Article

Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation

July 2009
Clinical Biochemistry 42(10-11):1174-7

July 2009
42(10-11):1174-7

DOI:10.1016/j.clinbiochem.2009.03.008

Source
PubMed

Authors:

Lei Fu

Sunnybrook Health Sciences Centre

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To determine the effect of vitamin D binding protein (DBP) genotypes on 25-hydroxyvitamin D [25(OH)D] changes with vitamin D supplements, we studied 98 adults receiving 600 or 4000 IU/d vitamin D(3) for one year. The DBP functional variant, T436K, was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Mean 25(OH)D increases were 97% for TT (n=48), 151% for TK (n=31) and 307% (n=6) for KK genotypes (p=.004). As with baseline 25(OH)D, T436K genotype predicts 25(OH)D changes after long-term vitamin D supplementation.

Genetic Variation of the Vitamin D Binding Protein Affects Vitamin D Status and Response to Supplementation in Infants

Article

Full-text available

Jul 2019
J CLIN ENDOCR METAB

Context: Single nucleotide polymorphisms (SNPs) of the vitamin D binding protein encoding GC (group component) gene affect 25-hydroxyvitamin D (25OHD) concentrations but their influence on vitamin D status and response to vitamin D supplementation in infants is unknown. Objective: To study GC genotype-related differences in 25OHD concentrations and response to supplementation during a vitamin D intervention study in infants. Design: In this randomized controlled trial, healthy term infants received 10 or 30 μg vitamin D3/day from 2 weeks to 24 months of age. GC SNPs rs2282679, rs4588, rs7041 and rs1155563 were genotyped, rs4588/7041 diplotype and haplotypes of rs2282679, rs4588 and rs7041 (Haplo3SNP) and of all four SNPs (Haplo4SNP) were determined. Main outcome measures: 25OHD measured in cord blood at birth and at 12 and 24 months during intervention. Results: Altogether 913 infants were included. Minor allele homozygosity of all studied GC SNPs, their combined haplotypes and rs4588/rs7041 diplotype 2/2 were associated with lower 25OHD concentrations at all time points in one or both intervention groups (analysis of covariance p<0.043), with the exception of rs7041 which did not affect 25OHD at birth. In the high-dose supplementation group, receiving 30 μg vitamin D3/day, but not in those receiving 10 µg/day, genotype of rs2282679, rs4588 and rs7041, diplotype and Haplo3SNP significantly affected intervention response (repeated measurement analysis of covariance pinteraction <0.019). Minor allele homozygotes had lower 25OHD concentrations and smaller increase in 25OHD throughout intervention. Conclusions: In infants, vitamin D binding protein genotype affects 25OHD concentration and efficiency of high-dose vitamin D3 supplementation.

Association of VDBP rs4701 Variant, but not VDR/RXR-α Over-Expression with Bone Mineral Density in Pediatric Well-Chelated β-Thalassemia Patients

Article

Full-text available

Jul 2020

Background: The reduced rate of bone formation despite the availability of vitamin D has been reported in β-thalassemia. Genetic factors, together with environmental ones, could be implicated in this condition. Since vitamin D binding protein (VDBP) maintains bioavailability of vitamin D which binds to vitamin D receptor (VDR)-retinoid X receptor alpha (RXRA) heterodimer to exert its molecular actions, we speculated that vitamin D metabolic-axis expression signature and variants could be potential molecular candidates for bone turnover/disease in thalassemia. To this end, this study aims to analyze VDR/RXRA expression signature, and two VDBP variants in a pilot sample of Egyptian β-thalassemia children in correlation with bone mineral density (BMD). Patients and methods: Forty-four well-chelated β-thalassemia children and 40 unrelated controls were enrolled. The serum bone chemistry profile was measured. Peripheral blood mononuclear cells (PBMN) VDR/RXRA expression levels were quantified by Real-Time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). VDBP rs7041 and rs4588 variants were identified by Real-Time allelic discrimination assay. All patients were subjected to lumbar-spine Dual-energy X-ray absorptiometry (DEXA). Results: VDR/RXRA expressions were significantly higher in β-thalassemia children compared to controls (P = 0.001 and <0.001, respectively) and showed higher values in β-thalassemia major relative to β-thalassemia intermedia. Expression levels of both genes were not associated with sex or BMD. However, VDBP rs4701 genotyping revealed lower BMD-L4 and a higher frequency of osteoporosis. Conclusions: β-Thalassemia children had higher expression levels of PBMN VDR/RXRA. VDBP rs4701 variant was associated with osteoporosis in our β-thalassemia patients on vitamin D supplementation. Further large-scale studies in other ethnic populations are warranted.

Genetic Components of 25-Hydroxyvitamin D Increase in Three Randomized Controlled Trials

Article

Full-text available

Feb 2020

The 25-Hydroxyvitamin D (25[OH)D) serum concentration depends on vitamin D intake, endogenous vitamin D production and genetic factors. The latter have been demonstrated in large genome-wide association studies indicating that single nucleotide polymorphisms (SNPs) in genes related to the vitamin D metabolism are as important for serum 25(OH)D levels as the influence of season. The mechanism on how these SNPs influence serum 25(OH)D levels are still unclear. The aim of the present study was to investigate the genetic effects of ten selected SNPs related to vitamin D metabolism on 25-hydroxyvitamin D increase (∆25(OH)D) after vitamin D supplementation in three randomized controlled trials. Genotypes of SNPs related to vitamin D metabolism were determined in 411 participants with 25(OH)D concentrations < 75 nmol/l receiving 20,000 IU cholecalciferol per week for 8 or 12 weeks after study inclusion. For the vitamin D receptor (VDR) rs10783219 polymorphism, the minor A-allele was associated with lower ∆25(OH)D values in the entire study population (p = 0.022), which was not consistent in all three cohorts when analysed separately. VDR rs10783219 might therefore be a genetic modulator of increasing 25-hydroxyvitamin D concentrations. Considering the widespread use of vitamin D supplementation, future large and well-designed randomized controlled trials (RCTs) should investigate the clinical impact of this polymorphism.

Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions

Article

Full-text available

May 2019

This review focuses on the biologic importance of the vitamin D binding protein (DBP) with emphasis on its regulation of total and free vitamin D metabolite levels in various clinical conditions. Nearly all DBP is produced in the liver, where its regulation is influenced by estrogen, glucocorticoids and inflammatory cytokines but not by vitamin D itself. DBP is the most polymorphic protein known, and different DBP alleles can have substantial impact on its biologic functions. The three most common alleles-Gc1f, Gc1s, Gc2-differ in their affinity with the vitamin D metabolites and have been variably associated with a number of clinical conditions. Although DBP has a number of biologic functions independent of vitamin D, its major biologic function is that of regulating circulating free and total levels of vitamin D metabolites. 25 hydroxyvitamin D (25(OH)D) is the best studied form of vitamin D as it provides the best measure of vitamin D status. In a normal non-pregnant individual, approximately 0.03% of 25(OH)D is free; 85% is bound to DBP, 15% is bound to albumin. The free hormone hypothesis postulates that only free 25(OH)D can enter cells. This hypothesis is supported by the observation that mice lacking DBP, and therefore with essentially undetectable 25(OH)D levels, do not show signs of vitamin D deficiency unless put on a vitamin D deficient diet. Similar observations have recently been described in a family with a DBP mutation. This hypothesis also applies to other protein bound lipophilic hormones including glucocorticoids, sex steroids, and thyroid hormone. However, tissues expressing the megalin/cubilin complex, such as the kidney, have the capability of taking up 25(OH)D still bound to DBP, but most tissues rely on the free level. Attempts to calculate the free level using affinity constants generated in a normal individual along with measurement of DBP and total 25(OH)D have not accurately reflected directly measured free levels in a number of clinical conditions. In this review, we examine the impact of different clinical conditions as well as different DBP alleles on the relationship between total and free 25(OH)D, using only data in which the free 25(OH)D level was directly measured. The major conclusion is that a number of clinical conditions alter this relationship, raising the question whether measuring just total 25(OH)D might be misleading regarding the assessment of vitamin D status, and such assessment might be improved by measuring free 25(OH)D instead of or in addition to total 25(OH)D.

Citation: The Impact of Vitamin D and L-Cysteine Co-Supplementation on Upregulating Glutathione and Vitamin D-Metabolizing Genes and in the Treatment of Circulating 25-Hydroxy Vitamin D Deficiency. The Impact of Vitamin D and L-Cysteine Co-Supplementation on Upregulating Glutathione and Vitamin D-Metabolizing Genes and in the Treatment of Circulating 25-Hydroxy Vitamin D Deficiency

Article

Full-text available

Jun 2024

Vitamin D receptors are expressed in many organs and tissues, which suggests that vitamin D (VD) affects physiological functions beyond its role in maintaining bone health. Deficiency or inadequacy of 25(OH)VD is widespread globally. Population studies demonstrate that a positive association exists between a high incidence of VD deficiency and a high incidence of chronic diseases, including dementia, diabetes, and heart disease. However, many subjects have difficulty achieving the required circulating levels of 25(OH)VD even after high-dose VD supplementation, and randomized controlled clinical trials have reported limited therapeutic success post-VD supplementation. Thus, there is a discordance between the benefits of VD supplementation and the prevention of chronic diseases in those with VD deficiency. Why this dissociation exists is currently under debate and is of significant public interest. This review discusses the downregulation of VD-metabolizing genes needed to convert consumed VD into 25(OH)VD to enable its metabolic action exhibited by subjects with metabolic syndrome, obesity, and other chronic diseases. Research findings indicate a positive correlation between the levels of 25(OH)VD and glutathione (GSH) in both healthy and diabetic individuals. Cell culture and animal experiments reveal a novel mechanism through which the status of GSH can positively impact the expression of VD metabolism genes. This review highlights that for better success, VD deficiency needs to be corrected at multiple levels: (i) VD supplements and/or VD-rich foods need to be consumed to provide adequate VD, and (ii) the body needs to be able to upregulate VD-metabolizing genes to convert VD into 25(OH)VD and then to 1,25(OH)2VD to enhance its metabolic action. This review outlines the association between 25(OH)VD deficiency/inadequacy and decreased GSH levels, highlighting the positive impact of combined VD+LC supplementation on upregulating GSH, VD-metabolizing genes, and VDR. These effects have the potential to enhance 25(OH)VD levels and its therapeutic efficacy.

The role of vitamin D and calcium in preventing recurrence of colon adenomas: is precision medicine the answer?

