar 

  7. Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. 2007;49:1063–9.

    Article  CAS  Google Scholar 

  8. Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009;20:1807–20.

    Article  CAS  Google Scholar 

  9. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol. 2005;289:F8–28.

    Article  CAS  Google Scholar 

  10. Mutchie TR, Yu OB, Di Milo ES, Arnold LA. Alternative binding sites at the vitamin D receptor and their ligands. Mol Cell Endocrinol. 2019;485:1–8.

    Article  CAS  Google Scholar 

  11. Meyer MB, Pike JW. Corepressors (NCoR and SMRT) as well as coactivators are recruited to positively regulated 1α,25-dihydroxyvitamin D3-responsive genes. J Steroid Biochem Mol Biol. 2013;136:120–4.

    Article  CAS  Google Scholar 

  12. Legarth C, Grimm D, Wehland M, Bauer J, Krüger M. The impact of vitamin D in the treatment of essential hypertension. Int J Mol Sci. 2018;19:455.

    Article  Google Scholar 

  13. Prasad M, Rajarajeswari D, Aruna P, Ramalingam K, Viswakumar R, Fathima N, et al. Status of vitamin D receptor gene polymorphism and 25-hydroxy vitamin D deficiency with essential hypertension. Indian J Clin Biochem. 2022;37:335–41.

    Article  CAS  Google Scholar 

  14. Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, et al. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol. 1997;11:1165–79.

    Article  CAS  Google Scholar 

  15. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338:143–56.

    Article  CAS  Google Scholar 

  16. Laragh JH, Sealey JE. The plasma renin test reveals the contribution of body sodium-volume content (V) and renin-angiotensin (R) vasoconstriction to long-term blood pressure. Am J Hypertens. 2011;24:1164–80.

    Article  CAS  Google Scholar 

  17. Vaidya A, Brown JM, Williams JS. The renin-angiotensin-aldosterone system and calcium-regulatory hormones. J Hum Hypertens. 2015;29:515–21.

    Article  CAS  Google Scholar 

  18. Connell JM, MacKenzie SM, Freel EM, Fraser R, Davies E. A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function. Endocr Rev. 2008;29:133–54.

    Article  CAS  Google Scholar 

  19. Vaidya A, Williams JS. The relationship between vitamin D and the renin-angiotensin system in the pathophysiology of hypertension, kidney disease, and diabetes. Metabolism. 2012;61:450–8.

    Article  CAS  Google Scholar 

  20. Vaidya A, Forman JP. Vitamin D and vascular disease: the current and future status of vitamin D therapy in hypertension and kidney disease. Curr Hypertens Rep. 2012;14:111–9.

    Article  CAS  Google Scholar 

  21. Simpson RU, Hershey SH, Nibbelink KA. Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse. J Steroid Biochem Mol Biol. 2007;103:521–4.

    Article  CAS  Google Scholar 

  22. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha- hydroxylase knockout mice. Kidney Int. 2008;74:170–9.

    Article  CAS  Google Scholar 

  23. Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension. 2010;55:1283–8.

    Article  CAS  Google Scholar 

  24. Vaidya A, Forman JP, Hopkins PN, Seely EW, Williams JS. 25-Hydroxyvitamin D is associated with plasma renin activity and the pressor response to dietary sodium intake in Caucasians. J Renin-Angiotensin-Aldosterone Syst. 2011;12:311–9.

    Article  CAS  Google Scholar 

  25. Carrara D, Bernini M, Bacca A, Rugani I, Duranti E, Virdis A, et al. Cholecalciferol administration blunts the systemic renin-angiotensin system in essential hypertensives with hypovitaminosis D. J Renin-Angiotensin-Aldosterone Syst. 2014;15:82–7.

    Article  CAS  Google Scholar 

  26. Vaidya A, Sun B, Larson C, Forman JP, Williams JS. Vitamin D3 therapy corrects the tissue sensitivity to angiotensin ii akin to the action of a converting enzyme inhibitor in obese hypertensives: an interventional study. J Clin Endocrinol Metab. 2012;97:2456–65.

