scholarly journals Very Low Vitamin D in a Patient with a Novel Pathogenic Variant in the GC Gene that encodes Vitamin D-Binding Protein

2021 ◽  
Author(s):  
Ronadip R Banerjee ◽  
Tara Spence ◽  
Stuart J Frank ◽  
Raj Pandian ◽  
Andrew N Hoofnagle ◽  
...  
Keyword(s):  
Vitamin D ◽  
Gene Deletion ◽  
Binding Protein ◽  
Pathogenic Variant ◽  
Plasma Vitamin ◽  
Vitamin D Metabolites ◽  
Vitamin D Binding Protein ◽  
Hydroxyvitamin D ◽  
Vitamin D Levels ◽  
Gc Gene

Abstract Circulating plasma vitamin D metabolites are highly bound to vitamin D-binding protein (DBP), also known as group-specific component or Gc-globulin. DBP, encoded by the GC gene, is a member of the albumin family of globular serum transport proteins. We previously described a homozygous GC gene deletion in a patient with apparent severe vitamin D deficiency, fragility fractures and ankylosing spondylitis. Here, we report an unrelated patient free of fractures or rheumatologic disease, but with very low 25-hydroxyvitamin D and 1,25-hydroxyvitamin D, as well as undetectable DBP measured by liquid chromatography-tandem mass spectrometry. A whole gene deletion was excluded by microarray, and Sanger sequencing of GC revealed a homozygous pathogenic variant affecting a canonical splice site (c.702-1G>A). These findings indicate that loss of function variants in GC that eliminate DBP, and severely reduced total circulating vitamin D levels, do not necessarily result in significant metabolic bone disease. Together with our previous report, these cases support the free-hormone hypothesis, and suggest free vitamin D metabolites may serve as preferable indicators of bone and mineral metabolism, particularly when clinical suspicion of DBP deficiency is high.

scholarly journals P431 Vitamin D binding protein in the limelight: IBD-related inflammation and circulating levels of vitamin D binding protein, total, free and bioavailable 25-hydroxyvitamin D

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S393-S393
Author(s):  
A Aksan ◽  
K Böttger ◽  
N Hein ◽  
Y Caicedo-Zea ◽  
I Diehl ◽  
...  
Keyword(s):  
Vitamin D ◽  
Binding Protein ◽  
Transferrin Saturation ◽  
Simultaneous Detection ◽  
Full Blood Count ◽  
Vitamin D Binding Protein ◽  
Vitamin D Metabolism ◽  
Hydroxyvitamin D ◽  
Vitamin D Levels ◽  
25 Hydroxyvitamin D

Abstract Background Vitamin D deficiency occurs frequently in patients with Crohn’s disease (CD) and ulcerative colitis (UC). While recent cohort studies support an association of vitamin D with important clinical parameters and outcomes in IBD, the complex interplay of inflammation with vitamin D metabolism in IBD poses a viscious circle. We sought to further illucidate the relation between inflammation and different vitamin D parameters. To the best our knowledge, this was the first study to focus on the relationship between vitamin D binding protein (VDBP), circulating total, free, and bioavailable 25-hydroxyvitamin D (25(OH)D), and inflammation, in adult IBD patients. Methods This was a comparative, single-centred, cross-sectional study in patients with IBD aged 18–65 years. Full blood count, transferrin, albumin and hsCRP were determined by standard methods. The presence/absence of inflammation was assessed based on serum hsCRP levels (cutoff <5mg/l). VDBP levels were determined by ELISA, and 25(OH)D by LCMS. Free and bioavailable vitamin D levels were calculated using the validated formula. IBM SPSS version 25.0 was used for statistical analysis. Results In total, 129 subjects with IBD (70 male/59 female; 82 CD/47 UC; mean age 41.7 ± 12.6 years) were enrolled. Of these, 38/129 had inflammation (19 m/19 f; 26 CD/12 UC; 39.6 ± 12.9 years) while 91/129 had no inflammation (40 m/51 f; 56 CD/35 UC; 42.5 ± 12.5 years). Subjects with disease activity had significantly higher leukocyte, erythrocyte sedimentation rate (ESR) and hsCRP, but lower transferrin, transferrin saturation (TSAT) and albumin levels than those without inflammation (p < 0.05). Average serum levels of 25(OH)D (24.6[6.8–54.8] vs. 26.4[5.0–74.4]ng/ml), free 25(OH)D (5.9[1.3–13.3] vs. 1.0[1.0–21.4]ng/ml) and bioavailable 25(OH)D(2.3 [0.1–4.7] vs. 2.4[0.5–19.5]ng/ml) were similar in patients with vs. without inflammation (p > 0.05). However, VDBP levels were significantly higher in inflammatory conditions (359.6[252.2–530.6] mg/l vs. 327.4[183.5–560.3]mg/l; p < 0.05) and showed a positive correlation with CRP levels (0.293, p < 0.001). Ratio of free/total 25(OH)D correlated negatively with CRP levels (−0.282, p = 0.002). Conclusion High levels of circulating VDBP were associated with inflammatory activity. Moreover, free/total 25(OH)D ratio was inversely associated with inflammation. Other vitamin D parameters including total, free and bioavailable 25(OH)D showed no association with inflammation. These findings suggest that VDBP may play a bigger role than thought as a modulator of vitamin D and inflammation, and that simultaneous detection and investigation of plasma VDBP may provide additional insights into this complex interaction.