Article

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Sep 2023

Role of Vitamin D in Head and Neck Cancer—Immune Function, Anti-Tumour Effect, and Its Impact on Patient Prognosis

Article

Full-text available

May 2023

Katarzyna Starska-Kowarska

Head and neck squamous cell carcinoma (HNSCC) describes a heterogeneous group of human neoplasms of the head and neck with high rates of morbidity and mortality, constituting about 3% of all cancers and ~1.5% of all cancer deaths. HNSCC constituted the seventh most prevalent human malignancy and the most common human cancer in the world in 2020, according to multi-population observations conducted by the GLOBOCAN group. Since approximately 60–70% of patients present with stage III/IV neoplastic disease, HNSCC is still one of the leading causes of death in cancer patients worldwide, with an overall survival rate that is too low, not exceeding 40–60% of these patients. Despite the application of newer surgical techniques and the implementation of modern combined oncological treatment, the disease often follows a fatal course due to frequent nodal metastases and local neoplastic recurrences. The role of micronutrients in the initiation, development, and progression of HNSCC has been the subject of considerable research. Of particular interest has been vitamin D, the pleiotropic biologically active fat-soluble family of secosteroids (vitamin-D-like steroids), which constitutes a key regulator of bone, calcium, and phosphate homeostasis, as well as carcinogenesis and the further development of various neoplasms. Considerable evidence suggests that vitamin D plays a key role in cellular proliferation, angiogenesis, immunity, and cellular metabolism. A number of basic science, clinical, and epidemiological studies indicate that vitamin D has multidirectional biological effects and influences anti-cancer intracellular mechanisms and cancer risk, and that vitamin D dietary supplements have various prophylactic benefits. In the 20th century, it was reported that vitamin D may play various roles in the protection and regulation of normal cellular phenotypes and in cancer prevention and adjunctive therapy in various human neoplasms, including HNSCC, by regulating a number of intracellular mechanisms, including control of tumour cell expansion and differentiation, apoptosis, intercellular interactions, angio- and lymphogenesis, immune function, and tumour invasion. These regulatory properties mainly occur indirectly via epigenetic and transcriptional changes regulating the function of transcription factors, chromatin modifiers, non-coding RNA (ncRNAs), and microRNAs (miRs) through protein-protein interactions and signalling pathways. In this way, calcitriol enhances intercellular communication in cancer biology, restores the connection with the extracellular matrix, and promotes the epithelial phenotype; it thus counteracts the tumour-associated detachment from the extracellular matrix and inhibits the formation of metastases. Furthermore, the confirmation that the vitamin D receptor (VDR) is present in many human tissues confirmed the physiopathological significance of vitamin D in various human tumours. Recent studies indicate quantitative associations between exposure to vitamin D and the incidence of HNC, i.e., cancer risk assessment included circulating calcidiol plasma/serum concentrations, vitamin D intake, the presence of the VDR gene polymorphism, and genes involved in the vitamin D metabolism pathway. Moreover, the chemopreventive efficacy of vitamin D in precancerous lesions of the head and neck and their role as predictors of mortality, survival, and recurrence of head and neck cancer are also widely discussed. As such, it may be considered a promising potential anti-cancer agent for developing innovative methods of targeted therapy. The proposed review discusses in detail the mechanisms regulating the relationship between vitamin D and HNSCC. It also provides an overview of the current literature, including key opinion-forming systematic reviews as well as epidemiological, prospective, longitudinal, cross-sectional, and interventional studies based on in vitro and animal models of HNSCC, all of which are accessible via the PubMed/Medline/EMBASE/Cochrane Library databases. This article presents the data in line with increasing clinical credibility.

Vitamin D3 supplementation as an adjunct in the management of childhood infectious diarrhea: a systematic review

Article

Full-text available

Mar 2023
BMC INFECT DIS

Background Some studies have reported the possible role of vitamin D3 in ameliorating disease outcomes in childhood infectious diarrhea. However, findings about its effectiveness and the association of serum vitamin D levels with diarrhea risk appear inconsistent. We aimed to determine the efficacy of oral vitamin D3 as an adjunct in managing childhood infectious diarrhea and the relationship between vitamin D status and the disease. Methods We searched the PubMed and Google Scholar electronic databases for relevant articles without limiting their year of publication. We selected primary studies that met the review’s inclusion criteria, screened their titles and abstracts, and removed duplicates. We extracted data items from selected studies using a structured data-extraction form. We conducted a quality assessment of randomized controlled trials (RCTs) and non-randomized studies with the Cochrane collaboration tool and the Newcastle Ottawa Scale, respectively. We assessed the strength of the relationship between serum vitamin D levels and diarrhea using the correlation model. We estimated the I² and tau² values to assess between-study heterogeneity. Results Nine full-text articles were selected, consisting of one RCT, three cross-sectional studies, two cohort studies, two longitudinal/prospective studies, and one case-control study. A total of 5,545 participants were evaluated in the nine studies. Six non-randomized studies provided weak evidence of the relationship between vitamin D levels and diarrhea risk as there was no correlation between the two variables. The only RCT failed to demonstrate any beneficial role of vitamin D3 in reducing the risk of recurrent diarrhea. The calculated I² and tau² values of 86.5% and 0.03, respectively suggested a high between-study heterogeneity which precluded a meta-analysis of study results. Conclusion Oral vitamin D3 may not be an effective adjunct in managing childhood infectious diarrhea. Additionally, the relationship between vitamin D status and infectious diarrhea appears weak. We recommend more adequately-powered RCTs to determine the effectiveness of vitamin D3 as an adjunct therapy in infectious diarrhea.

The impact of vitamin D supplementation as an adjuvant therapy on clinical outcomes in patients with severe atopic dermatitis: A randomized controlled trial

Article

Jan 2020

Vitamin D supplementation with standard treatment yielded positive clinical outcomes in mild and moderate atopic dermatitis; however, the potential benefit of vitamin D in severe cases remains unclear. This study aimed to evaluate the impact of vitamin D supplementation on response to standard treatment in pediatrics with severe atopic dermatitis. The patients were randomized to receive either vitamin D 3 1600 IU/day or placebo, plus baseline therapy of topical 1% hydrocortisone cream twice daily for 12 weeks. The primary endpoints were the change in mean Eczema Area and Severity Index (EASI) score at the end of the study and the mean percent change in EASI score from baseline to week 12. Eighty-six subjects completed the study. The treated group achieved a significant higher level of 25 hydroxy vitamin D (P < .001) compared to control group at week 12. The mean EASI score was significantly lower in the treatment group compared to placebo group (P = .035). The percent change in EASI score from baseline differed significantly between the sup-plementation (56.44 ± 29.33) and placebo (42.09 ± 19.22) groups after intervention (P = .039). Vitamin D supplementation could be an effective adjuvant treatment that improves the clinical outcomes in severe atopic dermatitis. K E Y W O R D S atopic dermatitis, Eczema, severe, vitamin D

Determinants and Effects of Vitamin D Supplementation in Postmenopausal Women: A Systematic Review

Article

Full-text available

Jan 2023

Hormonal fluctuations, excessive clothing covering, sunscreen use, changes in body fat composition, a vitamin D-deficient diet, and a sedentary lifestyle can all predispose postmenopausal women to vitamin D deficiency. An effective supplementation plan requires a thorough understanding of underlying factors to achieve the desired therapeutic concentrations. The objective of this study was to conduct a systematic review of the predictors that affect vitamin D status in postmenopausal women. From inception to October 2022, we searched MEDLINE, Embase, Web of Science, Scopus, and clinical trial registries. Randomized clinical trials of postmenopausal women taking supplements of vitamin D with serum 25-hydroxyvitamin D (25(OH)D) measurement as the trial outcome were included. Two independent reviewers screened selected studies for full-text review. The final assessment covered 19 trials within 13 nations with participants aged 51 to 78. Vitamin D supplementation from dietary and pharmaceutical sources significantly increased serum 25(OH)D to optimal levels. Lower baseline serum 25(OH)D, lighter skin color, longer treatment duration, and prolonged skin exposure were all associated with a better response to vitamin D supplementation in postmenopausal women.

Impact of daily vitamin D3 supplementation on the risk of vitamin D deficiency with the interaction of rs2282679 in vitamin D binding protein gene (GC) among overweight and obese children and adolescents: A one-year randomized controlled trial

Article

Full-text available

Dec 2022

Background The rs2282679 polymorphism in the vitamin D binding protein (DBP) gene may influence the response to vitamin D supplementation. Therefore, we examine the effect of 1-year vitamin D supplementation on vitamin D deficiency (VDD) with the interaction of rs2282679 polymorphism in overweight and obese children and adolescents. Materials and methods The participants (n = 300) were part of a randomized controlled trial who received a daily supplement of either 1,000 or 2,000 IU or four supplements of 1,000 IU weekly (equal to 600 IU daily) of vitamin D3 for 12 months. Genotyping was performed using amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Results The mean of 25(OH)D values at baseline for participants with the TT, TG, and GG genotypes were 15.4, 14.4, and 10.8 ng/mL, respectively, and were not different between the three genotype groups (P = 0.062). A significant reduction in VDD was observed after vitamin D supplementation with dosages of 1,000 or 2,000 IU compared to 600 IU. No significant association of genotypes with risk of VDD was observed in each intervention group after vitamin D supplementation, except, that individuals with TG genotype showed a higher risk of VDD compared to those with TT genotype in the 2,000 IU group after 6 months of supplementation [odds ratio (95% CI): 6.94; 1.30–37.02]. We observed no interaction between time duration, three genotypes, and dosages with serum 25(OH)D, calcium, phosphorus, alkaline phosphatase, and parathyroid hormone levels. Conclusion Response to vitamin D supplementation by three doses of 600, 1,000, and 2,000 IU could not be affected by rs2282679 polymorphism during 12 months in overweight and obese children and adolescents.

Vitamin D Deficiency and COVID-19: A Biological Database Study on Pathways and Gene-Disease Associations

Article

Full-text available

Nov 2022
INT J MOL SCI

Vitamin D (VD) is a fat-soluble vitamin, and pivotal for maintaining health. Several genetic markers have been related to a deficient VD status; these markers could confer an increased risk to develop osteoporosis and other chronic diseases. A VD deficiency could also be a determinant of a severe COVID-19 disease. This study aimed to interrogate genetic/biological databases on the biological implications of a VD deficiency and its association with diseases, to further explore its link with COVID-19. The genetic variants of both a VD deficiency and COVID-19 were identified in the genome-wide association studies (GWAS) catalog and other sources. We conducted enrichment analyses (considering corrected p-values < 0.05 as statistically significant) of the pathways, and gene-disease associations using tools, such as FUMA, REVIGO, DAVID and DisGeNET, and databases, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). There were 26 and 46 genes associated with a VD deficiency and COVID-19, respectively. However, there were no genes shared between the two. Genes related to a VD deficiency were involved in the metabolism of carbohydrates, retinol, drugs and xenobiotics, and were associated with the metabolic syndrome and related factors (obesity, hypertension and diabetes mellitus), as well as with neoplasms. There were few enriched pathways and disease connections for the COVID-19-related genes, among which some of the aforementioned comorbidities were also present. In conclusion, genetic factors that influence the VD levels in the body are most prominently associated with nutritional and metabolic diseases. A VD deficiency in high-risk populations could be therefore relevant in a severe COVID-19, underlining the need to examine whether a VD supplementation could reduce the severity of this disease.

IMPACT OF VITAMINS IN PREVENTION OF RISK FACTORS ASSOCIATED WITH TYPE-2 DIABETES MELLITUS

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Jan 2013

Diabetes mellitus is one of the most common metabolic disorders that cause micro and macro vascular complications.