    Article  CAS  Google Scholar 

  27. Yuan W, Pan W, Kong J, Zheng W, Szeto FL, Wong KE, et al. 1,25-Dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem. 2007;282:29821–30.

    Article  CAS  Google Scholar 

  28. Burgess ED, Hawkins RG, Watanabe M. Interaction of 1,25-dihydroxyvitamin D and plasma renin activity in high renin essential hypertension. Am J Hypertens. 1990;3(12 Pt 1):903–5.

    Article  CAS  Google Scholar 

  29. Freundlich M, Quiroz Y, Zhang Z, Zhang Y, Bravo Y, Weisinger JR, et al. Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. Kidney Int. 2008;74:1394–402.

    Article  CAS  Google Scholar 

  30. Kuhlmann A, Haas CS, Gross ML, Reulbach U, Holzinger M, Schwarz U, et al. 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol. 2004;286:F526–33.

    Article  CAS  Google Scholar 

  31. Swapna N, Vamsi UM, Usha G, Padma T. Risk conferred by FokI polymorphism of vitamin D receptor (VDR) gene for essential hypertension. Indian J Hum Genet. 2011;17:201–6.

    Article  CAS  Google Scholar 

  32. Wang L, Ma J, Manson JE, Buring JE, Gaziano JM, Sesso HD. A prospective study of plasma vitamin D metabolites, vitamin D receptor gene polymorphisms, and risk of hypertension in men. Eur J Nutr. 2013;52:1771–9.

    Article  CAS  Google Scholar 

  33. Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clin Chim Acta. 2006;371:1–12.

    Article  CAS  Google Scholar 

  34. Liu S. The role of vitamin D receptor gene polymorphisms in gestational diabetes mellitus susceptibility: a meta-analysis. Diabetol Metab Syndr. 2021;13:144.

    Article  CAS  Google Scholar 

  35. Tizaoui K, Hamzaoui K. Association between VDR polymorphisms and rheumatoid arthritis disease: systematic review and updated meta-analysis of case-control studies. Immunobiology. 2015;220:807–16.

    Article  CAS  Google Scholar 

  36. Magiełda-Stola J, Kurzawińska G, Ożarowski M, Karpiński TM, Drews K, Seremak-Mrozikiewicz A. The significance of VDR genetic polymorphisms in the etiology of preeclampsia in pregnant Polish women. Diagnostics. 2021;11:1698.

    Article  Google Scholar 

  37. Nam SW, Choi J, Jeon HJ, Oh TK, Lee DH. The associations between vitamin D receptor BsmI and ApaI polymorphisms and obesity in Korean patients with type 2 diabetes mellitus. Diabetes Metab Syndr Obes. 2021;14:557–64.

    Article  Google Scholar 

  38. Abouzid M, Kruszyna M, Burchardt P, Kruszyna Ł, Główka FK, Karaźniewicz-Łada M. Vitamin D receptor gene polymorphism and vitamin D status in population of patients with cardiovascular disease: a preliminary study. Nutrients. 2021;13:3117.

    Article  CAS  Google Scholar 

  39. Eweida SM, Salem A, Shaker YM, Samy N, Yassen I, Mohamed RH. Vitamin D levels and vitamin D receptor genetic variants in Egyptian cardiovascular disease patients with and without diabetes. Egypt J Med Hum Genet. 2021;22:1–2.

    Article  Google Scholar 

  40. Caccamo D, Cannata A, Ricca S, Catalano LM, Montalto AF, Alibrandi A, et al. Role of vitamin-D receptor (VDR) single nucleotide polymorphisms in gestational hypertension development: a case-control study. PLoS One. 2020;15:e0239407.

