Coronavirus disease 2019 (COVID-19) presents with various symptoms, and some patients develop post-COVID-19 condition (PCC). Vitamin D has shown therapeutic potential in COVID-19 and may offer benefits for PCC. The aim of this study was to evaluate the differences associated with two supplementation strategies (bolus and daily) on interleukin-6 (IL-6) levels, glutathione peroxidase (GPx) activity, and clinical outcomes in PCC patients, regardless of whether target 25 (OH) D levels reached the ideal range. We conducted a self-controlled study in which 54 participants with PCC were supplemented with vitamin D3 (n = 28 bolus and n = 26 daily) for 2 months. Blood samples were collected to measure IL-6 levels and GPx activity using spectrophotometric methods. The Hospital Anxiety and Depression Scale (HADS) was used to assess mental function. Both bolus and daily vitamin D supplementation were significantly associated with increased GPx activity and decreased IL-6 levels. Daily supplementation was additionally associated with a significant reduction in anxiety and depression scores. However, neither regimen was associated with improvements in cough, dyspnea, or fatigue. These findings suggest a potential association between vitamin D supplementation and improvements in antioxidant and neuropsychiatric parameters in PCC, possibly mediated by its immunomodulatory and antioxidant properties. Further placebo-controlled trials are warranted to determine whether these observed associations reflect causal relationships.

Serum total 25-hydroxyvitamin D [25(OH)D] concentration is the most widely used clinical biomarker for vitamin D status. Under certain physiological and pathological conditions, however, total 25(OH)D may not always be the best index for vitamin D status. Instead, the nonprotein-bound (free) fraction of total 25(OH)D has been suggested as a more appropriate marker in certain clinical situations.

Free 25(OH)D levels can either be calculated or measured directly. Calculated free 25(OH)D depends on the concentrations of total serum 25(OH)D, vitamin D binding protein (VDBP), and albumin, as well as the affinity between analyte and binding proteins. Differences in VDBP concentrations are observed between populations as a result of health status, gene polymorphisms, and the assay used for determination. Direct measurement methods for free 25(OH)D are often complicated (dialysis, ultrafiltration) or susceptible to interferences, cross-reactivity, and type of antibody (immunoassays). Therefore, it is very important to develop tools that allow either accurate and precise measurement of VDBP or direct measurement of free 25(OH)D. For the latter, liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) has recently shown promise for analysis of free vitamin D. In the current review, we present the importance and challenges regarding free 25(OH)D determination and the role of LC-MS-based methods in future studies.

More research is required to determine the role of free 25(OH)D in the assessment of vitamin D status in healthy subjects and in various clinical conditions. Recent advances in technology, including mass spectrometry, can provide the required assays for this purpose.

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.

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 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.

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.

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 D3 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.

To estimate supplemental vitamin D3 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).

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.

Daily vitamin D3 (1000 IU), calcium (1200 mg), both, or placebo.

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.

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 D3 relative to no vitamin D3, 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 D3 relative to no vitamin D3, 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.

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 D3 and/or calcium supplementation for colorectal adenoma prevention.

ClinicalTrials.gov Identifier: NCT00153816.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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 (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.

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 IU) 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 analysis of variance 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 = .021) and more risk alleles at rs7041 and rs4588 are associated with reduced plasma 25(OH)D (P = .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 = .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.

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.

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.

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.

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.

GC variants could have independent effects on the risk of T2DM and DN in the study population.

The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition.

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.

Exploratory study within a randomized trial.

2000 International Units of vitamin D3 per day (or matching placebo).

Community-based.

161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes.

Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2.

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).

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.

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.

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.

This study aimed to describe the vitamin D status of pregnant women in Western Australia and identify predictors of deficiency in pregnancy.

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.

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.

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.

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 six common GC haplotypes.

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.

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 1-6 months of supplementation.

One hundred ninety-two 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 toward 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, 1 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 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.

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.

This study aimed to identify risk factors for vitamin D deficiency/insufficiency among Puerto Rican adults from the Boston Puerto Rican Health Study (BPRHS).

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.

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).