Association of VDBP (rs4588 and rs7041) gene polymorphisms with susceptibility to postpartum depression in South Indian population: A cross-sectional study

Article

Jul 2022
PSYCHIAT RES

Low vitamin D levels have been implicated in postpartum depressive disorders (PPD). Our study aimed to demonstrate the association of Vitamin D Binding Protein (VDBP) genetic variants rs7041 and rs4588 with susceptibility to PPD and to investigate their possible relationship with serum vitamin D and VDBP levels in Indian women with PPD. A cross-sectional study involved 330 cases and 330 controls. Depressive symptoms were assessed using Edinburg Postnatal Depression Scale. Genotyping of SNPs was done by Taqman 5’allelic discrimination assay. Estimation of serum 25 hydroxyvitamin D [25(OH) D] and VDBP levels were done by ELISA. Serum total, free and bioavailable 25(OH) D levels were significantly lower in cases compared to controls, with similar levels of VDBP between the two groups. The study results showed that the VDBP rs4588 variant genotype AA was significantly associated with lower circulating levels of total 25(OH) D in cases. Also, the VDBP rs7041 variant TT genotype demonstrated significantly lower levels of total, free and bioavailable 25(OH) D levels in controls. However, VDBP rs7041 and rs4588 variants were not associated with PPD susceptibility. Also, VDBP haplotypes showed no association with PPD susceptibility. Our results demonstrated that VDBP polymorphisms rs4588 and rs7041 and their haplotypes are not associated with PPD susceptibility in the South Indian population. However, vitamin D levels were found to be influenced by the risk genotypes of VDBP SNPs rs4588 and rs7041.

Vitamin D Metabolites: Analytical Challenges and Clinical Relevance

Article

Full-text available

Mar 2022
CALCIFIED TISSUE INT

Recent research activities have provided new insights in vitamin D metabolism in various conditions. Furthermore, substantial progress has been made in the analysis of vitamin D metabolites and related biomarkers, such as vitamin D binding protein. Liquid chromatography tandem mass spectrometric (LC–MS/MS) methods are capable of accurately measuring multiple vitamin D metabolites in parallel. Nevertheless, only 25(OH)D and the biologically active form 1,25(OH)2D are routinely measured in clinical practice. While 25(OH)D remains the analyte of choice for the diagnosis of vitamin D deficiency, 1,25(OH)2D is only recommended in a few conditions with a dysregulated D metabolism. 24,25(OH)2D, free and bioavailable 25(OH)D, and the vitamin D metabolite ratio (VMR) have shown promising results, but technical pitfalls in their quantification, limited clinical data and the lack of reference values, impede their use in clinical practice. LC–MS/MS is the preferred method for the measurement of all vitamin D related analytes as it offers high sensitivity and specificity. In particular, 25(OH)D and 24,25(OH)2D can accurately be measured with this technology. When interpreted together, they seem to provide a functional measure of vitamin D metabolism beyond the analysis of 25(OH)D alone. The determination of VDBP, free and bioavailable 25(OH)D is compromised by unresolved analytical issues, lacking reference intervals and insufficient clinical data. Therefore, future research activities should focus on analytical standardization and exploration of their clinical value. This review provides an overview on established and new vitamin D related biomarkers including their pathophysiological role, preanalytical and analytical aspects, expected values, indications and influencing conditions.

Association between Polymorphisms in Vitamin D Pathway-Related Genes, Vitamin D Status, Muscle Mass and Function: A Systematic Review

Article

Full-text available

Sep 2021

An association between vitamin D level and muscle-related traits has been frequently reported. Vitamin D level is dependent on various factors such as sunlight exposure and nutrition. But also on genetic factors. We, therefore, hypothesize that single nucleotide polymorphisms (SNPs) within the vitamin D pathway-related genes could contribute to muscle mass and function via an impact on vitamin D level. However, the integration of studies investigating these issues is still missing. Therefore, this review aimed to systematically identify and summarize the available evidence on the association between SNPs within vitamin D pathway-related genes and vitamin D status as well as various muscle traits in healthy adults. The review has been registered on PROSPERO and was conducted following PRISMA guidelines. In total, 77 studies investigating 497 SNPs in 13 different genes were included, with significant associations being reported for 59 different SNPs. Variations in GC, CYP2R1, VDR, and CYP24A1 genes were reported most frequently, whereby especially SNPs in the GC (rs2282679, rs4588, rs1155563, rs7041) and CYP2R1 genes (rs10741657, rs10766197, rs2060793) were confirmed to be associated with vitamin D level in more than 50% of the respective studies. Various muscle traits have been investigated only in relation to four different vitamin D receptor (VDR) polymorphisms (rs7975232, rs2228570, rs1544410, and rs731236). Interestingly, all of them showed only very low confirmation rates (6–17% of the studies). In conclusion, this systematic review presents one of the most comprehensive updates of the association of SNPs in vitamin D pathway-related genes with vitamin D status and muscle traits in healthy adults. It might be used for selecting candidate SNPs for further studies, but also for personalized strategies in identifying individuals at risk for vitamin D deficiency and eventually for determining a potential response to vitamin D supplementation.

25-OHD response to Vitamin D supplementation in children: Effect of dose but not GC haplotype

Article

Jun 2021

Objective: GC/DBP effects on response to vitamin D supplementation have not been well-studied. Thus we assessed free and total 25-OHD after vitamin D treatment across the 6 common GC haplotypes. Design: This double-blind, randomized study compared two vitamin D3 doses in healthy, urban-dwelling 6-month to 10-year-old children at-risk for vitamin D deficiency. Randomization was stratified by GC haplotype. Methods: Children were randomized to receive 2800 or 7000 International Units of vitamin D3 weekly. 25-OHD and 1,25(OH)2D were sampled at baseline and after 1 and 6 months of supplementation. Results and Conclusions: 192 of 225 enrolled subjects completed the study. After one month, total 25-OHD increased with both doses, and were higher with 7000 IU/week (85.5 ± 22.8 nmol/L) compared to 2800 IU/week (76.8 ± 18.0 nmol/L), despite equivalent baseline levels. No further significant increase occurred at 6 months (89.8 ± 35.5 and 74.3 ± 18.3 nmol/L, respectively). Free 25-OHD similarly changed. 25-OHD differed among GC groups at baseline. Although no significant effects of individual GC haplotypes on incremental changes were evident, a trend towards an effect of combined “at risk” GC alleles on response was evident (P=0.06). Total 1,25(OH)2D showed modest increases, moreso with the larger dose. In urban-dwelling children at-risk for vitamin D deficiency, one month of vitamin D3 2800 IU/week increased 25-OHD across all GC haplotype groups, and somewhat enhanced with 7000 IU/week with no further significant increases after 6 months of supplementation. Free 25-OHD measures offer no monitoring advantage over total 25-OHD.

Vitamin D Status and Its Role in First-Time and Recurrent Urinary Tract Infections in Children: A Case-Control Study

Article

Full-text available

May 2021

Vitamin D has emerged as a key factor in innate immunity. Its involvement in the pathogenesis of urinary tract infections (UTIs) has gained a lot of attention recently. The objective of this study is to investigate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and first-time or recurrent UTIs in children. A prospective, case-control study was conducted on 101 pediatric patients, who were divided into two groups: 59 patients with UTIs and 42 age-matched healthy controls. Serum 25(OH)D was determined in each child and expressed in ng/mL. Vitamin D presented significantly lower values in study group subjects than in healthy controls (p < 0.01). Moreover, a significantly higher prevalence of vitamin D insufficiency and deficiency was found in children with UTIs (p < 0.01). Patients with recurrent UTIs presented significantly lower levels of vitamin D than those with first-time UTIs (p = 0.04). Urinary tract abnormalities did not seem to exercise an additional effect upon vitamin D levels within the study group. In conclusion, first-time and recurrent UTIs are associated with lower vitamin D levels. Further studies are necessary to validate our findings, as well as future longitudinal research regarding efficacy of vitamin D supplementation in children with UTIs.

Association between Cardiometabolic risk factor and responsiveness to vitamin D supplementation: a new approach using artificial neural network analysis

Article

Full-text available

Apr 2021

Background There are increasing data highlighting the effectiveness of vitamin D supplementation in the treatment of vitamin D deficiency. But individuals vary in their responsiveness to vitamin D supplementation. In this study, the association between several cardiometabolic risk factors and the magnitude of response to vitamin D supplementation (change in vitamin D level) was investigated using a novel artificial neural networks (ANNs) approach. Methods Six hundred eight participants aged between 12 to 19 years old were recruited to this prospective interventional study. Nine vitamin D capsules containing 50,000 IU vitamin D/weekly were given to all participants over the 9 week period. The change in serum 25(OH) D level was calculated as the difference between post-supplementation and basal levels. Suitable ANNs model were selected between different algorithms in the hidden and output layers and different numbers of neurons in the hidden layer. The major determinants for predicting the response to vitamin D supplementation were identified. Results The sigmoid in both the hidden and output layers with 4 hidden neurons had acceptable sensitivity, specificity and accuracy, assessed as the area under the ROC curve, was determined in our study. Baseline serum vitamin D (30.4%), waist to hip ratio (10.5%), BMI (10.5%), systolic blood pressure (8%), heart rate (6.4%), and waist circumference (6.1%) were the most important factors in predicting the response to serum vitamin D levels. Conclusion We provide the first attempt to relate anthropometric specific recommendations to attain serum vitamin D targets. With the exception of cardiometabolic risk factors, the relative importance of other factors and the mechanisms by which these factors may affect the response requires further analysis in future studies (Trial registration: IRCT201509047117N7; 2015-11-25; Retrospectively registered).

Risk Factors Associated with Vitamin D Status among Older Puerto Rican Adults

Article

Mar 2021

Background Vitamin D deficiency has been associated with health problems globally, but there is limited information on vitamin D status and associated risk factors among adults in underserved populations. Objective This study aimed to identify risk factors for vitamin D deficiency/insufficiency among Puerto Rican adults from the Boston Puerto Rican Health Study (BPRHS). Methods A total of 822 adults (45–75 y, at baseline) were included in these analyses. Deficiency was defined as serum 25-hydroxyvitamin D [25(OH)D] <30 and insufficiency as 30 to <50 nmol/L. Dietary intake was assessed with a validated FFQ. Associations between risk factors, including dietary vitamin D, supplement use, ancestry, skin pigmentation, months in the past year spent in a southern climate, and serum 25(OH)D were assessed with multivariable general linear models. Results Approximately 13% of participants were deficient in 25(OH)D and another 43% insufficient. Skin pigment was associated with 25(OH)D using 3 measures, greater African ancestry (β ± SE) (–7.74 ± 2.91, P = 0.01); interviewer assessed dark or medium, compared with white, skin tone, (–5.09 ± 2.19, P = 0.02 and –5.89 ± 1.58, P < 0.001, respectively); and melanin index of the upper inner right arm, assessed using a spectrophotometer (–2.04 ± 0.84, P = 0.02). After adjusting for ancestry, factors associated with lower serum 25(OH)D included smoking (–4.49 ± 1.58, P = 0.01); BMI (–0.21 ± 0.10, P = 0.04); and spring compared with autumn blood draw (–4.66 ± 1.68, P = 0.004). Factors associated with higher serum 25(OH)D included female sex compared with male (4.03 ± 1.58, P = 0.01); dietary vitamin D intake μg/d (0.71 ± 0.25, P < 0.004); vitamin D supplement use (4.50 ± 1.87, P = 0.02); income to poverty ratio (0.01 ± 0.01, P = 0.06), and months in a southern climate during the past year (0.96 ± 0.56, P = 0.09). Conclusions Vitamin D deficiency/insufficiency was prevalent in this Puerto Rican population living in the northeastern USA. Several factors were associated with this, which may assist in identifying those at risk. Interventions are needed to improve serum 25(OH)D concentration, particularly among those with limited exposure to sunlight.

PRESENCE OF LOW VITAMIN D AND HIGH SERUM LIPOPROTEIN 'A' LEVELS IN CAD: DO THEY IMPART RISK IN SYNERGISM?

Article

Jan 2021

Aims: Coronary artery disease (CAD) is an inflammatory disorder. Recently low vitamin D and high lipoprotein ‘a’ (Lp‘a’) have been linked in causation of coronary artery disease. This study was conducted to see the the combined effect of these two modifiable risk factors i.e. low vitamin D and high Lp‘a’ in etiology of CAD. Methods: It was a cross sectional study. Triple vessel disease patients (n=31) admitted for bypass surgery were taken as cases and age and gender matched healthy persons were taken as controls (n=30). Serum vitamin D estimation was done by competitive ELISA method. Serum Lp‘a’ estimation was done by immunoturbidimetric assay. Results: when subjects were compared for dual risk factor (Vitamin D deficiency and Hyperlipoproteinemia‘a’), it was observed that the odds of having disease were very high (OR=30.00; p=0.0004) than the single risk factor (OR for Hypovitaminosis D = 3.33; p=0.03 and OR for Hyperlipoproteinemia ‘a’ = 5.00; p=0.004). The Pearson’s correlation coefficient for the relationship between serum Vitamin D and Lipoprotein ‘a’ shows no correlation (r = ̶ 0.1019). Conclusion: Risk of having CAD increases many folds when subject has vitamin D deficiecy as well as high Lp‘a’.

Association of vitamin D pathway gene polymorphisms with vitamin D level during pregnancy was modified by season and vitamin D supplement

Article

Full-text available

Dec 2020
CLIN NUTR

Background & Aims This study aims to explore the associations of vitamin D (VD) metabolic pathway gene with 25(OH)D level in pregnant women and the interactions of SNP with season and VD supplement. Methods A total of 2658 pregnant women were selected from Zhoushan Pregnant Women Cohort study. Gestational 25(OH)D level and single nucleotide polymorphism (SNP) of VD metabolic pathway gene were detected. Multilinear regression models were used to estimate associations of SNPs with gestational 25(OH)D levels. Stratified analyses were performed to test the interactions of SNP with season and VD supplements. Results The mutations of rs2298849 and rs7041 on the GC gene were respectively associated with higher 25(OH)D in the first and third trimester; the mutations of seven SNPs (rs1155563, rs16846876, rs17467825, rs2282679, rs2298850, rs3755967, and rs4588) on the GC gene were respectively associated with lower 25(OH)D both in the first and third trimester, and lower changes in 25(OH)D during late pregnancy. The mutations of above seven SNPs, except for rs1155563, were also respectively associated with lower 25(OH)D in the second trimester, but to a lesser extent; Besides, pregnant women with mutation on CYP24A1-rs2209314 had a higher increment in 25(OH)D than their counterparts in the second trimester. The increasing dose effect of Gc isoform on 25(OH)D was observed. The associations of GC and LRP2 genes with 25(OH)D modified by season and VD supplements. Conclusions The polymorphisms of VD metabolic pathway gene were associated with gestational 25(OH)D, and the associations differ by seasons and VD supplements. Gc isoform exerted a profound influence on gestational 25(OH)D.

The impact of vitamin D supplementation as an adjuvant therapy on clinical outcomes in patients with severe atopic dermatitis: A randomized controlled trial

Article

Full-text available

Nov 2020

Vitamin D supplementation with standard treatment yielded positive clinical outcomes in mild and moderate atopic dermatitis; however, the potential benefit of vitamin D in severe cases remains unclear. This study aimed to evaluate the impact of vitamin D supplementation on response to standard treatment in pediatrics with severe atopic dermatitis. The patients were randomized to receive either vitamin D 3 1600 IU/day or placebo, plus baseline therapy of topical 1% hydrocortisone cream twice daily for 12 weeks. The primary endpoints were the change in mean Eczema Area and Severity Index (EASI) score at the end of the study and the mean percent change in EASI score from baseline to week 12. Eighty-six subjects completed the study. The treated group achieved a significant higher level of 25 hydroxy vitamin D (P < .001) compared to control group at week 12. The mean EASI score was significantly lower in the treatment group compared to placebo group (P = .035). The percent change in EASI score from baseline differed significantly between the supplementation (56.44 ± 29.33) and placebo (42.09 ± 19.22) groups after intervention (P = .039). Vitamin D supplementation could be an effective adjuvant treatment that improves the clinical outcomes in severe atopic dermatitis.

Association Between cardiometabolic risk factor and responsiveness to vitamin D supplementation: A New Approach using Artificial Neural Network analysis

Preprint

Full-text available

Sep 2020

Background Accumulating data have highlighted the prominence of supplementation as an effective approach for vitamin D deficiency. But individuals vary in their response to vitamin D supplementation. In this study, the effect of cardiometabolic risk factors were evaluate on magnitude of response to vitamin D supplementation by using novel statistical analysis, artificial neural networks(ANNs). Methods 608 participants aged between 12 to 19 years old were assed in this prospective interventional study. Nine vitamin D capsules containing 50000IU vitamin D/weekly were given to all participants over the 9 week period. The change in serum 25(OH)D level was calculated as the difference between post-supplementation and basal levels. Suitable ANNs model were selected between different algorithms in the hidden and output layers and different numbers of neurons in the hidden layer. Then, the major determinants in predicting response to vitamin D supplementations were identified (Trial registration: IRCT201509047117N7; 2015-11-25; Retrospectively registered) Results Sigmoid in both hidden and output layers with 4 hidden neurons had acceptable sensitivity, specificity and accuracy area under the ROC curve in our study. Baseline serum vitamin D (30.4%), waist to hip ratio (10.5%), BMI (10.5%), systolic blood pressure (8%), heart rate (6.4%), and waist circumference (6.1%) were the greatest importance in predicting the response in serum vitamin D levels. Conclusion We provide the first attempt to relate anthropometric specific recommendations to attain serum vitamin D targets. With the exception of cardiometabolic risk factor, the relative importance of other factors and the mechanisms by which these factors may affect the response requires further analysis in future studies.

Vitamin D in Type 2 Diabetes: Genetic Susceptibility and the Response to Supplementation

Article

Full-text available

Jun 2020

Variants of vitamin D metabolism-genes may predispose to type 2 diabetes (T2D). This study investigated the impact of these variants on disease susceptibility, Vitamin D, parathyroid hormone, C-peptide and HbA1c levels before and after cholecalciferol supplementation in patients with T2D. Twelve polymorphisms within CYP2R1, CYP27B1, DBP, VDR and CYP24A1 were genotyped in 553 T2D patients and 916 controls. In addition 65 patients receiving either cholecalciferol or placebo were analyzed during 6 months intervention and 6 months follow-up. T2D risk alleles are VDR rs7975232 “G” (pc=0.031), rs1544410 “G” (pc=0.027) and CYP2R1 rs10741657 “A” (pc=0.016). Patients with genotypes CYP27B1 rs10877012 “CC” (pc=4x10-5), DBP rs7041 “GG” (pc=0.003), rs4588 “CC” (pc = 3x10-4), CYP24A1 rs2585426 “CG” (pc=0.006) and rs2248137 “CG” (pc=0.001) showed lower 25(OH)D3 and DBP rs4588 “CC” lower 1,25(OH)2D3 levels (pc=0.005). Whereas DBP rs4588 “CC” (pc=0.009), CYP27B1 rs10877012 “AC” (pc=0.059), VDR rs7975323 “AG” (pc=0.033) and rs1544410 “GG” (pc=0.013) are associated with higher 25(OH)D3 levels at 6 months’ follow-up. Significant PTH suppression was detected for CYP2R1 “AG“ (pc=0.002), DBP rs4588 “CC” (pc<0.001), VDR rs110735810 “CT” (pc<0.001) and CYP24A1 rs2248137 “GG” (pc=0.021). Genetic variants of the vitamin D system predispose to type 2 diabetes and regulate – partially - vitamin D metabolism, concentrations and the vitamin D status. Vitamin D insufficiency is a T2D risk factor. The response to cholecalciferol supplementation can be measured as 25(OH)D3 increment and PTH suppression. This process is regulated by genes of the vitamin D system conferring modest T2D risk.

Association of Circulating Vitamin D With Colorectal Cancer Depends on Vitamin D-Binding Protein Isoforms: A Pooled, Nested, Case-Control Study

Article

Full-text available

Oct 2019

Background: Higher circulating 25-hydroxyvitamin-D [25(OH)D] concentrations are consistently inversely associated with colorectal cancer (CRC) risk in observational studies. However, it is unknown whether this association depends on the functional GC-rs4588*A (Thr436Lys) variant encoding the vitamin D-binding protein-2 (DBP2) isoform, which may affect vitamin D status and bioavailability. Methods: We analyzed data from 1710 incident CRC cases and 1649 incidence-density-matched controls nested within three prospective cohorts of mostly Caucasians. Study-specific incidence rate ratios (RRs) for associations of prediagnostic, season-standardized 25(OH)D concentrations according to DBP2 isoform with CRC were estimated using multivariable unconditional logistic regression and were pooled using fixed-effects models. All statistical significance tests were two-sided. Results: The odds of having 25(OH)D concentrations less than 50 nmol/L (considered insufficient by the Institute of Medicine) were 43% higher for each DBP2-encoding variant (rs4588*A) inherited (per DBP2 odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.27 to 1.62, Ptrend = 1.2 × 10-8). The association of 25(OH)D concentrations with CRC risk differed by DBP2: 25(OH)D concentrations considered sufficient (≥ 50 nmol/L), relative to deficient (< 30 nmol/L), were associated with a 53% lower CRC risk among individuals with the DBP2 isoform (RR = 0.47, 95% CI = 0.33 to 0.67), but with a non-statistically significant 12% lower risk among individuals without it (RR = 0.88, 95% CI = 0.61 to 1.27) (Pheterogeneity = .01). Conclusions: Our results suggest that the 25(OH)D-CRC association may differ by DBP isoform, and those with a DBP2-encoding genotype linked to vitamin D insufficiency may particularly benefit from adequate 25(OH)D for CRC prevention.

Associations between common polymorphisms in CYP2R1 and GC, Vitamin D intake and risk of colorectal cancer in a prospective case-cohort study in Danes

Article

Full-text available

Feb 2020
PLOS ONE

Background The association between vitamin D and incidence of colorectal cancer has been thoroughly investigated, but the results are conflicting. The objectives in this study were to investigate whether two functional polymorphisms in GC and CYP2R1, respectively, previously shown to predict vitamin D concentrations, were associated with risk of colorectal cancer; and further, to assess gene-environment interaction between the polymorphisms and intake of vitamin D through diet and supplementation in relation to risk of colorectal cancer. Methods A nested case-cohort study of 920 colorectal cancer cases and 1743 randomly selected participants from the Danish prospective “Diet, Cancer and Health” study was performed. Genotypes CYP2R1/rs10741657 and GC/rs4588 were determined by PCR-based KASP™ genotyping assay. Vitamin D intake from supplements and diet was assessed from a validated food frequency questionnaire. Incidence rate ratios were estimated by the Cox proportional hazards model, and interactions between polymorphisms in GC and CYP2R1 and vitamin D intake in relation to risk of colorectal cancer were assessed. Results Neither of the two polymorphisms was associated with risk of colorectal cancer per se. Heterozygote carriage of CYP2R1/rs10741657 and GC/rs4588, and carriage of two risk alleles (estimated by a genetic risk score) were weakly associated with 9–12% decreased risk of colorectal cancer per 3 μg intake of vitamin D per day (IRRCYP2R1/rs10741657 = 0.88, 95% CI: 0.79–0.97; IRRGC/rs4588 = 0.91, 95% CI: 0.82–1.01, IRRGRS2 = 0.90, 95% CI: 0.81–0.99). Conclusions The results suggest that genetic variation in vitamin D metabolising genes may influence the association between vitamin D intake, through food and supplementation, and risk of colorectal cancer. Clinical trial registry NCT03370432. Registered 12 December 2017 (retrospectively registered).

Structure and function of the vitamin D-binding proteins

Chapter

Full-text available

Jan 2020

Daniel Bikle

The Relationship Between Vitamin D and Postpartum Depression: A Review of Current Literature

Article

Oct 2019

There is increased interest in the relationship between vitamin D and postpartum depression. This review evaluates the 3 studies that have examined associations between prenatal vitamin D status and postpartum depressive symptoms. Based on the evidence, there is an association between low prenatal vitamin D levels and an increased risk of postpartum depressive symptoms. Vitamin D at a dose of 2000 IU/d may be a convenient choice to correct serum levels safely and reduce the incidence of depressive symptoms. Health care professionals should facilitate adequate vitamin D intake during pregnancy to mitigate depressive consequences of deficiency in the postpartum period.

Group-specific component exon 11 haplotypes (D432E and T436K) and risk of albuminuria in type 2 diabetes mellitus patients

Article

Sep 2019

Background: Emerging evidence indicates group-specific component (GC) variants are associated with ethnicity. We aimed to investigate the association of GC variants and protein expression level with T2DM and diabetic nephropathy (DN) in Saudi patients. Subjects and methods: A total of 200 participants (120 T2DM/80 controls) were genotyped for GC-rs7041/GC-rs4588 by real-time polymerase chain reaction. Serum GC was assessed by ELISA and in silico analysis was executed. Results: GC-rs7041 frequency distribution showed no difference between the study groups, while GC-rs4588 showed association with T2DM under all genetic models. rs4588*AA variant was correlated with higher serum GC globulin, albuminuria, and poor glycaemic control. A higher frequency of rs7041*TT and rs4588*AA was evident in macroalbuminuria vs. normoalbuminuria group. Carrying GC-2 haplotype was 2.5 more likely to develop diabetes and correlated with the levels of albuminuria. Conclusions: GC variants could have independent effects on the risk of T2DM and DN in the study population.

Can low Vitamin D Binding Protein levels be a cause of infertility in females?

Article

Jul 2019
J Pakistan Med Assoc

Endometriosis is a chronic, debilitating gynecological condition characterized by existence of endometrial tissue at sites other than the uterine cavity. The presence of such tissue results in chronic inflammation at the site, which, in turn, results in adhesions and tissue scarring, distorting the woman's pelvic anatomy in its course. Such women present with pelvic pain, dysmenorrhea, dyspareunia and infertility.1 Increased prevalence of endometriosis has been reported in infertile patients in comparison to the fer tile patients

Common Polymorphisms in Genes Related to Vitamin D Metabolism Affect the Response of Cognitive Abilities to Vitamin D Supplementation

Article

Full-text available

Sep 2019
J MOL NEUROSCI

It is possible that vitamin D acts as a neurosteroid and that vitamin D deficiency may have an adverse impact on brain function and cognitive function. There are a few reports that have demonstrated an association between polymorphisms of genes involved in vitamin D metabolism and neurodegenerative disease. We aimed to evaluate the relationship between common, functional vitamin D–associated gene variants and cognitive abilities and to investigate the effect size of this polymorphism on cognitive capabilities associated with high-dose vitamin D supplementation. A total of 319 healthy adolescents received a high dose of vitamin D (50,000 IU)/week for 9 weeks. A questionnaire was used to assess cognitive abilities at baseline and after treatment. The genotypes of the CYP2R1-rs10766197 and GC-rs4588 variants were determined using TaqMan genotyping techniques. At baseline, total cognitive ability scores were higher in the AA group who were homozygous for the uncommon allele, compared with the other (AG and GG) genotypes of the CYP2R1-rs10766197 polymorphism (104.9 ± 27.8 vs. 79.1 ± 38.8 vs. 73.1 ± 25.6; p < 0.001, respectively). During the supplementation period, cognitive ability scores increased in individuals with the AG and GG genotypes, while individuals with a AA genotype did not show significant change in total score after intervention (p = 0.17). For GC SNP (rs4588), no major differences at baseline and trial-net change of cognitive tasks score were observed between the genotypes under three genetic models (pSNP = 0.67). Vitamin D supplements have trait-dependent effects on cognitive performance that suggests a causal role for vitamin D in cognitive performance. The rs10766197 variant, near the CYP2R1 gene locus, significantly modified the efficacy of high-dose vitamin D3 supplementation for its effects on improving cognitive abilities indicate that some subjects might require a higher dose to benefit from in terms of cognitive performance.

Impact of a single oral dose of 100,000 IU vitamin D3 on profiles of serum 25(OH)D3 and its metabolites 24,25(OH)2D3, 3-epi-25(OH)D3, and 1,25(OH)2D3 in adults with vitamin D insufficiency

Article

Full-text available

Jun 2019
CLIN CHIM ACTA

Nutrigenetik: Kişisel Beslenme Bilimini Uygulamak

Book

Jan 2023

Genotı̇p Temelli Beslenme Kararlarıİçin Zaman Geldi̇ mı̇? Merve İNCE PALAMUTOĞLU Genetik Geçiş Nasıl Çalışır? Merve İNCE PALAMUTOĞLU Nutrigenetik Farklılıklar Nereden Gelmektedir? Merve İNCE PALAMUTOĞLU Besin Öğeleri Genetikten Nasıl Etkilenir? Simge SİPAHİ, Bartu Eren GÜNEŞLİOL Nutrigenetik Uzun Süreli SağlığıNasıl Etkiler? İpek AĞACA ÖZGER Son Bulguların Ne Anlama Geldi̇ği̇ni̇ Nasıl Bi̇lebi̇liriz? İpek AĞACA ÖZGER Nutrigenetiğin Pratik Kullanımları Bartu Eren GÜNEŞLİOL Genetik Bilgiyi Güvende Tutmak Bartu Eren GÜNEŞLİOL

The potential role of vitamin D binding protein in kidney disease: a comprehensive review

Article

Jan 2024

Chronic kidney disease (CKD) is a growing health concern with a complex etiological landscape. Among the numerous factors implicated, vitamin D binding protein (VDBP) has emerged as a focal point of scientific studies because of its critical role in vitamin D metabolism and immune modulation. The relationship between VDBP and CKD reveals a complex web of molecular and biochemical details that have great potential for improving diagnostic understanding and treatment strategies for CKD. This review summarizes the multifaceted roles of VDBP, including its molecular dynamics, interactions with vitamin D, and subsequent implications for kidney function. The main focus of the discussion is how VDBP affects bone mineral homeostasis, highlighted by the dysregulation of calcium and phosphorus metabolism, which is a part of the pathophysiology of CKD. The discussion also touches on the immunomodulatory scope of VDBP and how it may reduce the chronic inflammatory environment that accompanies CKD. The diagnostic potential of VDBP as a biomarker for CKD has been rigorously examined, highlighting its capacity to improve early detection and prognostic assessment. Modification of VDBP activity has the potential to slow the course of CKD and improve patient outcomes. Furthermore, a detailed examination of the genetic polymorphisms of VDBP and their implications for CKD susceptibility and treatment responsiveness provides a perspective for personalized medical methods. Prospects for the future depend on the expansion of studies that try to understand the molecular mechanisms underlying the VDBP-CKD interaction, in addition to clinical trials that evaluate the effectiveness of VDBP-focused treatment approaches.

Vitamin D–binding protein

Chapter

Jan 2024

Pharmacology and pharmacokinetics of vitamin D

Chapter

Jan 2024

Single nucleotide polymorphisms in vitamin D binding protein and 25-hydroxylase genes affect vitamin D levels in adolescents of Arab ethnicity in Kuwait

Article

Full-text available

Oct 2023

Vitamin D deficiency (VDD) is widespread in the Arab world despite ample sunshine throughout the year. In our previous study, lifestyle and socio-demographic factors could explain only 45% of variability in vitamin D levels in Kuwaiti adolescents, suggesting that genetics might contribute to VDD in this region. Single nucleotide polymorphisms (SNP) in the 25-hydroxylase ( CYP2R1 ) and the GC globulin ( GC ) genes have been reported to affect vitamin D levels in various ethnic groups in adults. In this study, we investigated the association of two SNPs from GC (rs4588 and rs7041) and three SNPs from CYP2R1 (rs10741657, rs11023374 and rs12794714) with vitamin D levels and VDD in a nationally representative sample of adolescents of Arab ethnicity from Kuwait. Multivariable linear regression, corrected for age, sex, parental education, governorate, body mass index, and exposure to sun, demonstrated that each of the 5 study variants showed significant associations with plasma 25(OH)D levels in one or more of the additive, recessive, and dominant genetic models - the rs10741657 under all the three models, rs12794714 under both the additive and recessive models, rs7041 under the recessive model; and rs4588 and rs11023374 under the dominant model. Minor alleles at rs4588 (T), rs7041 (A), rs11023374 (C), and rs12794714 (A) led to a decrease in plasma 25(OH)D levels - rs4588:[β (95%CI) = -4.522 (-8.66,-0.38); p=0.033]; rs7041:[β (95%CI) = -6.139 (-11.12,-1.15); p=0.016]; rs11023374:[β (95%CI) = -4.296 (-8.18,-0.40); p=0.031]; and rs12794714:[β (95%CI) = -3.498 (-6.27,-0.72); p=0.014]. Minor allele A at rs10741657 was associated with higher levels of plasma 25(OH)D levels [β (95%CI) = 4.844 (1.62,8.06); p=0.003)] and lower odds of vitamin D deficiency (OR 0.40; p=0.002). These results suggest that the CYP2R1 and GC SNP variants are partly responsible for the high prevalence of VDD in Kuwait. Genotyping these variants may be considered for the prognosis of VDD in Kuwait.

.Association of VDBP (rs4588 and rs7041) gene polymorphisms with susceptibility to postpartum depression in South Indian population: a cross- sectional study.

Article

Full-text available

Mar 2023

Raji Agiesh

Interaction between vitamin D deficiency and COVID-19

Chapter

Jan 2023

Impact of Common Vitamin D–Binding Protein Isoforms on Supplemental Vitamin D 3 and/or Calcium Effects on Colorectal Adenoma Recurrence Risk: A Secondary Analysis of a Randomized Clinical Trial

Article

Jan 2023

Importance Variants in the vitamin D–binding protein (DBP) gene ( GC ) encode DBP isoforms that may affect vitamin D metabolism. However, whether these isoforms modify the effects of vitamin D 3 and/or calcium supplementation on colorectal adenoma recurrence is unclear. We hypothesized that supplementation effects may be stronger among those with the DBP2 isoform (encoded by the rs4588*A allele), which is associated with vitamin D deficiency and modified the associations of circulating vitamin D with risk for colorectal neoplasms in observational studies. Objective To estimate supplemental vitamin D 3 and/or calcium effects on colorectal adenoma recurrence according to 3 common DBP isoforms (DBP1s, DBP1f, DBP2) encoded by 2 missense variants: rs7041 ( NG_012837 .3:g.57904T>G NP_001191235 .1:p.Asp432Glu) and rs4588 ( NG_012837 .3:g.57915C>A NP_001191235 .1:p.Thr436Lys). Design, Setting, and Participants Secondary analysis of a randomized, double-blind, placebo-controlled clinical trial of 2259 participants with a recently diagnosed adenoma and no remaining polyps after complete colonoscopy in the US from July 1, 2004, to August 31, 2013. The current analyses were performed from August 12, 2019, to July 16, 2022. Interventions Daily vitamin D 3 (1000 IU), calcium (1200 mg), both, or placebo. Main Outcomes and Measures One or more adenomas diagnosed during 3 to 5 years of follow-up. Treatment effects were estimated according to DBP isoform as risk ratios (RRs) and 95% CIs using Poisson regression analysis. Results Of the 2259 participants randomized (mean [SD] age, 58 [6.8] years; 1033 [64%] men), 1604 non-Hispanic White participants (chosen to avoid population stratification bias) were included in the analysis. Among those with the DBP2 isoform (rs4588*AC or AA), the RRs (95% CI) for adenoma recurrence were 0.84 (0.72-1.00) with vitamin D 3 relative to no vitamin D 3 , 0.83 (95% CI, 0.70-0.99) with calcium relative to no calcium, and 0.76 (95% CI, 0.59-0.98) with both agents relative to neither agent. Conversely, among those without DBP2 (rs4588*CC), the corresponding values were 1.08 (95% CI, 0.93-1.26; P = .03 for interaction) with vitamin D 3 relative to no vitamin D 3 , 0.98 (95% CI, 0.84-1.14; P = .37 for interaction) with calcium relative to no calcium, and 1.09 (0.88-1.36; P = .03 for interaction) with both agents relative to neither agent. Among DBP2 homozygotes (rs4588*AA), the RR for adenoma recurrence was 0.57 (95% CI, 0.31-1.08) with both agents relative to neither agent. Conclusions and Relevance The findings of this secondary analysis of a randomized clinical trial suggest that individuals with the DBP2 isoform–encoding rs4588*A allele may particularly benefit from vitamin D 3 and/or calcium supplementation for colorectal adenoma prevention. Trial Registration ClinicalTrials.gov Identifier: NCT00153816

Nutritional status in tuberculosis: A comprehensive problem to be addressed

Chapter

Jan 2023

Vitamin D Binding Protein Gene Polymorphisms Are Associated with Lower Plasma 25-Hydroxy-Cholecalciferol Concentrations in Ethiopian Lactating Women

Article

Sep 2022
NUTR RES

Ethiopian women have been reported to have low plasma 25-hydroxy- cholecalciferol (25(OH)D) concentrations despite an abundance of sunshine. Low dietary vitamin D intake, limited skin exposure to sun, and genetics are among factors suggested to affect vitamin D status in this population. In this study (Clinical Trial NCT02210884), we hypothesized that polymorphisms in the vitamin D binding protein (VDBP) gene (rs7041, rs4588) are associated with reduced plasma 25(OH)D concentrations in Ethiopian women. Lactating Ethiopian women (n=110) were randomly assigned to weekly administration of vitamin D3 (15,000 IUs) or a placebo. Plasma 25(OH)D was measured at baseline (within 2 weeks of delivery, before supplementation) and at 3, 6, and 12 months after delivery. Associations between VDBP polymorphism status for rs7041 and rs4588 and plasma 25(OH)D were determined by ANOVA and multiple linear and logistic regressions. Multiple linear regression with maternal age as a covariate revealed that rs7041 is associated with reduced plasma 25(OH)D (p=0.021) and more risk alleles at rs7041 and rs4588 are associated with reduced plasma 25(OH)D (p=0.017). Logistic regression models for vitamin D insufficiency showed that additional risk alleles for rs7041 and rs4588 are associated with increased odds ratios (OR=1.66, 95% CI 1.10-2.62, p=0.019) for plasma 25(OH)D below 40 nmol/L. Supplementation increased plasma 25(OH)D at 3 months in women with fewer risk alleles and across all genotypes at 6 and 12 months. VDBP polymorphisms may contribute to vitamin D insufficiency in Ethiopian lactating women. Furthermore, VDBP polymorphisms may blunt short-term responses to vitamin D supplementation and require longer periods of intervention.

Serum Vitamin D: Correlates of Baseline Concentration and Response to Supplementation in VITAL-DKD

Article

Sep 2021

Context The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition. Objective To assess the total serum vitamin D response to vitamin D3 supplementation and whether it varies according to participant characteristics. To compare results with corresponding results for total serum 25-hydroxyvitamin D (25(OH)D), which is used clinically and measured in supplementation trials. Design Exploratory study within a randomized trial. Intervention 2,000 International Units of vitamin D3 per day (or matching placebo). Setting Community-based. Participants 161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes. Main Outcome Measures Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2. Results At baseline, there was a positive, nonlinear relation between total serum vitamin D and total serum 25(OH)D concentrations. Adjusted effects of supplementation were a 29.2 (95% CI: 24.3, 34.1) nmol/L increase in serum vitamin D and a 33.4 (95% CI: 27.7, 39.2) nmol/L increase in serum 25(OH)D. Among those with baseline 25(OH)D < 50 compared with ≥ 50 nmol/L, the serum vitamin D response to supplementation was attenuated (15.7 vs 31.2 nmol/L; interaction p-value = 0.02), whereas the serum 25(OH)D response was augmented (47.9 vs 30.7 nmol/L; interaction p-value = 0.05). Conclusions Vitamin D3 supplementation increases total serum vitamin D and 25(OH)D concentrations with variation according to baseline 25(OH)D, which suggests that 25-hydroxylation of vitamin D3 is more efficient when serum 25(OH)D concentration is low.

Conundrum of vitamin D on glucose and fuel homeostasis

Article

Full-text available

Sep 2021

As an endocrine hormone, vitamin D plays an important role in bone health and calcium homeostasis. Over the past two decades, the non-calcemic effects of vitamin D were extensively examined. Although the effect of vitamin D on beta cell function were known for some time, the effect of vitamin D on glucose and fuel homeostasis has attracted new interest among researchers. Yet, to date, studies remain inconclusive and controversial, in part, due to a lack of understanding of the threshold effects of vitamin D. In this review, a critical examination of interventional trials of vitamin D in prevention of diabetes is provided. Like use of vitamin D for bone loss, the benefits of vitamin D supplementation in diabetes prevention were observed in vitamin D-deficient subjects with serum 25-hydroxyvitamin D < 50 nmol/L (20 ng/mL). The beneficial effect from vitamin D supplementation was not apparent in subjects with serum 25-hydroxyvitamin D > 75 nmol/L (30 ng/mL). Furthermore, no benefit was noted in subjects that achieved serum 25-hydroxyvitamin D > 100 nmol/L (40 ng/mL). Further studies are required to confirm these observations.

Demographic and clinical predictors of vitamin D status in pregnant women tested for deficiency in Western Australia

Article

Full-text available

Sep 2021

Objective: This study aimed to describe the vitamin D status of pregnant women in Western Australia and identify predictors of deficiency in pregnancy. Methods: A cross-sectional study was conducted using linked data from statewide administrative data collections. Participants included pregnant women aged 18-44 years who gave birth between 2012 and 2014. Results: The mean 25-hydroxyvitamin D (25[OH]D) concentration was 70.7 nmol L-1 (SD 25.7; range 5-255 nmol L-1 ). Approximately one-fifth of the pregnant women were vitamin D deficient (<50 nmol L-1 ). Maternal age (under 25 years) was identified as an independent risk factor of vitamin D deficiency in addition to known predictors. Only 20% of women were screened within the first 10 weeks of their pregnancy. Conclusions: In addition to the existing risk factors for deficiency, maternal age was an independent predictor of vitamin D deficiency. There was a large discrepancy between the time of first antenatal visit and screening for vitamin D deficiency. Implications for public health: Our findings support the addition of maternal age (under 25 years) to the current clinical guidelines for targeted screening of 25(OH)D levels in pregnancy and the practical application of screening for vitamin D deficiency at the first antenatal visit.

Effect of Vitamin D3 (Cholecalciferol) Supplementation on Serum Vitamin D3 and 25-hydroxyvitamin D (25(OH)D) Concentrations Among Participants in the VITAL-DKD Study

Article

Full-text available

Jun 2020

Objectives To compare the serum vitamin D3 and 25(OH)D responses to vitamin D3 supplementation in the VITAL-DKD study. Methods The Vitamin D and OmegA-3 TriaL (VITAL)-DKD was a 2 × 2 factorial, randomized, placebo-controlled trial of vitamin D3 (2000 IU/day) and omega-3 fatty acids (1 g/day) for prevention of chronic kidney disease among adults with type 2 diabetes. For the first 200 enrolled participants, we measured baseline and year 2 serum vitamin D3 concentration with a new validated liquid chromatography-tandem mass spectrometry method. Linear regression was used to test the effects of D3 treatment on changes in serum D3 and 25(OH)D concentrations and to examine possible effect modification by relevant clinical characteristics. Results Participants were 70 ± 6 years of age, 64% male, 70% non-Hispanic white, and 15% black. At baseline and year 2, serum D3 concentration and 25(OH)D3 concentration were positively related, with a threshold effect at a 25(OH)D3 concentration of 50 nmol/L. Below this threshold, serum D3 concentration rarely exceeded 5 nmol/L. Above it, serum D3 concentration was much more variable. Supplementation increased mean serum D3 concentration from 12 nmol/L at baseline to 41 nmol/L at year 2 (difference compared with placebo 30 nmol/L; 95% CI 25 to 35 nmol/L) and increased mean serum 25(OH)D concentration from 76 nmol/L to 102 nmol/L (difference compared with placebo 33 nmol/L; 95% CI 26 to 40 nmol/L). The effect of treatment on change in serum 25(OH)D was modified by body weight (−0.48 nmol/L per kg of weight; P < 0.01), baseline 25(OH)D concentration (−0.30 nmol/L per nmol/L of baseline 25(OH)D; P < 0.01), baseline D3 concentration (−5 nmol/L per 100% increase in baseline D3; P = 0.04), and non-study vitamin D supplement use (smaller effect as dose of non-study supplement increased). The effect of treatment on change in serum D3 concentration was modified only by body weight (−0.33 nmol/L per kg of weight; P = 0.01). Conclusions Among older adults, 2 years of 2000 IU/day vitamin D3 led to similar mean increases in serum D3 and 25(OH)D. Unlike the serum 25(OH)D response, the serum D3 response to supplementation did not depend on baseline vitamin D status. The serum vitamin D concentration may be an additional, valuable marker of exposure to vitamin D during supplementation. Funding Sources NIDDK NIH ODS NHLBI.