    Article  CAS  Google Scholar 

  41. Aristizabal-Pachon AF, Gonzalez-Giraldo Y, Garcia AY, Suarez DX, Rodriguez A, Gonzalez-Santos J. Association between VDR gene polymorphisms and melanoma susceptibility in a colombian population. Asian Pac J Cancer Prev. 2022;23:79–85.

    Article  CAS  Google Scholar 

  42. Santoro D, Buemi M, Gagliostro G, Vecchio M, Currò M, Ientile R, et al. Association of VDR gene polymorphisms with heart disease in chronic kidney disease patients. Clin Biochem. 2015;48:1028–32.

    Article  CAS  Google Scholar 

  43. Zhu YB, Li ZQ, Ding N, Yi HL. The association between vitamin D receptor gene polymorphism and susceptibility to hypertension: a meta-analysis. Eur Rev Med Pharmacol Sci. 2019;23:9066–74.

    Google Scholar 

  44. Kulah E, Dursun A, Acikgoz S, Can M, Kargi S, Ilikhan S, et al. The relationship of target organ damage and 24-hour ambulatory blood pressure monitoring with vitamin D receptor gene Fok-I polymorphism in essential hypertension. Kidney Blood Press Res. 2006;29:344–50.

    Article  CAS  Google Scholar 

  45. Abd El Gawad SS. Abdul Samee ER, Metwali AA, Abd El Gawad MS. vitamin D receptor gene polymorphism and its association with 1,25-dihydroxyvitamin D3 in patients with graves disease in an Egyptian population: a pilot study. Endocr Pract. 2012;18:132–9.

    Article  Google Scholar 

  46. Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K, et al. A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res. 1997;12:915–21.

    Article  CAS  Google Scholar 

  47. Nunes IF, Cavalcante AA, Alencar MV, Carvalho MD, Sarmento JL, Teixeira NS, et al. Meta-analysis of the association between the rs228570 vitamin D receptor gene polymorphism and arterial hypertension risk. Adv Nutr. 2020;11:1211–20.

    Article  Google Scholar 

  48. Jurutka PW, Remus LS, Whitfield GK, Thompson PD, Hsieh JC, Zitzer H, et al. The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol. 2000;14:401–20.

    Article  CAS  Google Scholar 

  49. Whitfield GK, Remus LS, Jurutka PW, Zitzer H, Oza AK, Dang HT, et al. Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol. 2001;177:145–59.

    Article  CAS  Google Scholar 

  50. Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta- analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5:819–29.

    Article  CAS  Google Scholar 

  51. Liu JL, Zhang SQ, Zeng HM. ApaI, BsmI, FokI and TaqI polymorphisms in the vitamin D receptor (VDR) gene and the risk of psoriasis: a meta-analysis. J Eur Acad Dermatol Venereol. 2013;27:739–46.

    Article  CAS  Google Scholar 

  52. Alizadeh S, Djafarian K, Alizadeh H, Mohseni R, Shab-Bidar S. Common variants of vitamin D receptor gene polymorphisms and susceptibility to coronary artery disease: a systematic review and meta-analysis. J Nutrigenet Nutrigenomics. 2017;10:9–18.

    CAS  Google Scholar 

  53. Shi XY, Huang AP, Xie DW, Yu XL. Association of vitamin D receptor gene variants with polycystic ovary syndrome: a meta-analysis. BMC Med Genet. 2019;20:32.

    Article  Google Scholar 

  54. Liu Y, Li C, Chen P, Li X, Li M, Guo H, et al. Polymorphisms in the vitamin D receptor (VDR) and the risk of ovarian cancer: a meta-analysis. PLoS One. 2013;8:e66716.

    Article  CAS  Google Scholar 

  55. Zhao J, Yang M, Shao J, Bai Y, Li M. Association between VDR FokI polymorphism and intervertebral disk degeneration. Genomics Proteomics Bioinformatics. 2015;13:371–6.

    Article  Google Scholar 

  56. Lu S, Guo S, Hu F, Guo Y, Yan L, Ma W, et al. The associations between the polymorphisms of vitamin D receptor and coronary artery disease: a systematic review and meta-analysis. Medicine. 2016;95:e3467.

