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A plethora of laboratory protocols for vitamin D receptor (VDR) gene variants detection: a systematic review of associations with hypertensive disorders of pregnancy

BMC Pregnancy and Childbirth volume 25, Article number: 539 (2025) Cite this article

Abstract

Introduction

Genetic variations in the vitamin D receptor (VDR) gene have been inconsistently linked to hypertensive disorder of pregnancy (HDP) across different populations. This systematic review aims to evaluate the laboratory protocols of VDR detection and association with HDP.

Methods

We performed a systematic review using the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guideline and conducted an article search using the Web of Science, PubMed, Scopus, EBSCOhost (MEDLINE and CINAHL) databases. We included all studies involving one or more of the major VDR gene variants (FokI, BsmI, ApaI, and TaqI) and association with HDP.

Results

Of the 9 studies evaluated, 6 (67%) studies were reported from Asia, 2 (22%) from Europe, and 1 (11%) from Latin America. Our analysis of VDR variant detection protocols revealed that approximately 6 (67%) studies used polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP), of which 3 (33%) reported a significant association with FokI variant. Two (22%) of studies used TaqMan PCR and found an association with FokI variant. Only 1 (11%) study utilised allele-specific PCR (AS-PCR) for ApaI variant genotyping. For association analysis of the variants with HDP in populations, 4 studies (44%) reported an association with FokI variant in Asians. Two studies (22%) reported BsmI variant in Caucasians. TaqI variant was not associated with HDP in all the populations studied.

Conclusions

Our findings suggest an association between VDR genetic variation and HDP across different populations. To enhance consistency in these associations, future studies should use reliable detection methods and strict adherence to quality control measures. This could help in the identification of population-specific biomarkers, prevalent variants, and support personalized management strategies to reduce maternal morbidity and mortality related to HDP.

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Introduction

Hypertensive disorder of pregnancy (HDP) includes gestational hypertension (GH), preeclampsia (PE), and eclampsia, which accounts for almost 14% of maternal mortality and morbidity globally [1]. Gestational hypertension, also known as pregnancy-induced hypertension (PIH), is defined as two blood pressure measurements above 140/90 mmHg measured at least 6 h apart or once above 160/110, after 20 weeks of gestation [2, 3]. Preeclampsia (PE) occurs when the gestational hypertension is accompanied by any one of these: proteinuria or maternal organ dysfunction (pulmonary oedema, acute renal failure, liver complications, neurological or hematological abnormality) [4]. HDP are among the primary causes of mortality and morbidity in pregnancy and infancy, particularly in developing countries [5, 6], complicating 2–8% of pregnancies [7]. Previous studies found that vitamin D insufficiency frequently coexists with HDP [5, 8,9,10,11]. Vitamin D is essential in biological processes during pregnancy, including placental angiogenesis, implantation, and immune system modulation [12,13,14,15].

The vitamin D receptor (VDR) belongs to the nuclear receptor superfamily, mediating the biological effects of vitamin D. Structurally, VDR consists of two functional domains: the N-terminal dual zinc finger DNA-binding domain and the C-terminal ligand-binding domain, connected by a flexible linking region [12, 16,17,18]. VDRs are widely expressed across various tissues including the bone, placenta, pancreas, kidney, and skin, and exhibit high affinity and specificity for vitamin D3 binding. Upon activation, VDR forms a heterodimer with the retinoid X receptor (RXR), which binds to vitamin D response elements (VDREs) within gene promoter regions [16, 19]. This VDR-RXR complex regulates the transcription of genes that control both classical functions, such as calcium homeostasis and skeletal health, and non-classical roles in immune modulation and vascular function [20, 21].

The VDR gene is located on chromosome 12 (12q12-14) [19], and genetic variations within this gene significantly influence individual responses to vitamin D. These variations have been associated with HDP, gestational diabetes mellitus (GDM), and preterm birth [17, 19]. Several well-characterized VDR polymorphisms, including FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236), have been shown to alter VDR expression or function, disrupting key molecular pathways and increasing susceptibility to HDP [22, 23].

The FokI variant is located in exon 2 and involves a thymine-to-cytosine (T > C) transition, which induces a translational frameshift by shifting the open reading frame to the next initiation codon (ATG) [24,25,26]. This mutation results in the synthesis of a truncated VDR protein with 424 amino acids. In contrast, the wild-type protein contains 427 amino acids, where methionine is encoded by ATG in the f allele (M1 form) and by ACG in the F allele (M4 form) [27]. These genotypes, FF, Ff, and ff, generate VDR proteins of differing sizes and functions, impacting receptor activity [28]. BsmI involves an A > G base change, producing genotypes BB, Bb, and bb, while ApaI involves a C-to-A transition, resulting in genotypes AA and Aa. Although these polymorphisms do not alter the amino acid sequence, they are believed to affect mRNA stability, potentially reducing antioxidant enzyme expression and promoting oxidative stress [28,29,30]. TaqI, another polymorphism, involves a T > C transition, producing the genotypes TT, Tt, and tt. While this variant also does not change the amino acid sequence, it may impair mRNA stability, influencing VDR activity [31].

VDR gene polymorphisms play a critical role in the development of HDP by disrupting essential molecular pathways, including those related to vascular health, immune regulation, and placental function [32]. The FokI variant, through altered VDR isoforms, reduces transcriptional activity, impairing calcium homeostasis, nitric oxide production, and antioxidant defences. This disruption leads to endothelial dysfunction, increased vascular tone, and oxidative stress [23]. The BsmI and ApaI, although silent polymorphisms, impact mRNA stability, reducing antioxidant levels and exacerbating oxidative injury and placental hypoxia [24, 33]. Furthermore, these variants contribute to pro-inflammatory responses and dysregulate the renin–angiotensin–aldosterone system (RAAS), promoting vasoconstriction and hypertension [24]. Collectively, these molecular disruptions result in endothelial dysfunction, immune imbalance, oxidative stress, and abnormal calcium signaling, all of which contribute to the onset and progression of HDP (Fig. 1).

Fig. 1
figure 1

Association between VDR gene polymorphisms and development of hypertensive disorder of pregnancy at molecular level

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Numerous studies have explored the role of VDR genetic polymorphisms in the pathogenesis of pregnancy complications, including GH, PE, GDM, preterm birth and miscarriages [30, 33,34,35,36,37,38]. It was hypothesized that VDR gene polymorphisms play a critical role in the etiopathogenesis of GH. The mechanisms involve calcium regulation affecting vascular smooth muscle function leading to elevated blood pressure, and influence on inflammatory processes and immune response, contributing to vascular inflammation and endothelial dysfunction, leading to HDP (1, 4).

Among common laboratory protocols currently used in detecting VDR variants are polymerase chain reaction-restriction fragment length polymorphisms (PCR–RFLP), TaqMan allelic discrimination and allele specific PCR (26–30). It is important to emphasise that there are myriads of VDR variant detection methods with varying sensitivity, specificity, cost, and application. PCR–RFLP is cost effective but takes longer to complete due to post-PCR processing [39], whereas AS-PCR is faster but more likely to produce false positive result [40, 41]. Allele discrimination PCR and PCR-HRM are highly, sensitive, accurate and efficient techniques suitable for large-scale genotyping, but they require sophisticated systems [42,43,44]. Although, the choice of method depends on resource availability, throughput needs, and precision requirements and this is important for accurate VDR gene variants genotyping studies.

Despite extensive studies, the association between VDR gene variants and the risk of developing HDP remains inconclusive. Therefore, our objective was to conduct a systematic review to examine the laboratory detection protocols of VDR variants and the association of these variants with HDP in the studied population.

Methods

This systematic review was performed in accordance with the PRISMA guideline (Supplementary File 1). The protocol was registered in the PROSPERO (CRD42022362561) database on 5th October 2022 and amended on 14th September 2023.

Database selection and search strategy

We conducted a structured searches in PubMed, Web of Science, Scopus, and EBSCOhost and systematically compare search strategies across multiple biomedical and scientific databases. These databases were selected due to their widespread use in health and biomedical research.

Search query construction

Search queries were constructed using Boolean operators (AND, OR, NOT), nesting (mixing Boolean operators) with parentheses, and Medical Subject Headings (MeSH) terms, where applicable. The search terms for the present study focused on three main concepts; Vitamin D receptor ("Vitamin D receptor", "VDR", "vitamin D receptor gene", genetic polymorphisms ("polymorphism", "single nucleotide polymorphisms", "mutation", "variant", SNP identifiers such as "rs2228570", “rs1544410”, “rs7975232”, “rs731236”), hypertensive disorders of pregnancy ("gestational hypertension", "pregnancy-induced hypertension", "PIH", "preeclampsia", "eclampsia"). Each query was adapted to meet the unique search syntax and indexing characteristics of the respective databases.

Database-specific search strategies

PubMed

On PubMed database, a combination of MeSH terms and keyword-based searching was used. The search queries include MeSH terms for hypertensive disorders of pregnancy ("hypertensive disorders of pregnancy"), “All Fields” searching for genetic polymorphisms and vitamin D receptor variations, extensive nesting with parentheses to structure Boolean logic was used to ensure comprehensive retrieval of synonyms and related terms.

Web of science

The Web of Science database does not support the use of MeSH terms and relies on keyword-based searches. The search strategy used included direct Boolean searching, example, ("Vitamin D receptor" OR "VDR") AND ("polymorphism" OR "SNP”), with a focus on capturing key variations through simple logical structures.

Scopus

The Scopus database has a similar keyword-based approach like the Web of Science but allows for slightly more advanced Boolean structuring. The strategy we used on this database was the use of keyword searches without controlled vocabulary like MeSH (example, ((“polymorphism” OR “single nucleotide polymorphism” OR “SNP” OR “variant” OR “genotype”), use of alternative phrase structures to account for variations (example, "pregnancy induced hypertension" OR "pregnancy-induced hypertension") and application of wildcards and truncation where applicable (e.g., "polymorph*" to capture multiple word forms).

EBSCOhost

EBSCOhost integrates multiple databases, however, in our study we used the most popular databases on EBSCOhost (MEDLINE and CINAHL). The search approach used was the utilization of keyword-based searching similar to Web of Science and Scopus, use of controlled vocabulary and use of structured Boolean searches with moderate use of nesting. Details of the article search strategy across the databases and the differences and similarities in search queries were shown in Supplementary Table 1 and 2 respectively.

Inclusion criteria

The study included case‒control studies reported in English and published in bibliographic databases from inception until 31st March 2023. Only studies that provided sufficient information on laboratory detection protocols and the association of one or more of the common VDR variants, FokI, BsmI, ApaI, and TaqI, with HDPs were included.

Exclusion criteria

Studies containing duplicate data or overlapping or review articles, conference abstracts or proceedings, short communications, cross-sectional or cohort studies, animal studies, randomized controlled trials, and studies including disorders other than HDP were excluded from the review. Additionally, grey literature materials such as article preprints, theses and dissertations were excluded due to concerns of quality, as these sources often lack formal peer review, at risk of bias with limited accessibility and the risk of duplication, as findings may later appear in peer-reviewed journals. Other articles related to VDR variants and HDP reported in nonpregnant women or other diseases were also excluded. Furthermore, to ensure a standardised and rigorous evaluation of the included studies, non-English language and other than case control studies were excluded due to potential limitations in translation and challenges in interpretation.

The exclusion of cohort studies, which may have added additional insights into long-term outcomes is one of the limitations of the study. Additionally, restricting the included studies to English language may have led to the omission of relevant studies, potentially affecting the comprehensiveness of the findings.

Extraction of data

The data extraction sheet was designed to systematically collect relevant information from included studies, such as author (year), country, population, VDR variants analyzed, association, VDR variant(s) associated, method of genotyping, major finding and quality assessment criteria. The development of the extraction sheet was guided by the objectives of the review and adopted the established reporting frameworks of PRISMA. The data extraction sheet was validated by two independent reviewers and discrepancies was resolved through discussion with a third reviewer. It was then piloted on a subset of studies to identify missing fields and ensure clarity and consistency before finalising the sheet for full data extraction.

Two authors (YI and NIB) carried out the article selection and data extraction. The percentage agreement between the two reviewers during study selection and data extraction was calculated to assess consistency. To account for chance in agreement, inter-rater reliability was assessed using Cohen’s kappa, The analysis yielded a kappa value of 0.90, indicating a near perfect agreement (Supplementary File 2). Any discrepancies were resolved through discussion with the third author (AAMJ). The studies evaluated were expressed in number and percentages.

Quality assessment of the included studies

The Newcastle–Ottawa Scale (NOS) for case–control studies was used to evaluate the methodological quality of the included studies (Supplementary File 3). This tool evaluates studies based on three domains: selection, comparability, and exposure or outcome. The selection domain assesses the adequacy of case definitions, representativeness of cases, and appropriateness of control selection. Comparability examines the control of confounding factors through statistical adjustments or matching. Exposure evaluates the reliability of exposure assessment methods, consistency in data collection, and potential selection bias due to non-response. Studies scoring ≥ 7 stars were classified as moderate to high quality, while those scoring < 7 stars were considered low quality [45]. Two authors (YI and NIB) conducted the quality assessment of the included studies (Table 1), Any conflicts during the process were resolved through discussion with a third author (AAMJ) in cases of unresolved disagreement.

Table 1 Quality assessment of studies using the Newcastle Ottawa scale (NOS) for case‒control studies
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Results

Identification and selection of articles

The present study identified 170 candidate articles through an electronic database search. After duplicates were removed, the abstracts of 143 articles were accessed for review, out of which 124 articles were screened. A total of 19 full-text articles were assessed for eligibility, and 10 were excluded after the eligibility criteria applied. Eventually, a total of nine (9) full-text articles that fully met the inclusion criteria of the study were included in the review synthesis [28,29,30,31, 36, 46,47,48,49]. The article selection flowchart is shown in Fig. 2. One study appeared to have met the inclusion criteria for the study, but it was excluded as it was a prospective cohort study [33].

Fig. 2
figure 2

Flowchart of articles selection process

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Characteristics of the studies included

Out of the 9 eligible studies, 6 (67%) studies were reported in Asia [29, 31, 36, 46, 47, 49], 2 (22%) from Europe [30, 48], and 1 (11%) from Latin America [28], as shown in Table 2. The study design for all the included studies was case‒control, with varying sample size proportions among the case and control subjects. About 4 (44%) of the studies had case‒control matched sample sizes [36, 46, 47, 49], 4 (44%) of the studies had varying proportions of sample size among case and control subjects [28,29,30, 48], and 1 (11%) study assessed both maternal blood and placental tissues for VDR gene variants [31]. The sample size proportion among cases and controls of the studies, from highest to lowest, included the Chinese Han population, 402/554 [29], Latin American pregnant women, 316/213 [28], pregnant women in Iran, 152/160 [31], Caucasian pregnant women in Poland [30], Caucasians in Italy, 116/69 [48], Madura ethnic pregnant women in Indonesia, 105/105 [36], 100/100 each for Asian Iranian [46, 47], and the Pakistan study, 40/40 [49]. The study’s characteristics are presented in Table 3.

Table 2 The sequences and background information of vitamin D receptor (VDR) gene variants included in the study
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Table 3 Summary of the studies’ characteristics
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Association analysis of laboratory detection protocols of VDR gene variants

Table 4 showed the association analysis of different laboratory protocols of VDR variant detection. 6 (67%) studies used PCR–RFLP [28, 30, 31, 36, 47], of which 3 (33%) reported a significant association with the FokI variant and HDP [46], 1 (11%) found a significant relation with the ApaI variant [47], and 1 (11%) study found a significant association with BsmI [30]. However, 1 (11%) study from Latin America (Brazil) did not show a significant association with FokI, ApaI, and BsmI when PCR–RFLP was used [28]. 2 (22%) of the studies conducted in China and Italy used TaqMan PCR, and they found an association with the FokI variant [29, 48], with one of the studies reported association of both FokI and BsmI combined variants and an increased risk of HDP [48]. In contrast, 1 (11%) study utilized AS-PCR for ApaI variant detection and found no significant association with the risk of HDP [49].

Table 4 Association of VDR gene variants laboratory detection protocols with risk of HDP among the included studies
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Association of VDR gene variants with HDP in the studied populations

Our evaluation of VDR variants association with HDP among studied population found that about 4 (44%) studies showed association of FokI variant reported in Asian populations [29, 31, 36, 46]. However, one study among Caucasians in Italy reported an association with the combined variant of FokI and BsmI [48]. Interestingly, 2 (22%) of the studies which reported an association with the BsmI variant were both from the Caucasian population in Italy and Poland [30, 48]. 1 (11%) study conducted in Asia (Pakistan) did not find any association with the ApaI variant [49]. Moreover, despite the 3 (34%) studies that analyzed the TaqI variant, none of the studies showed any association with HDP in the populations studied [36,37,38].

Discussion

HDP remains one of the major causes of maternal morbidity and mortality. Although the pathogenesis is not yet fully elucidated, genetic predisposition involving VDR variants has been thought to contribute to the likelihood of developing HDP. Studies on association between VDR variants and HDP were inconsistently reported. These discrepancies could be due to different laboratory protocols in detecting the variants and their association with HDP in different populations. Thus, we carried out a systematic review aiming to provide insight on the laboratory detection protocols of VDR gene variants, evaluate the variants association with HDPs in different populations and highlight the future perspective of these variants in precision medicine.

Association of VDR gene variants with HDP detected using different laboratory protocols

Genotyping gene variant is a crucial task in population genetics and association studies. Each variant detection method has its own peculiar advantages and limitations. Thorough analysis is needed to determine the most suitable protocol for detecting a particular variant(s) in a population. In the present study, approximately 6 (67%) studies used PCR–RFLP [28, 30, 31, 36, 46, 47]. All studies utilising PCR–RFLP demonstrated an association with FokI and were reported among Asian populations [31, 36, 46]. On the other hand, one study reported an association with the ApaI variant [47]. Another study in Brazil did not show any relationship with any of the variants when PCR–RFLP was used [28]. This could be due to the low sensitivity of PCR–RFLP in detecting rare alleles of VDR variants, which could have the potential to underestimate or possibly miss some genotypes. The evaluated studies analysed many VDR variants, however only a few studies reported an association with some variants whilst some reported no association. Optimisation of VDR detection protocols is essential to ensure the accuracy and reproducibility of genotyping of VDR variants.

Two (22%) of the studies used TaqMan PCR [32, 37]. Study among Chinese Han population reported an association with the FokI variant [29], while FokI and BsmI combined variants were associated with HDP in Italian population [37]. TaqMan PCR is faced with some drawbacks, such as the challenge of designing probes for specific regions of the genome, the inability to simultaneously analyse many variations, and the potential for uncertainty in genotyping complex polymorphisms.

AS-PCR was used to genotype ApaI VDR variant and found no association with HDP in a Pakistani population [49]. In contrast, ApaI variant genotyping using PCR–RFLP method found an association with HDP in Iranian subjects [47]. Despite the fact that both studies were conducted among Asian descents, there was discrepancy in their findings. This could be due to the complexity of AS-PCR in designing primers in regions with similar sequences, the difficulty of genotyping multiple alleles at once [51], variable sensitivity and efficiency influenced by primer design and template DNA concentration [41]. The limitations of detecting novel variants without knowledge of the sequence, and the requirement for validation and replication of results, are among the difficulties associated with AS-PCR [42].

From our evaluation, the inconsistent association of the variants might not be protocol specific alone but could be due to other factors. Adherence to robust quality control (QC) could go a long way in ameliorating the inadequacies of these protocols. Although no single technique is regarded as perfect in genotyping VDR polymorphisms, certain advantages of a particular protocol should be considered, such as sensitivity and accuracy, potential of detecting rare alleles, availability of the genotyping platform, and the desired gene or variants to be detected. None of the studies included in this review validated their genotyping results using sequencing. For quality control purposes and to ensure accuracy and precision, it is crucial to validate genotyping protocol with gene sequencing [52,53,54]. This gold-standard approach involves randomly selecting representative DNA samples for sequencing. This has the potential to effectively identify variations and reduce genotyping errors. In addition, this could ensure reproducibility and enable others to replicate the results.