scholarly journals Polymorphism of gene GC, encoding vitamin D binding protein, in aboriginal populations of Siberia

2020 ◽  
Author(s):  
Boris Malyarchuk
Keyword(s):  
Vitamin D ◽  
Binding Protein ◽  
Synonymous Substitution ◽  
Vitamin D Binding Protein ◽  
Coding Region ◽  
Hydroxyvitamin D ◽  
Gene Environment ◽  
Aboriginal Populations ◽  
25 Hydroxyvitamin D ◽  
Gc Gene

The analysis of the nucleotide sequences of exons and adjacent non-coding regions of the GC gene in 108 representatives of various ethnic groups of aboriginal population of Siberia was carried out. Polymorphism was found in four nucleotide positions: non-synonymous substitutions at the rs4588 and rs7041 loci, a synonymous substitution at the rs4752 locus, and a replacement in the non-coding region at the rs3733359 locus. Seven haplotypes of the GC gene were identified. Of these, 4 haplotypes encode the Gc1F isoform, 2 haplotypes encode the Gc1S isoform, and 1 haplotype encodes the Gc2 isoform. Between-regional differences were found in the distribution of variants of the GC gene: in the northeast and in the central part of Siberia, the highest prevalence of the Gc1F and Gc1F / Gc1F variants is observed, and in the south and west of Siberia, the Gc2, Gc1S / Gc2 and Gc2 / Gc2 variants are most common. In the case of the GC gene, gene-environment interactions are apparently aimed at creating a balance between the activity of vitamin D-binding protein and the level of 25-hydroxyvitamin D in the blood serum.

scholarly journals MON-372 Treatment-Resistant Vitamin D Deficiency: Is It a Vitamin D Binding Protein Issue?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sirisha Thambuluru ◽  
Imran Unal ◽  
Stuart Frank ◽  
Amy Warriner ◽  
Fernando Ovalle ◽  
...  
Keyword(s):  
Vitamin D ◽  
Alkaline Phosphatase ◽  
Vitamin D Deficiency ◽  
Binding Protein ◽  
High Dose ◽  
Vitamin D Metabolites ◽  
Vitamin D Binding Protein ◽  
Treatment Resistant ◽  
Vitamin D Levels ◽  
25 Oh Vitamin D