    Article  CAS  Google Scholar 

  57. Cao Y, Wang X, Cao Z, Cheng X. Vitamin D receptor gene FokI polymorphisms and tuberculosis susceptibility: a meta-analysis. Arch Med Sci. 2016;12:1118–34.

    Article  Google Scholar 

  58. Jiao J, Li Y, Xu S, Wu J, Yue S, Liu L. Association of FokI, TaqI, BsmI and ApaI polymorphisms with diabetic retinopathy: a pooled analysis of case-control studies. Afr Health Sci. 2018;18:891–9.

    Article  Google Scholar 

  59. Colin EM, Weel AE, Uitterlinden AG, Buurman CJ, Birkenhäger JC, Pols HA, et al. Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1, 25-dihydroxyvitamin D3. Clin Endocrinol (Oxf). 2000;52:211–6.

    Article  CAS  Google Scholar 

  60. Cottone S, Guarino L, Arsena R, Scazzone C, Tornese F, Guarneri M, et al. Vitamin D receptor gene polymorphisms and plasma renin activity in essential hypertensive individuals. J Hum Hypertens. 2015;29:483–7.

    Article  CAS  Google Scholar 

  61. Muray S, Parisi E, Cardús A, Craver L, Fernández E. Influence of vitamin D receptor gene polymorphisms and 25-hydroxyvitamin D on blood pressure in apparently healthy subjects. J Hypertens. 2003;21:2069–75.

    Article  CAS  Google Scholar 

  62. Lee BK, Lee GS, Stewart WF, Ahn KD, Simon D, Kelsey KT, et al. Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and delta-aminolevulinic acid dehydratase genes. Environ Health Perspect. 2001;109:383–9.

    CAS  Google Scholar 

  63. Nugroho P, Lydia A, Suhardjono S, Harimurti K. Association of BsmI polymorphisms in the vitamin D receptor gene among Indonesian population with diabetic kidney disease. Acta Med Indones. 2021;53:149–55.

    Google Scholar 

  64. Glocke M, Lang F, Schaeffeler E, Lang T, Schwab M, Lang UE. Impact of vitamin D receptor VDR rs2228570 polymorphism in oldest old. Kidney Blood Press Res. 2013;37:311–22.

    Article  CAS  Google Scholar 

  65. Errouagui A, Charoute H, Ghalim N, Barakat A, Kandil M, Rouba H. Relationship with vitamin D receptor (RVD) gene and essential arterial hypertension in Moroccan population. Int J Innov Appl Stud. 2014;8:556.

    Google Scholar 

  66. Jia J, Shen C, Mao L, Yang K, Men C, Zhan Y. Vitamin D receptor genetic polymorphism is significantly associated with decreased risk of hypertension in a Chinese Han population. J Clin Hypertens (Greenwich). 2014;16:634–9.

    Article  CAS  Google Scholar 

  67. Gussago C, Arosio B, Guerini FR, Ferri E, Costa AS, Casati M, et al. Impact of vitamin D receptor polymorphisms in centenarians. Endocrine. 2016;53:558–64.

    Article  CAS  Google Scholar 

  68. Wang L, Chu A, Buring JE, Ridker PM, Chasman DI, Sesso HD. Common genetic variations in the vitamin D pathway in relation to blood pressure. Am J Hypertens. 2014;27:1387–95.

    Article  CAS  Google Scholar 

Download references


The authors are grateful to Prof. Abha Chandra, the Head of the Institution of Integral Institute of Medical Sciences and Research, Integral University, Lucknow, India.



Author information

Authors and Affiliations



RA, PTM, and RKK conceived, received, wrote, and edited the article. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Priyanka Thapa Manger.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Awasthi, R., Manger, P.T. & Khare, R.K. Fok I and Bsm I gene polymorphism of vitamin D receptor and essential hypertension: a mechanistic link. Clin Hypertens 29, 5 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: