Vitamin D-binding Protein Genotype Research Articles

Free, bioavailable 25-hydroxyvitamin D levels and their association with diabetic ketoacidosis in children with type 1 diabetes at diagnosis.

Considering the roles of 25-hydroxyvitamin D (25OHD) in glucose homeostasis and immune modulation, vitamin D deficiency may be related to the development of type 1 diabetes (T1DM) and diabetic ketoacidosis (DKA). We evaluated the total, free, bioavailable 25OHD levels and vitamin D binding protein (VDBP) levels and genotypes between T1DM patients and controls. This retrospective, cross-sectional study included 84 children with T1DM (38 boys and 46 girls, 8.0 ± 3.6 years) and 1:1 age- and sex-matched healthy controls. A multiplex liquid chromatography-tandem mass spectrometry-based assay was used to simultaneously measure vitamin D metabolites. Patients with T1DM had lower levels of total 25OHD (16.3 ± 5.1 vs. 19.9 ± 6.5 ng/mL, P< 0.001) and VDBP (146.0 ± 27.8 vs. 224.9 ± 36.1 µg/mL, P = 0.001), but higher free 25OHD (8.0 ± 2.5 vs. 6.5 ± 2.3 pg/mL, P< 0.001) than controls. Patients who presented with DKA had lower levels of 25OHD in the total (15.0 ± 4.6 vs. 17.6 ± 5.2 ng/mL, P = 0.020), free (7.5 ± 2.6 vs. 8.4 ± 2.4 pg/mL, P = 0.059), and bioavailable (2.3 ± 0.9 vs. 2.8 ± 0.8 ng/mL, P = 0.014) forms than those without DKA at the T1DM diagnosis. The lower the total, free, and bioavailable 25OHD levels at diagnosis, the lower the pH and HCO3-. The proportions of the VDBP genotypes did not differ between the patients and controls. Patients with T1DM had higher levels of free 25OHD than healthy children, despite lower levels of total 25OHD. However, patients with DKA exhibited lower levels of bioavailable 25OHD than those without DKA at the T1DM diagnosis. The lower the concentrations of free and bioavailable 25OHD, the more severe the acidosis at the initial T1DM presentation.

Maternal and Neonatal Vitamin D Binding Protein Polymorphisms and 25-Hydroxyvitamin D Cutoffs as Determinants of Neonatal Birth Anthropometry.

Background: Vitamin D-binding protein (VDBP) is a vital regulator of optimal vitamin D homeostasis and bioavailability. Apart from its well-documented role as a key component in vitamin D dynamic transfer and circulation, it has a myriad of immunoregulatory functions related to innate immunity, which becomes particularly critical in states of increased immunological tolerance including pregnancy. In this regard, VDBP dyshomeostasis is considered to contribute to the development of several fetal, maternal, and neonatal adverse outcomes. However, precise physiological pathways, including the contribution of specific VDBP polymorphisms behind such phenomena, are yet to be fully deciphered. Our aim was to assess the combined effect of maternal and neonatal VDBP polymorphism heterogeneity in conjunction with different maternal and neonatal 25(OH)D cutoffs on the neonatal anthropometric profile at birth. Methods: The study included data and samples from a cohort of 66 mother–child pairs at birth. The inclusion criterion was full-term pregnancy (gestational weeks 37–42). Neonatal and maternal 25(OH)D cutoffs were included according to vitamin D status at birth and delivery. Concentrations of 25(OH)D2 and 25(OH)D3 were measured using liquid chromatography–tandem mass spectrometry. Results: The upper arm length of neonates with 25(OH)D ≤ 25 nmol/L was higher in neonate CC carriers for rs2298850. The upper thigh neonatal circumference was also higher in the ones with either 25(OH)D ≤ 50 or ≤75 nmol/L in rs2298850 CG + GG or rs4588 GT + TT carriers. We did not observe any significant effect for maternal VDBP polymorphisms nor for birth maternal 25(OH)D concentrations, on birth neonatal anthropometry. Conclusions: Our findings emphasize a potential role for neonatal VDBP genotypes rs2298850 and rs4588, in conjunction with specific neonatal 25(OH)D cutoffs, in the range of sufficiency on neonatal growth and development.