Moreover, the limitation of this technique may be overcome by other reliable, sensitive and specific methods, with the potential of detecting rare alleles such as the polymerase chain reaction-high resolution melting (PCR-HRM) method. HRM relies on the changes in the DNA melting temperature and gradual monitoring of fluorescence as the DNA strands break [30, 45]. However, sequencing of fragments is warranted to validate the genotyping results, as reported by previous studies [44, 55, 56]. Validating genotyping by gene sequencing has significant implications in biomarker identification, early disease diagnosis and risk prediction as well as personalised management of HDP.

Association analysis of VDR variants with HDP among populations

More than half of the included studies reported an association between FokI variant and an increased risk of HDP [29, 31, 36, 46, 48]. Study among pregnant women in Indonesia reported the FokI TT genotype was associated with threefold increased risk of GH [36]. Similarly, FF/bB combined haplotype was associated with two-fold increased risk of GH among individuals with vitamin D deficiency [48]. FokI variant was also reported to be associated with severe preeclampsia in Iranian and Chinese Han pregnant women while FokI Ff + ff + genotypes were reported to decrease the risk of developing PE [31]. This could be due to the impact of FokI polymorphism on the renin-angiotensin system, which regulates blood pressure leading to the modification of protein structure and transcriptional activity [27, 57, 58]. The FokI polymorphism upregulates renin mRNA transcription activity resulting in an increase in plasma renin activity. This crucial mechanism in blood pressure regulation is known to have a substantial role in the development of hypertension. Covert genetic markers may be discovered as a result of the complex interaction between genes and environmental factors such as sunlight exposure, dietary habits and socioeconomic factors, as well as gene‒gene interactions [59] and epigenetic influences [60]. These factors all together influence the VDR variants and may result in higher risk of HDP.

Numerous studies have examined the association of BsmI variants and the risk of HDP. However, findings have been inconsistent across different populations, highlighting the complex biological role of these variants. While some studies found no significant link between the BsmI and risk of HDP [29, 31, 36, 46, 47], other have identified specific genotypes (Bb and bb) to be significantly associated with HDP [30, 48]. In a Polish cohort, the BsmI AA genotype found twofold increase risk of PE [30]. Likewise, an Italian study demonstrated that the combined variants (FokI and BsmI) increased risk of GH by twofold, with three times greater risk among vitamin D-insufficient mothers [48]. These findings suggest that BsmI and other VDR variants may play a significant role in the biological mechanisms of HDP, particularly in Caucasian populations. The role of BsmI variant in HDP pathogenesis could involve the modulation of VDR activity, which is essential for calcium homeostasis, immune system, and regulation of blood pressure. Genetic variations in VDR could alter receptor expression or function, leading to dysregulation of these pathways and contributing to the development of HDP. Further research is necessary to elucidate the precise mechanisms involved and to determine variants associations across different populations.

On the contrary, studies in Latin American populations did not establish any significant association with any of the VDR variants and HDP [32]. However, this finding should be interpreted with caution considering that the VDR gene also interacts with numerous other genes and environmental factors such as sunlight exposure, dietary habits, lifestyle and economic factors, influencing access to vitamin D-rich nutrients and use of vitamin D supplements. Considering the role of these variants in vitamin D metabolism, it is imperative to consider strategies to increase vitamin D intake through diet or supplements and addressing the socioeconomic and lifestyle barriers.

The association between ApaI variant and HDP, particularly PE, remained underexplored. While an Iranian study suggested that the ApaI VDR variant doubles the risk of developing PE [47], studies by Rezende et al. [28] and Aziz et al. [49], failed to find any association. Additionally, the ApaI variant appears to be more strongly associated with HDP in Asians than in Caucasians [61]. Disruptions in this pathway could impair normal homeostatic mechanism regulating blood pressure, particularly under the physiological stress of pregnancy, thereby increasing the risk of HDP.