Abstract Introduction Vitamin D is present in free and bound forms; the bound form is complexed mainly to vitamin D binding protein (DBP). Vitamin D levels are affected by age, pregnancy, liver disease, obesity, and DBP mutations. We report a patient with treatment-resistant vitamin D deficiency suggestive of a DBP with abnormal vitamin D binding. Clinical Case A 58-year-old Pakistani male with a history of hypertension, sleep apnea and hypogonadism presented to endocrine clinic with symptoms including fatigue, generalized muscle cramps, and joint pain. Evaluation of common causes of fatigue, such as anemia, thyroid dysfunction and adrenal insufficiency were ruled out with CBC, thyroid hormone levels and ACTH stimulation test results all within normal ranges. A 25-OH vitamin D level was profoundly low (4.2 ng/ml; normal 30-100), and a 1,25-OH vitamin D level was undetectable (<8 pg/ml; normal 18-72), leading to a presumptive diagnosis of severe vitamin D deficiency. However, his calcium, phosphorus, alkaline phosphatase and kidney function were in the normal range. Furthermore, the absence of osteoporosis, fracture history, or kidney stones suggested adequate vitamin D action at target tissues; PTH levels were high-normal to minimally elevated, ranging 70-94 pg/ml (12-88pg/mL). Aggressive supplementation with vitamin D3 at 50,000 IU 3 times a week and 5,000 IU daily failed to normalize 25-OH vitamin D (ranged 4.6-10ng/ml; normal 30-100) and 1,25-OH vitamin D levels remained undetectable. Addition of calcitriol resulted in mild hypercalcemia and was discontinued. Malabsorption did not appear to be a contributing factor, as a negative tTG antibody (with normal IgA) excluded celiac disease. Vitamin D metabolites levels measured with mass spectrometry showed undetectable 25-OH vitamin D levels (D2 <4 ng/ml, D3 <2 ng/ml; total <6ng/ml; normal 20-50) and 1,25-OH vitamin D levels (<8 pg/ml). Urine N-telopeptide, 24-hour urine calcium (177mg; 100-240) and bone-specific alkaline phosphatase were all normal. Repeat testing over more than five years showed similar results. DBP levels of 269 ug/ml [104-477] excluded DBP deficiency. Clinical Lesson Vitamin D deficiency is increasingly part of routine testing in internal medicine and endocrinology clinics, as is repletion with high-dose vitamin D. However, in rare cases such as this, relying on 25-OH vitamin D levels can be misleading, and supplementation unnecessary or potentially harmful. Thus, treatment decisions should consider the full clinical context and further evaluation performed when warranted. This patient’s labs are suggestive of an abnormality in the DBP, supporting future examination using molecular testing.

scholarly journals Vitamin D Metabolites and Binding Protein Predict Preeclampsia in Women with Type 1 Diabetes

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2048
Author(s):  
Clare B. Kelly ◽  
Carol L. Wagner ◽  
Judith R. Shary ◽  
Misti J. Leyva ◽  
Jeremy Y. Yu ◽  
...  
Keyword(s):  
Vitamin D ◽  
Type 1 Diabetes ◽  
Binding Protein ◽  
Vitamin D Metabolites ◽  
Vitamin D Binding Protein ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Healthy Pregnancy ◽  
25 Hydroxyvitamin D

The risk for preeclampsia (PE) is enhanced ~4-fold by the presence of maternal type 1 diabetes (T1DM). Vitamin D is essential for healthy pregnancy. We assessed the total, bioavailable, and free concentrations of plasma 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and vitamin D binding protein (VDBP) at ~12, ~22, and ~32 weeks’ gestation (“Visits” (V) 1, 2, and 3, respectively) in 23 T1DM women who developed PE, 24 who remained normotensive, and 19 non-diabetic, normotensive women (reference controls). 25(OH)D deficiency was more frequent in diabetic than non-diabetic women (69% vs. 22%, p < 0.05), but no measure of 25(OH)D predicted PE. By contrast, higher 1,25(OH)2D concentrations at V2 (total, bioavailable, and free: p < 0.01) and V3 (bioavailable: p < 0.05; free: p < 0.01), lower concentrations of VDBP at V3 (p < 0.05), and elevated ratios of 1,25(OH)2D/VDBP (V2, V3: p < 0.01) and 1,25(OH)2D/25(OH)D (V3, p < 0.05) were all associated with PE, and significance persisted in multivariate analyses. In summary, in women with T1DM, concentrations of 1,25(OH)2D were higher, and VDBP lower, in the second and third trimesters in women who later developed PE than in those who did not. 1,25(OH)2D may serve as a new marker for PE risk and could be implicated in pathogenesis.