The association of vitamin D binding protein levels and genotypes with type 1 diabetes in the black South African population

BackgroundVitamin D deficiency and the vitamin D pathway have previously been associated with type 1 diabetes (T1D). The majority of vitamin D is transported through the blood bound to the vitamin D binding protein (VDBP). Two polymorphisms in the VDBP gene (rs4588 and rs7041) result in different VDBP variants and have been associated with T1D, however the results are not consistent. The association of VDBP levels and its polymorphisms with T1D have not been investigated in the black South African population. Therefore, this study aimed to determine whether rs4588, rs7041 or serum VDBP levels were associated with T1D in this population.MethodsParticipants with type 1 diabetes and controls were recruited from the greater Johannesburg area, South Africa. Participants were genotyped for rs4588 and rs7041 using PCR-RFLP and serum VDBP levels were determined by ELISA.ResultsThere was no difference in VDBP allelic or genotypic frequencies between participants with T1D and controls (rs4588 C allele frequency 0.92 vs. 0.94; p = 0.390 and rs7041 T allele frequency 0.95 vs. 0.95; p = 0.890). In univariate analysis, the rs4588 CC genotype was associated with increased serum VDBP levels, however, this association was lost with multivariate analysis. The VDBP genotypes were not associated with any other study variables. In logistic regression analysis, higher VBDP levels were associated with T1D (OR: (95% CI): 6.58 (1.45–29.9); p = 0.015), and within a linear regression analysis, T1D disease status was found to be associated with 0.044 mg/ml higher VDBP levels (p = 0.028).ConclusionsThese data suggest that serum VDBP levels are positively associated with the presence of T1D in the African population. Whether VDBP lies in the causal pathway or its elevation is an effect of T1D is uncertain and requires further investigation.

Distribution and Determinants of Vitamin D-Binding Protein, Total, "Non-Bioavailable", Bioavailable, and Free 25-Hydroxyvitamin D Concentrations among Older Adults.

Background: serum 25-hydroxyvitamin D (25(OH)D) (“total 25 OH(D)”) is the most commonly used indicator of vitamin D status. However, 25(OH)D is mostly bound to the vitamin D binding protein (VDBP) or albumin in blood, and it has been suggested that the remaining bioavailable or free 25(OH)D may be more relevant for vitamin D associated health outcomes. We aimed to explore distributions and determinants of VDBP, total, bioavailable, complementary “non-bioavailable”, and free 25(OH)D in a large cohort of older adults in Germany. Methods: total 25(OH)D, VDBP, and albumin concentrations were measured in blood samples of 5899 men and women aged 50–75 years and used to calculate bioavailable (and complementary “non-bioavailable”) and free 25(OH)D concentrations. Linear regression models were used to evaluate associations of potential determinants of the various vitamin D biomarkers. Results: mean concentrations of VDBP, total, non-bioavailable, bioavailable, and free 25(OH)D were 323.6 µg/mL, 49.8 nmol/L, 43.4 nmol/L, 2.5 ng/mL, and 5.7 pg/mL, respectively. Seasonal variations were observed for all markers, with peak values in spring for VDBP and in summer for total, non-bioavailable, bioavailable, and free 25(OH)D. Consistent inverse associations were seen with age and body mass index for all markers, but divergent associations were seen with C-reactive protein. Strong variations by VDBP genotypes were seen for bioavailable and free 25(OH)D, and, in opposite direction for non-bioavailable 25(OH)D. Conclusion: commonalities and differences in determinants of various markers of vitamin D status were observed, which may help to enable a better understanding of their potential role for various vitamin D related health outcomes.

Reduction in circulating vitamin D binding protein in patients with multiple sclerosis

BackgroundIn this study, we aimed to determine the risk association between vitamin D binding protein (VDBP) polymorphism in patients with multiple sclerosis (MS) in a MS biobank and the difference in VDBP serum levels in MS patients who were recently diagnosed.MethodThe current case-control study was performed on 296 MS patients and 313 controls. Thereafter, two common missense VDBP polymorphisms, named rs7041and rs4588, were evaluated in all the participants. Serum levels of vitamin D and vitamin D binding protein were assessed in 77 MS patients who were diagnosed since one year ago and in 67 healthy people who were matched in terms of age and sex.ResultThe frequency distributions of VDBP genotypes and alleles of SNP rs7041 and rs4588 were observed to be similar in both the MS and control groups (p > 0.05). The VDBP haplotypes, as Gc2/Gc2, Gc1/Gc1, and Gc1/Gc2, were found to be similar in the MS and control groups (p > 0.05).In subgroup analysis, circulating VDBP was lower in MS patients (Ln-VDBP (μgr/ml): 3.64 ± 0.91 vs. 5.31 ± 0.77, p = 0.0001) even after adjusting for vitamin D levels, body mass index, and taking vitamin D supplement. There was no significant association between VDBP haplotypes and vitamin D levels in the two groups.ConclusionThe present study suggested an association between lower levels of circulating VDBP and multiple sclerosis in newly diagnosed patients. However, the VDBP causative role in the development of MS is still unclear, so it needs more studies.