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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" (p_c=0.031), rs1544410 "G" (p_c=0.027) and CYP2R1 rs10741657 "A" (p_c=0.016). Patients with genotypes CYP27B1 rs10877012 "CC" (p_c=4x10^-5), DBP rs7041 "GG" (p_c=0.003), rs4588 "CC" (p_c = 3x10^-4), CYP24A1 rs2585426 "CG" (p_c=0.006) and rs2248137 "CG" (p_c=0.001) showed lower 25(OH)D3 and DBP rs4588 "CC" lower 1,25(OH)2D3 levels (p_c=0.005). Whereas DBP rs4588 "CC" (p_c=0.009), CYP27B1 rs10877012 "AC" (p_c=0.059), VDR rs7975323 "AG" (p_c=0.033) and rs1544410 "GG" (p_c=0.013) are associated with higher 25(OH)D3 levels at 6 months' follow-up. Significant PTH suppression was detected for CYP2R1 "AG" (p_c=0.002), DBP rs4588 "CC" (p_c<0.001), VDR rs110735810 "CT" (p_c<0.001) and CYP24A1 rs2248137 "GG" (p_c=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.

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).

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).

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.

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.

Supplementation provides the best means of improving vitamin D status; however, individual responses vary partly owing to genetics. The aim of this study was to determine whether 28 single nucleotide polymorphisms (SNPs) in six key vitamin D pathway genes (GC, DHCR7, CYP2 R1, CYP24 A1, CYP27 B1, VDR) were associated with differences in response to supplementation.

Participants (N = 313; n = 160 vitamin D, n = 153 placebo) were part of VIDARIS (Vitamin D and Acute Respiratory Infections Study), a double-blind, randomized controlled trial involving oral monthly supplementation of either vitamin D₃ (200 000 IU each for the first 2 mo, thereafter 100 000 IU monthly) or placebo for 18 mo. Circulating 25-hydroxyvitamin D (25[OH]D) concentrations at baseline and 2, 6, 12, and 18 mo, and vitamin D binding protein (Gc-globulin) and calculated free 25(OH)D concentrations at baseline and 2 mo were obtained. Multiple regression was used to model associations between genetic variants and 25(OH)D, Gc-globulin, and free 25(OH)D concentrations.

SNPs within GC, CYP2 R1, and CYP27 B1 were associated with 25(OH)D concentrations following supplementation. However, only two GC gene SNPs (rs2282679, rs1155563) were significant after adjustment for multiple testing. This effect disappeared after more than 2 mo 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 25(OH)D concentrations in the supplemented arm.

Only variants of GC were associated with 25(OH)D concentrations after supplementation. This effect was modest and disappeared after >2 mo of supplementation, suggesting it may be time/dose-dependent and saturable.

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.

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.

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, P trend = 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) (P heterogeneity = .01).

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.

Single nucleotide polymorphisms (SNPs) of the vitamin D binding protein encoding the 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.

To study GC genotype-related differences in 25OHD concentrations and the response to supplementation during a vitamin D intervention study in infants.

In this randomized controlled trial, healthy term infants received vitamin D3 (10 or 30 μg/d) 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.

25OHD measured in cord blood at birth and at 12 and 24 months during intervention.

A total of 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 (ANCOVA) P < 0.043], with the exception of rs7041, which did not affect 25OHD at birth. In the high-dose supplementation group receiving 30 μg/d vitamin D3, but not in those receiving 10 µg/d, genotype of rs2282679, rs4588, and rs7041; diplotype; and Haplo3SNP significantly affected intervention response (repeated measurement ANCOVA Pinteraction < 0.019). Minor allele homozygotes had lower 25OHD concentrations and smaller increases in 25OHD throughout the intervention.

In infants, vitamin D binding protein genotype affects 25OHD concentration and efficiency of high-dose vitamin D3 supplementation.

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.

Sarcoidosis is a rare multisystem granulomatous disease with unknown etiology. The interplay of vitamin D deficiency and genetic polymorphisms in genes coding for the proteins relevant for metabolism of vitamin D is an important, but unexplored area. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588), and VDR (rs2228570) genes and sarcoidosis, as well as the association between these SNPs and 25(OH)D levels in sarcoidosis patients.

For that purpose we genotyped 86 sarcoidosis patients and 50 healthy controls using the PCR-RFLP method.

Subjects carrying the CC genotype of CYP27B1 rs10877012 have 10 times lower odds of suffering from sarcoidosis. Moreover, DBP rs4588 AA genotype was shown to be a susceptibility factor, where carriers of this genotype had eight times higher odds for developing sarcoidosis. In addition, the A allele of the DBP gene (rs4588) was associated with lower levels of 25(OH)D in sarcoidosis patients.

These results suggest that patients with vitamin D deficiency should be regularly tested for genetic modifiers that are related to sarcoidosis in order to prevent development of serious forms of sarcoidosis.

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.

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.