scholarly journals Association of blood lead level with vitamin D binding protein, total and free 25-hydroxyvitamin D levels in middle school children

2021 ◽  
pp. 1-28
Author(s):  
Abdur Rahman ◽  
Reem Al-Sabah ◽  
Reem Jallad ◽  
Muddanna S. Rao
Keyword(s):  
Vitamin D ◽  
Blood Lead Level ◽  
Binding Protein ◽  
Lead Level ◽  
Blood Lead ◽  
Negative Association ◽  
Vitamin D Metabolites ◽  
Vitamin D Binding Protein ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D

Abstract A negative association between blood lead level (BPbL) and vitamin D metabolites in occupationally exposed populations has been reported but data from the general population are scarce. Furthermore, the association between BPbL and vitamin D binding protein (DBP) and free 25-hydroxyvitamin D [25(OH)D] has not been reported. We investigated the association of BPbL with DBP, total and free 25(OH)D in healthy adolescents (N=1347; age range 11-16 years) cross-sectionally selected from all Governorates of Kuwait, utilizing multi-stage cluster random sampling. Pb in whole blood was analyzed by inductively coupled plasma mass spectrometry, and DBP with ELISA. Plasma 25(OH)D was analyzed by LC-MS/MS and free 25(OH)D was calculated utilizing the levels and binding affinities of DBP and albumin for 25(OH)D. DBP was positively associated with BPbL [β (95%CI)= 0.81 (0.14 −0.22); p< 0.001]. A negative association between BPbL and total 25(OH)D was non-significant (p=0.24) when BPbL was used as continuous variable but was significant when used as quartiles (p=0.02). The negative association between BPbL and free 25(OH)D was significant whether BPbL was used as continuous, as quartiles or as cut-off point of <5µg/dL. In multinomial logistic regression, the odds of vitamin D insufficiency and deficiency were more than two-fold higher in the upper quartiles of BPbL compared to the lowest quartile. The negative correlation of BPbL with free 25(OH)D was more robust than its correlation with total 25(OH)D. Future studies must consider the levels of DBP when assessing the association between Pb and vitamin D metabolites.

scholarly journals Vitamin D Binding Protein Is Not Involved in Vitamin D Deficiency in Patients with Chronic Kidney Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Marta Kalousova ◽  
Sylvie Dusilova-Sulkova ◽  
Oskar Zakiyanov ◽  
Milada Kostirova ◽  
Roman Safranek ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Kidney Disease ◽  
Vitamin D Deficiency ◽  
Binding Protein ◽  
Plasma Vitamin ◽  
Separate Determination ◽  
Vitamin D Binding Protein ◽  
Enhanced Production ◽  
Vitamin D Levels

Objective. This study was designed to evaluate vitamin D status with separate determination of 25-OH D2and 25-OH D3and its relationship to vitamin D binding protein (VDBP) in patients with chronic kidney disease (CKD) and long-term haemodialysis patients (HD).Methods. 45 CKD patients, 103 HD patients, and 25 controls (C) were included. Plasma vitamin D concentrations were determined using chromatography and VDBP in serum and urine in CKD using enzyme immunoassay.Results. Plasma vitamin D levels were lower in CKD (30.16 ± 16.74 ng/mL) and HD (18.85 ± 15.85 ng/mL) versus C (48.72 ± 18.35 ng/mL),P<0.0001. 25-OH D3was the dominant form of vitamin D. Serum VDBP was higher in CKD (273.2 ± 93.8 ug/mL) versus C (222 ± 87.6 ug/mL) and HD (213.8 ± 70.9 ug/mL),P=0.0003. Vitamin D/VDBP ratio was the highest in C and the lowest in HD; however, there was no correlation between vitamin D and VDBP. Urinary concentration of VDBP in CKD (0.25 ± 0.13 ug/mL) correlated with proteinuria(r=0.43,P=0.003).Conclusions. Plasma levels of vitamin D are decreased in CKD patients and especially in HD patients. 25-OH D3was the major form of vitamin D. Despite urinary losses of VDBP, CKD patients had higher serum VDBP concentrations, indicating compensatory enhanced production. Vitamin D binding protein is not involved in vitamin D deficiency.