Vitamin D binding protein genotype frequency in familial Mediterranean fever patients

Objective: Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent short episodes (1–3 days) of inflammation and fever. FMF is associated with MEFV gene mutations but some patients with FMF symptoms do not have a mutation in the coding region of the MEFV gene. Vitamin D binding protein (VDBP) has important functions, including transporting vitamin D and its metabolites to target cells. Circulating levels of vitamin D are decreased in several inflammatory conditions, including FMF. Thus, we hypothesize that VDBP may play a crucial role in FMF pathogenesis, in addition to the MEFV gene. Method: VDBP genotyping was performed by polymerase chain reaction (PCR)–restriction fragment length polymorphism in 107 FMF patients and 25 healthy individuals without FMF or family history. For this, after amplification of genomic DNA, PCR products were digested with restriction enzymes HaeIII and StyI and evaluated electrophoretically. Results: We observed a statistically significant difference in the frequency of the 1F–2 genotype. The frequency of allele 2 was significantly higher and allele 1S was significantly lower compared to the [MEFV(−)] group and healthy controls (p = 0.034, 0.001, and 0.012, respectively). We observed a significant association between the presence of allele 2 and amyloidosis (p = 0.026) and arthritis (p = 0.044) in the [MEFV(−)] group. Conclusion: Our results suggest that FMF symptoms in the absence of MEFV gene mutations may be due to the presence of VDBP allele 2. Therefore, VDBP genotype may explain the symptoms in FMF [MEFV(−)] patients.

Vitamin D Binding Protein and Complement Factor C5a Influence Neutrophil Chemotaxis Following HSCT

Background Vitamin D binding protein (VDBP) is an abundant protein in human serum, related to albumin and alpha-fetoprotein. The VDBP gene is polymorphic, with three major alleles (Gc1F, Gc1S and Gc2) and four frequent genotypes. These genotype differences effect the glycosylation state of the molecule. VDBP has many diverse functions in addition to transporting vitamin D, and only about 4% of VDBP is bound to vitamin D at any one time. Acute inflammation leading to graft-vs-host disease (GVHD) may involve chemotaxis of leukocytes into damaged tissue mediated by chemotactic factors. Complement activation peptide C5a is a potent chemoattractant and together with VDBP has been shown to markedly enhance the motility of leukocytes. In previous work, we have shown that VDBP levels are significantly lower in those with acute GVHD (p=0.026), and 1-year NRM (p=0.03). Here we have reproduced these data analyzing serum from Day 100 post-HSCT with a new 110 patient cohort. Acute GVHD was reduced in those with VDBP levels above the median at Day 100 (0.03 v 0.18, p=0.037). 1-year NRM cumulative incidence (0.02 vs 0.2, p=0.002) was similarly reduced in those with VDBP levels above the median at Day 100, in agreement with our previous findings. In an effort to identify mechanisms whereby VDBP improves survival, we hypothesized that higher levels of VDBP will have a beneficial effect on neutrophil chemotaxis following HSCT. Previous VDBP animal model studies show chemotaxis of neutrophils to lung injuries can exacerbate pulmonary inflammation, but too little chemotaxis and the animals can succumb to infection. Here we observe a similar paradoxical effect with VDBP and chemotaxis. Methods VDBP was measured in serum at Day 100 in 110 transplant recipients using a polyclonal VDBP ELISA. Genotypes were determined by Taqman allele discrimination. Neutrophils from whole blood were negatively enriched from a normal adult donor and incubated in 10% patient serum in HBSS for 1 hr. For modified Transwell assay, put 4 × 105 cells in a 3-um-pore, 12-mm-diameter Transwell and place on top of 20 nM C5a in HBSS in a fibrinogen coated 12-well plate. Allow neutrophils to migrate for 2 hrs then count cells by hemocytometer. Results VDBP levels above the median at Day 100 were associated with significantly lower cumulative incidence of both NRM and GVHD 1-year post transplant (Fig 1 & 2). High levels of VDBP in patients with GcS1/GcS1 genotype decelerate chemotaxis towards a C5a bait. However, VDBP of a similar level but different genotype gives contrasting results; high VDBP levels with a GcS1/Gc2 genotype increase chemotaxis (Fig 3). Conclusions Our data demonstrate that VDBP-containing serum from children post-BMT modifies chemotaxis, potentially in a genotype dependent manner. We are extending our studies to test additional samples and genotypes. Moreover, we are exploring the effect of VDBP genotype on other transplant outcomes.