Evaluation of Vitamin D binding protein (DBP) gene polymorphism in Vitamin D deficient patients attending a tertiary care hospital–a pilot study

Article

Full-text available

Mar 2020

Polymorphism in Vitamin D binding protein (DBP) has been implicated as one of the causes for Vitamin D deficiency. However there is paucity of data regarding the effect of genetic polymorphism in DBP in Vitamin D deficient patients in our population. This pilot study was undertaken to analyze the common genetic polymorphism in vitamin DBP in these population and its effect on vitamin D supplementation. 80 vitamin D deficient subjects were selected by convenient sampling. Genetic analysis for DBP (GC) gene polymorphism (rs7041 + rs4588) was carried out in all these individuals after informed consent and correlated with the vitamin D levels post supplementation. Six combinations of genotype were obtained (rs7041 + rs4588): TT+CA, TG+CC, TT+CA, TT+CC, TT+AA, GG+CC. A third of all individuals (33%) were found to have the TG+CA genotype, followed by about 26 % of individuals having the GG+CC genotype. TT+CA group was found to have 13% individuals and a tenth of all individuals belonged to each of the groups with TG+CC and TT+AA genotypes. Least proportion of individuals was found to have the TT+CA genotype (6%). There was no significant difference in the vitamin D levels with individual polymorphism (p value <0.01). However the combined genotype had an effect, with homozygotes for both such as TT-CC, TT-AA showing least response and heterozygotes such TG-CA and CG-CC showing better response : In this study, the individual SNP (rs7041 and rs4588) did not seem to significantly influence the response to vitamin D supplementation. However the combined genotype seem ed to influence the proportion of patients showing improvement after supplementation. The homozygotes for both such as TT-CC, TT-AA showing least response and heterozygotes such TG-CA and CG-CC showing better response.

Effect of genetic factors on the response to vitamin D3 supplementation in the VIDARIS randomised controlled trial

Article

Feb 2020
NUTRITION

Objectives : Supplementation provides the best means of improving vitamin D status but individual responses vary, which is partly genetically determined. We examined whether 28 single nucleotide polymorphisms in six key vitamin D pathway genes (GC, DHCR7, CYP2R1, CYP24A1, CYP27B1, VDR) were associated with differences in response to supplementation. Methods/Subjects : Participants (n=313; n= 160 vitamin D, n= 153 placebo) were part of the Vitamin D and Acute Respiratory Infections Study (VIDARIS), a double-blind, randomized, controlled trial involving oral monthly supplementation of either vitamin D3 (200,000IU each of the first two months, thereafter 100,000IU monthly) or placebo for 18 months. Circulating 25OHD concentrations at baseline, 2, 6, 12 and 18 months, and vitamin D binding protein (Gc-globulin) and calculated free 25OHD concentrations at baseline and two months were obtained. Multiple regression was used to model associations between genetic variants and 25OHD, Gc-globulin and free 25OHD concentrations. Results : SNPs within GC, CYP2R1 and CYP27B1 were associated with 25OHD concentrations following supplementation. However, only two GC gene SNPs (rs2282679, rs1155563) were significant after adjustment for multiple testing. This effect disappeared after more than two months of supplementation. None of the SNPs were significantly associated with Gc-globulin concentrations, however there was a significant interaction with one SNP in DHCR7 (rs12785878), which was associated with reduced free 25OHD concentrations in the supplemented arm. Conclusion : Only variants of GC were associated with 25OHD concentrations following supplementation. This effect was modest and disappeared after more than two months of supplementation, suggesting it may be time/dose-dependent and saturable.

Polymorphisms within vitamin D binding protein gene within a Preeclamptic South African population

Article

Sep 2019

Objectives: The vitamin D binding protein encoded by the GC gene contains two single nucleotide polymorphisms (rs4588 and rs7041) that have been associated with disease outcome, these include periodontitis coronary heart disease and hypertension. In pregnancy, these SNPs influence vitamin D metabolism that could result in hypertensive disorders such as PE. The etiology of PE, still remains elusive. The aim of this study was to evaluate the distribution of rs4588 and rs7041 within the GC gene among PE and normotensive pregnant women, residing in Durban, KwaZulu-Natal, South Africa. Study design: Our study consisted of n = 600 participants (normotensive (n = 246, N); early onset PE (n = 167, EOPE); and late-onset PE (n = 246, LOPE)). We extracted DNA from whole blood and genotyped for rs4588 and rs7041 SNPs using the TaqMan assay. Results: Regardless of HIV status, we observed the rs4588 (CC genotype) more frequently in PE (EOPE+LOPE) compared to the normotensive participants with an OD ratio of 0.74 (95% CI, 0.35–1.5; p < 0.001). We report a significant difference in the frequency of rs7041 (GT genotype) in the EOPE group compared to the normotensive group with an OD ratio of 11.48 (95% CI, 2.6–103.7; p < 0.001). The rs7041 GT genotype had a higher frequency in the EOPE compared to the LOPE group, with an OD ratio of 15.15 (95% CI, 2.3–639.2; p < 0.001). Conclusion: This is the first study to describe the prevalence of SNPs of the rs4588 and rs7041 within the GC gene in women with PE within the high HIV endemic area of KZN, South Africa. Notably, a significant association of the rs7041 (TT genotype) and rs4588 (CC genotype) occurred at a higher frequency in PE compared to the normotensive cohort. Future studies will examine the functional effect of the GC region in relation to pregnancy and vitamin D deficiency.

Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women

Article

Full-text available

Jan 2009
AM J CLIN NUTR

Vitamin D status, determined on the basis of 25-hydroxyvitamin D [25(OH)D] concentrations, is associated with the risk of several diseases. Vitamin D binding protein (DBP) is the major carrier of vitamin D and its metabolites, but the role of DBP single nucleotide polymorphisms (SNPs) on 25(OH)D concentrations is unclear. The objective was to evaluate the association of 2 DBP gene SNPs with 25(OH)D concentrations and explore whether such association varies according to the amount of vitamin D that needs to be transported. This cross-sectional study included 741 premenopausal white women, mostly of French descent. Plasma 25(OH)D concentrations were measured by radioimmunoassay. DBP-1 (rs7041) and DBP-2 (rs4588) were genotyped with a Sequenom MassArray platform. Associations and interactions were modeled by using multivariate linear regression. DBP-1 and DBP-2 SNPs were in strong linkage disequilibrium and were both associated with 25(OH)D concentrations. An additional copy of the rare allele of DBP-1 or DBP-2 was associated with lower 25(OH)D concentrations (beta = -3.29, P for trend = 0.0003; beta = -4.22, P for trend < 0.0001, respectively). These DBP polymorphisms explained as much of the variation in circulating 25(OH)D as did total vitamin D intake (r2 = 1.3% for DBP-1, r2 = 2.0% for DBP-2, and r2 < or = 1.2% for vitamin D intake). Circulating 25(OH)D concentrations in premenopausal women are strongly related to DBP polymorphisms. Whether DBP rare allele carriers have a different risk of vitamin D-related diseases and whether such carriers can benefit more or less from dietary interventions, vitamin D supplementation, or sun exposure need to be clarified.

Genetic and Environmental Determinants of 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Levels in Hispanic and African Americans

Article

Full-text available

Aug 2008

Vitamin D deficiency is associated with many adverse health outcomes, yet little is known about the genetic epidemiology of vitamin D or its metabolites. Our objective was to examine the relationship among three vitamin D-related genes and levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in Hispanics (HAs) and African Americans (AAs). The cross-sectional Insulin Resistance Atherosclerosis Family Study recruited and examined subjects in: Los Angeles, California (AAs; 513 individuals from 42 families); San Luis Valley (SLV), Colorado (HAs; 513 individuals from 30 families); and San Antonio (SA), Texas (HAs; 504 individuals from 58 families). Plasma levels of 25(OH)D and 1,25(OH)2D were measured. Levels of 25(OH)D were highest in SLV-HAs [18.3 +/- 7.7 ng/ml (45.7 +/- 19.2 nmol/liter)], lower in SA-HAs [14.6 +/- 6.4 ng/ml (36.4 +/- 16.0 nmol/liter)], and lowest in AAs [11.0 +/- 5.4 ng/ml (27.5 +/- 13.5 nmol/liter)]. Levels of 1,25(OH)2D were similar in AAs [43.5 +/- 13.9 pg/ml (113.1 +/- 36.1 pmol/liter)] and SLV-HAs [43.2 +/- 13.3 pg/ml (112.3 +/- 34.6 pmol/liter)], but higher in SA-HAs [48.6 +/- 17.0 pg/ml (126.4 +/- 44.2 pmol/liter)]. After adjusting for gender and age within the site, two single nucleotide polymorphisms (SNPs) in the vitamin D binding protein gene (DBP), rs4588 and rs7041, were associated with 25(OH)D, and one SNP in the DBP, rs4588, was associated with 1,25(OH)2D at all three study centers. SNPs in the DBP are associated with levels of 25(OH)D and 1,25(OH)2D in HA and AA participants in the Insulin Resistance Atherosclerosis Family Study.

Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism

Article

Jan 2006
CLIN CHIM ACTA

Molecular analysis of the gene for the human vitamin-D-binding protein (group-specific component): Allelic differences of the common genetic GC types

Article

Jul 1992

DNA sequence analysis of the polymerase chain reaction products, including the coding region for amino acids 416 and 420, of the vitamin-D-binding protein (DBP, group-specific component, GC) shows allele-specific differences. The GC2 and GC1F phenotypes have an aspartic acid residue at amino acid position 416, whereas the GC1S phenotype has a glutamic acid at this position. In the GC2 phenotype, amino acid 420 is a lysine residue, and in the both common GC1 phenotypes, it is a threonine residue. The nucleotide exchanges involve a HaeIII (position 416) and a StyI (position 420) restriction site: the HaeIII restriction site is specific for the GC*1S allele and the StyI restriction site is specific for the GC*2 allele. We have tested 140 individual genomic DNA samples for the HaeIII site and 148 samples for the StyI site by restriction fragment length polymorphism (RFLP) analysis with a DBP-specific direct genomic DNA probe, and have compared these findings with the GC phenotype classification, by isoelectric focusing (IEF) of the corresponding plasma. The results of the HaeIII RFLP analysis and the IEF typing were in complete agreement. By using our DNA probe, we could disclose, in addition to the StyI site at amino acid position 420, two further StyI site downstream: one was specific for the GC*1S allele and another for the GC*1F allele. In 147 samples, there was agreement between the IEF GC typing and the analysis of the StyI restriction sites. In a single case, the observed result of the StyI-digest differed from the result expected after IEF classification: homozygous GC 1F-1F by IEF and heterozygous by StyI RFLP analysis. We discuss this finding as a recombination event or a possible silent allele in IEF typing. The GC polymorphism revealed by Southern blot analysis of StyI-digests provides an informative DNA marker system for chromosome 4q11-q13.