scholarly journals Vitamin D Binding Protein Impact on 25-Hydroxyvitamin D Levels under Different Physiologic and Pathologic Conditions

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Pegah Yousefzadeh ◽  
Sue A. Shapses ◽  
Xiangbing Wang
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Race And Ethnicity ◽  
Binding Protein ◽  
Vitamin D Binding Protein ◽  
Total Vitamin ◽  
Hydroxyvitamin D ◽  
Vitamin D Levels ◽  
High Prevalence ◽  
25 Hydroxyvitamin D

There is a high prevalence of vitamin D deficiency worldwide, but how to define vitamin D deficiency is controversial. Currently, the plasma concentration of total 25-hydroxyvitamin D [25(OH)D] is considered an indicator of vitamin D status. The free hormone hypothesis states that protein-bound hormones are inactive while unbound hormones are free to exert biological activity. The majority of circulating 25(OH)D and 1,25(OH)2D is tightly bound to vitamin D binding protein (DBP), 10–15% is bound to albumin, and less than 1% of circulating vitamin D exists in an unbound form. While DBP is relatively stable in most healthy populations, a recent study showed that there are gene polymorphisms associated with race and ethnicity that could alter DBP levels and binding affinity. Furthermore, in some clinical situations, total vitamin D levels are altered and knowing whether DBP is also altered may have treatment implications. The aim of this review is to assess DBP concentration in different physiological and pathophysiological conditions. We suggest that DBP should be considered in the interpretation of 25(OH)D levels.

Calcium-Regulating Hormones and Minerals From Birth to 18 Months of Age: A Cross-Sectional Study. I. Effects of Sex, Race, Age, Season, and Diet on Vitamin D Status

PEDIATRICS ◽  
1986 ◽  
Vol 77 (6) ◽  
pp. 883-890
Author(s):  
P. Lichtenstein ◽  
B. L. Specker ◽  
R. C. Tsang ◽  
F. Mimouni ◽  
C. Gormley
Keyword(s):  
Vitamin D ◽  
Human Milk ◽  
Binding Protein ◽  
Vitamin D Metabolites ◽  
Vitamin D Status ◽  
Vitamin D Binding Protein ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D

The influence of sex, race, age, season, and diet (cow's milk formula v human milk) on the vitamin D and vitamin D-binding protein status in infants less than 18 months of age was investigated in this crosssectional, prospective study of 198 infants. No differences by sex were observed in serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, or vitamin D-binding protein concentrations. By race, black infants had significantly elevated serum 1,25-dihydroxyvitamin D levels relative to white infants. By age, vitamin D-binding protein concentrations increased with increasing age. By season, serum 25-hydroxyvitamin D concentrations were low in winter, whereas 1,25-dihydroxyvitamin D and vitamin D-binding protein were high in winter compared with summer. By diet, formula-fed infants had higher serum concentrations of all measured vitamin D metabolites and vitamin D-binding protein than human milk-fed infants. Thus, race, age, season, and diet exert, individually or in combination, different and significant effects on vitamin D metabolites; these should be considered in assessing infant vitamin D status.

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

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhila Maghbooli ◽  
Abolfazl Omidifar ◽  
Tarlan Varzandi ◽  
Tayebeh Salehnezhad ◽  
Mohammad Ali Sahraian
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Binding Protein ◽  
Serum Levels ◽  
Causative Role ◽  
Vitamin D Binding Protein ◽  
Control Groups ◽  
Current Case ◽  
Vitamin D Levels ◽  
And Control

Abstract Background In 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. Method The 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. Result The 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. Conclusion The 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.

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