Association of vitamin D deficiency and VDBP gene polymorphism with the risk of AMI in a Pakistani population.

Objective:To investigate the relationship of vitamin D deficiency and risk of AMI in a Pakistani population, and to find out any association between vitamin D binding protein (VDBP) genotypes and risk of AMI in this population.Methods:In a comparative cross-sectional study, 246 patients (age: 20-70 years; 171 males and 75 females) with first AMI were enrolled with informed consent. Similarly, 345 healthy adults (230 males and 115 females) were enrolled as controls. Their fasting serum samples were analyzed for 25 (OH) vitamin D, lipids and other biomarkers using kit methods, while DNA was analyzed for VDBP genotypes using PCR-RFLP based methods. Chi-squared test and logistic regression were used for association of vitamin D deficiency and VDBP genotypes with AMI.Results:Mean serum concentration of 25(OH) vitamin D was significantly lower in AMI patients compared to healthy subjects (p=0.015) and percent vitamin D deficiency was higher in AMI patients compared to healthy subjects (p=0.003). VDBP IF-IF genotype was positively associated with the risk of AMI in subject above 45 years after adjusting for potential confounders [OR = 9.86; 95% CI=1.16 to 83.43].Conclusion:Vitamin D deficiency and VDBP IF-IF genotype are associated with AMI in Pakistani adults.

High Vitamin D-Binding Protein Concentration, Low Albumin, and Mode of Remission Predict Relapse in Crohn's Disease.

Vitamin D (25(OH)D) deficiency occurs in active Crohn's disease (CD) and may be secondary to reduced sunlight exposure and oral intake. Vitamin D-binding protein (VDBP) levels, however, fluctuate less with season and sunlight. The aim, therefore, was to examine patients with CD in remission and determine any associations between VDBP, serum 25(OH)D, and the calculated free 25(OH)D concentrations with the risk of disease flare. Subjects were identified from prospectively maintained inflammatory bowel disease databases at 3 teaching hospitals in Australia. Patients were in steroid-free clinical remission at the time of blood draw and were followed for at least 12 months. Total and epimer-25(OH)D3, VDBP concentrations, and genotypes were determined. A total of 309 patients with CD (46% men) met the inclusion criteria. A disease flare occurred in 100 (32.4%). Serum 25(OH)D3 was deficient (<50 nmol/L) in 36 (12%) and insufficient (50-75 nmol/L) in 107 (35%) patients. Total, free, and epimer-25(OH)D3 serum levels did not predict disease flare. Higher VDBP concentrations, however, significantly correlated with increased risk of disease flare (hazard ratio 1.2, 95% CI, 1.0-1.5). On multivariate analysis, VDBP concentration, low albumin, and medication-induced remission were significantly more associated with disease flare. VDBP genotypes were significantly associated with 25(OH)D and VDBP concentrations but not disease flare. Vitamin D deficiency was uncommon in our patients with CD in remission, and serum 25(OH)D3 did not predict disease flare, whereas higher VDBP concentrations were significantly associated with disease flare. Further investigations to explore the possible mechanisms for this association are warranted.

VDBP Gene Polymorphism in COPD

Chronic obstructive pulmonary disease (COPD) is a disease which genetic and environmental factors play an important role in COPD development. VDBP (Vitamin D Binding Protein ) gene might be responsible for COPD development. The purpose of this study to investigate the possible effect of VDBP on progression of COPD. We studied VDBP genotypes in 75 COPD patients, 36 smoker healthy subjects and 19 non-smoker healthy subjects with PCR-RFLP method to analyze the association between VDBP and COPD. In our study, the most frequently seen genotype was 1S-2 with a frequency of 32% in COPD group; and 1F-1S genotype with a frequency of 33.3% in smoker healthy group. There was no significant difference between these genotypes. In our study groups, we did not find any 2-2 genotype in non-smoker healthy subject group while it has been found 4% and 8% in COPD and healthy smoker subject groups, respectively. Although we did not find any significant difference for protective effect of the 2 allele on the disease or susceptibility of 1F allele to COPD formation in COPD patients and smoker healthy subjects (p: 0.346, p: 0.249, respectively), the only significant difference was between the patient and the healthy non-smoker groups with 1S-1S genotype (p=0.032). Our results do not show any evidence that indicate a protective or susceptibility effect of VDBP 2 and 1F alleles in progression of COPD, respectively but results indicate that having the 1S-1S genotype may be associated with the etiology of COPD.