Implications and future directions

Proper selection of VDR variant detection protocol along with stringent quality control is essential to reduce inconsistencies in the association of VDR gene variants with HDP across diverse populations. Enhancing the accuracy of genetic findings can facilitate precision medicine, allowing for individualized treatment, timely intervention, and preventive strategies such as vitamin D supplementation and tailored dietary modifications [62]. Moreover, integrating VDR variant screening into clinical and public health frameworks is strongly advocated [63]. This could help in developing population-specific recommendations, addressing disparities in pregnancy-related complications, and ultimately reducing maternal morbidity and mortality.

This review underscores the importance of robust VDR detection methods in ensuring the reliability of variant association studies. However, a potential limitation is the absence of haplotype analysis, which could provide a deeper understanding into the combined effects of multiple genetic variants on HDP risk. The lack of comprehensive meta-analysis and the limited number of available case–control studies highlight the need for further research in this area. Expanding case–control and cohort studies and incorporating haplotype-based approaches will strengthen the evidence based, improve the consistency of findings, and support the integration of VDR variant screening into public health policies for better pregnancy outcomes.

Conclusion

In conclusion, our study highlights the association between VDR gene variants with HDP, emphasizing the need for reliable detection protocols to minimize discrepancies across populations which could enhance precision medicine. Proper detection protocols, stringent quality control measures are warranted to strengthen genetic research, providing evidence of the integration of VDR variant screening into public health policies to reduce the risks of HDP.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary tables, files and materials.

Abbreviations

AS-PCR:

Allele specific polymerase chain reaction

DNA:

Deoxyribonucleic acid

GDM:

Gestational diabetes mellitus

GH:

Gestational hypertension

HDP:

Hypertensive disorder of pregnancy

HRM:

High resolution melting

M:

Maternal

MeSH:

Medical subject headings

mRNA:

Messenger ribonucleic acid

NOS:

Newcastle Ottawa scale

P:

Placental

PCR:

Polymerase chain reaction

PCR-HRM:

Polymerase chain reaction- High resolution melting

PCR-RFLP:

Polymerase chain reaction-restriction fragment length polymorphisms

PE:

Preeclampsia

PIH:

Pregnancy induced hypertension

PRISMA:

Preferred reporting items for systematic review and meta-analysis

QC:

Quality control

SNPs:

Single nucleotide polymorphisms

UTR:

Untranslated region

VDR:

Vitamin D receptor

VDRE:

Vitamin D responsive elements

RXR:

Retinoid X receptor

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Acknowledgements

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Funding

This research was supported by a grant from the Ministry of Higher Education Malaysia under Fundamental Research Grant Scheme FRGS/1/2022/SKK01/UPM/02/1, awarded to NIB. The funder has no role in the design, data collection, analysis, decision to publish, and preparation of this manuscript.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, 43400, Malaysia

    Yakubu Ibrahim, Nurul Iftida Basri & Amilia Afzan Mohd Jamil

  2. Department of Medical Laboratory Science, Faculty of Allied Health Sciences, College of Medical Sciences, Ahmadu Bello University, Zaria, Kaduna State, Nigeria

    Yakubu Ibrahim

  3. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, 43400, Malaysia

    Norshariza Nordin

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  1. Yakubu Ibrahim
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Conception of the study; YI, NIB, AAMJ, and NN, Article search and quality assessment of studies; YI and NIB, Analysis and in terpretation of data; YI, NN, Manuscript writing; YI, Manuscript revision for important intellectual content; YI, NIB, AAMJ and NN, Approval of the submitted manuscript and agreed to be accountable for the work; YI, NIB, AAMJ and NN.

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Ibrahim, Y., Basri, N.I., Jamil, A.A.M. et al. A plethora of laboratory protocols for vitamin D receptor (VDR) gene variants detection: a systematic review of associations with hypertensive disorders of pregnancy. BMC Pregnancy Childbirth 25, 539 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12884-025-07510-6

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BMC Pregnancy and Childbirth

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