Ethnic variation in vitamin D-binding protein (GC): a review of isoelectric focusing studies in human populations

Article

May 1986

Since the discovery in 1977 that the GC1 gene could be resolved into two common subcomponents on an isoelectric focusing (IEF) gel, a large number of ethnic groups have been screened to analyze the extent of genetic variation in human populations. Using the IEF technique, approximately 50,000 individuals from 160 different populations have been tested for the GC polymorphism. A marked variation in common GC suballele frequencies in different geographic areas seems to correlate with skin pigmentation and intensity of sun light. Pigmented (black) and keratinized (yellowish) skin type populations have a relatively high frequency of the GC *IF allele as compared to white skin populations. By comparison non-pigmented and non-keratinized white skin populations are generally characterized by having the maximum values of the GC *IS allele. The anthropologic significance of the GC locus has been enhanced further by detecting additional unique GC variants which provide useful information about evolutionary links between different populations. However, the presence of some electrophoretically identical unique variants in genetically and geographically distinct populations demand further investigation of these allelic variants to shed more light on their origins.

Simple Method for Determining Specific Binding Capacity of Vitamin D-Binding Protein and Its Use to Calculate the Concentrationof "Free" 1,25-DihydroxyvitaminD

Article

Mar 1994

Reinhold Vieth

A quantitative method to measure the specific binding capacity for 25-hydroxyvitamin D (25D-binding capacity) is described that resembles the qualitative "T3-uptake" assay. Patient's serum or standard (10 microL) is mixed with 0.5 mL of reagent containing 0.5 mumol/L 25-hydroxyvitamin D [25(OH)D3] plus 3000 counts/min [3H]25(OH)D3. After 0.5 h at 37 degrees C, the samples are treated with dextran/charcoal on ice for 1 h and centrifuged. The radioactivity of the bound tracer in the supernate is counted. Calibration is linear to approximately 10 mumol/L. 25D-binding capacity in reference-group serum samples was 4.33 (0.58 SD) mumol/L. The relationship between the inverse of 25D-binding capacity and the free fraction of [3H]1,25-dihydroxyvitamin D3 [1,25(OH)2D3] measured by ultrafiltration isodialysis was essentially linear (r = 0.934, P < 0.0001). Given this relationship, the calculated free fraction of 1,25(OH)2D3 equals 4.88 x 10(-3)/25D-binding capacity. The 25D-binding capacity was significantly lower in newborn babies and in adults with liver disease, and was increased during pregnancy (P < 0.01 for each). This method is applicable to situations where the biologically available concentration of 1,25(OH)2D is of interest.

Affinity differences for Vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBF)

Article

Oct 1993

Human vitamin D binding protein (DBP) displays considerable polymorphism with 120 described alleles. Among these, three alleles are frequently observed, Gc 1F (pI 4.94-4.84), Gc 1S (pI 4.95-4.85) and Gc 2 (pI 5.1). Differences between these genetic forms of the protein in affinity for vitamin D metabolites have been detected by electrophoretic methods. The constant affinity (Ka) values determined in this study confirm these differences. The affinities of six rare variants were also examine. Those of the DBP genetic forms to the vitamin D derivatives 25-OH-D3 and 1,25-(OH)2-D3 seem to be related to the isoelectric point of the proteins: a high affinity corresponding to a low isoelectric point. The Gc 1A9 and 1A11 mutants were associated with higher affinity for the vitamin D derivatives and the Gc 1C1 and 1C21 mutants were deficient.

Genetic Contribution to Bone Metabolism, Calcium Excretion, and Vitamin D and Parathyroid Hormone Regulation

Article

Mar 2001

A classical twin study was performed to assess the relative contribution of genetic and environmental factors to bone metabolism, calcium homeostasis, and the hormones regulating them. It was examined further whether the genetic effect is menopause dependent. The subjects were 2136 adult twins (98.3% female): 384 monozygotic (MZ) and 684 dizygotic (DZ) twin pairs. The intraclass correlations were calculated, and maximum likelihood model fitting was used to estimate genetic and environmental variance components. The intraclass correlations for all of the variables assessed were higher in MZ twin pairs. The heritabilities (95% CIs) obtained from model fitting for hormones regulating bone metabolism and calcium homeostasis were parathyroid hormone (PTH), 60% (54-65%); 25-hydroxyvitamin D [25(OH)D]; 43% (28-57%), 1,25-hydroxyvitamin D [1,25(OH)], 65% (53-74%); and vitamin D binding protein 62% (56-66%). The heritabilities (95% CIs) for markers of bone formation also were assessed; bone-specific alkaline phosphatase (BSAP), 74% (67-80%), and osteocalcin, 29% (14-44%); marker of bone resorption deoxypyridinoline (DPD), 58% (52-64%); and measure of calcium homeostasis 24 h urine calcium, creatinine (Cr), 52% (41-61%). The magnitude of genetic influence differed with menopause for most variables. This study provides evidence for the importance of genetic factors in determining bone resorption and formation, calcium excretion, and the hormones regulating these processes. It shows for the first time a clear genetic effect on bone resorption in premenopausal women and the regulation of PTH, vitamin D metabolism, and calcium excretion. The genes controlling bone hormones and markers are likely to be useful therapeutic and diagnostic targets.

The relationship between Vitamin D and parathyroid hormone: Calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis

Article

Jul 2004
BONE

It is evident from several studies that not all patients with hypovitaminosis D develop secondary hyperparathyroidism. What this means for bone biochemistry and bone mineral density (BMD) remains unclear. The aim of this study was to investigate the effects of hypovitaminosis D (defined as a 25OHD < or = 30 nmol/l) and patients with a blunted PTH response (defined arbitrarily as a PTH within the standard laboratory reference range in the presence of a 25OHD < or = 30 nmol/l) in comparison to patients with hypovitaminosis D and secondary hyperparathyroidism (defined arbitrarily as a PTH above the standard laboratory reference range in the presence of a 25OHD < or = 30 nmol/l) and vitamin D-replete subjects (25OHD > 30 nmol/l). Four hundred twenty-one postmenopausal women (mean age: 71.2 years) with established vertebral osteoporosis were evaluated by assessing mean serum calcium, 25OHD, 1,25(OH)2D, bone turnover markers, and BMD. The prevalence of hypovitaminosis D was 39%. Secondary hyperparathyroidism was found in only one-third of these patients who maintained calcium homeostasis at the expense of increased bone turnover relative to the vitamin D-replete subjects (bone ALP mean difference: 43.9 IU/l [95% CI: 24.8, 59.1], osteocalcin: 1.3 ng/ml [95% CI: 1.1, 2.5], free deoxypyridinoline mean difference: 2.6 nmol/nmol creatinine [95% CI: 2.5, 4.8]) and bone loss (total hip BMD mean difference: 0.11 g/cm2 [95% CI: 0.09, 0.12]). Patients with hypovitaminosis D and a blunted PTH response were characterized by a lower serum calcium (mean difference: 0.07 mmol/l [95% CI: 0.08, 0.2]), a reduction in bone turnover (bone ALP mean difference: 42.4 IU/l [95% CI: 27.8, 61.9], osteocalcin: 1.6 ng/ml [95% CI: 0.3, 3.1], free-deoxypyridinoline mean difference: 3.0 nmol/nmol creatinine [95% CI: 1.9, 5.9]), but protection in bone density (total hip BMD mean difference: 0.10 g/cm2, [95% CI: 0.08, 0.11]) as compared to those with hypovitaminosis D and secondary hyperparathyroidism. This study identifies a distinct group of patients with hypovitaminosis D and a blunted PTH response who show a disruption in calcium homeostasis but protected against PTH-mediated bone loss. This has clinical implications with respect to disease definition and may be important in deciding the optimal replacement therapy in patients with hypovitaminosis D but a blunted PTH response.

Plasma concentrations of 25-Hydroxy-Vitamin D and 1,25-Dihydroxy-Vitamin D are Related to the Phenotype of Gc (Vitamin D-Binding Protein): A Cross-sectional Study on 595 Early Postmenopausal Women

Article

Jul 2005

The major transporter of vitamin D metabolites in the circulation is the multifunctional plasma protein Gc, also known as group-specific component, Gc globulin, vitamin D-binding protein, or DBP. There are several phenotypes of Gc, and we examined the influence of Gc phenotype and Gc concentration on vitamin D status. By using isoelectric focusing we identified the Gc phenotype of 595 caucasian recent postmenopausal women enrolled into the Danish Osteoporosis Prevention Study (DOPS). We measured plasma concentration of Gc by immunonephelometry (coefficient of variation [CV] < 5%), 25-hydroxy vitamin D (25OHD) by a competitive protein-binding assay (CV 10%), and 1,25-dihydroxy-vitamin D (1,25(OH)(2)D) by a radioimmunoassay (CV 6--14%), and calculated index as the molar ratio of vitamin concentration divided by Gc concentration. Plasma levels of Gc, 25OHD, 25OHD index, and 1,25(OH)(2)D, but not 1,25(OH)(2)D index, differed significantly between women with different Gc phenotype, being highest in Gc1-1, intermediate in Gc1-2, and lowest in Gc2-2. In multiple regression analysis, Gc concentration was an independent predictor of 1,25(OH)(2)D, whereas Gc phenotype was a significant predictor of 25OHD concentration, even after adjustment for the effects of season, sunbathing habits, skin thickness, use of vitamin supplements, smoking, and body mass index (BMI). Plasma parathyroid hormone (PTH) level did not differ between Gc phenotypes. Despite the fact that more than 60% of the women with Gc phenotype Gc2-2 had plasma 25OHD levels of less than 50 nmol/L none of them had plasma PTH higher than reference limits. Bone mineral content (BMC), Bone mineral density (BMD), and bone markers did not differ between Gc phenotypes. In conclusion, plasma 1,25(OH)(2)D, 25OHD, and 25OHD index are related to Gc phenotype, and we speculate that the thresholds for vitamin D sufficiency differ between Gc phenotypes.

Speeckaert M, Huang G, Delanghe JR, Taes YEBiological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin Chim Acta 372(1-2): 33-42

Article

Nov 2006
CLIN CHIM ACTA

The vitamin D binding protein (DBP) is the major plasma carrier protein of vitamin D and its metabolites. Unlike other hydrophobic hormone-binding systems, it circulates in a considerably higher titer compared to its ligands. Apart from its specific sterol binding capacity, DBP exerts several other important biological functions such as actin scavenging, fatty acid transport, macrophage activation and chemotaxis. The DBP-gene is a member of a multigene cluster that includes albumin, alpha-fetoprotein, and alpha-albumin/afamin. All four genes are expressed predominantly in the liver with overlapping developmental profiles. DBP is a highly polymorphic serum protein with three common alleles (Gc1F, Gc1S and Gc2) and more than 120 rare variants. The presence of unique alleles is a useful tool for anthropological studies to discriminate and to reveal ancestral links between populations. Many studies have discussed the link between DBP-phenotypes and susceptibility or resistance to osteoporosis, Graves' disease, Hashimoto's thyroiditis, diabetes, COPD, AIDS, multiple sclerosis, sarcoidosis and rheumatic fever. This article reviews the general characteristics, functions and clinical aspects of DBP.

Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation

Abstract

No full-text available

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