Abstract 670: Cigarette smoking, race, and genetic ancestry in association with plasma vitamin D-binding protein (VDBP) in healthy African Americans (AA) and Caucasian Americans (CA)

Abstract Vitamin D and VDBP affect several pathways involved in inflammation, tumor growth, and immune surveillance relevant to carcinogenesis. In a previous pilot study (Bortner et al., 2010), using a proteomics approach, VDBP was down-regulated in the plasma of chronic cigarette smokers by as much as 3-fold. Therefore, using an existing study of healthy AA and CA participants, we conducted an investigation of the differences in VDBP between 39 current smokers and 82 never smokers, frequency matched on age, sex and race/ethnicity. VDBP plasma concentrations were determined in duplicate using the Quantikine® Human VDBP ELISA (CV%, 5.6%). Genotyping was conducted for a set of 112 previously validated Ancestry Informative Markers for the percent West African and European genetic ancestry, and VDBP coding region changes via rs7041 (Asp416Glu, T/G) and rs4588 (Thr420Lys, C/A). Vitamin D metabolites (25OHD3 and 24,25(OH)2D3) were determined using LC-MS/MS (CV% 2.7 and 6.3, respectively). T-test, Chi-Square, Fisher's Exact, and Spearman's correlation coefficients were used to determine statistically significant bivariate differences. Multiple logistic regression was used to adjust for multiple factors using the log-normal transformation of VDBP concentration with the Cochran-Armitage test for trend for VDBP genotype. Multiplicative interaction terms were tested along with their main-effects, adjusted for co-variates. There were no significant differences between current smokers and never smokers by age, VDBP genotype, body mass index, vitamin D metabolites, or genetic ancestry. VDBP concentrations were significantly negatively correlated with body mass index (BMI, r=−0.19, p=0.033), West African ancestry (r=−0.66, p&amp;lt;0.001), vitamin D metabolites (p-values&amp;lt;0.001), VDBP rs4588-A and rs7041-T alleles (VDBP genotypes were 100% correlated). VDBP genotypes coding Asp416Asp and Lys420Lys were at least 3.3-fold lower, compared with Glu416Glu and Thr420Thr, respectively, and this was regardless of smoking status (p-trend&amp;lt;0.001). There was no association between VDBP concentration and age or smoking status. In multiple regression models, serum vitamin D metabolites, self-reported race/ethnicity, West African ancestry and GC genotypes remained significantly associated with VDBP concentration. The magnitude of difference in these variables was similar among current and never smokers, although BMI remained significantly negatively associated with VDBP concentrations among never smokers (p-interaction =0.028). Smoking status was not highly correlated with VDBP plasma concentration, although may have some interactive effect with BMI. Future studies will need to account for the strong correlations with VDBP genotype and genetic ancestry. Support: 1K22CA120092-01A2 and 3K22CA120092-02S1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 670. doi:1538-7445.AM2012-670

Vitamin D‐binding protein polymorphisms are not associated with development of (multiple) basal cell carcinomas

Vitamin D-binding protein (VDBP) single nucleotide polymorphisms (SNP) may affect skin carcinogenesis. The objective was to test the association between two functional VDBP SNPs and the susceptibility to (multiple) basal cell carcinomas (BCCs). Of the 7983 participants, 5790 (72.5%) and 5823 (72.9%) participants were genotyped for rs7041 and rs4588, respectively, and three haplotypes (Gc1s, Gc2 and Gc1f) were analysed. Two hundred and thirty-three persons developed a BCC of whom 122 (52.4%) developed multiple BCCs during a mean follow-up of 11.6 years. The VDBP genotype was not associated with (multiple) BCC development using Cox proportional hazards and Andersen-Gill analyses, respectively. Stratifying age groups demonstrated that in the youngest age-group, the A/T variant of rs7041 was associated with BCC development [adjusted hazard ratio (HR) = 1.88 (95%CI 1.10-3.20)], while homozygote Gc1s carriers had a significantly lower BCC risk [adjusted HR = 0.53 (95%CI 0.31-0.91)]. In conclusion, the VDBP polymorphisms were not associated with susceptibility to (multiple) BCCs, but age-gene interactions were observed.