T1 Diabetes 6.5 X more likely in South African Blacks if poor Vitamin D Binding Protein – July 2022

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

BMC Endocr Disord. 2022 Jul 17;22(1):182. doi: 10.1186/s12902-022-01097-1.
Eleanor M Cave 1, Sureka Bhola 1 2, Nigel J Crowther 1 2, Carolyn J Padoa 3 4

Background: Vitamin 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.

Methods: Participants 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.

Results: There 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).

Conclusions: These 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.
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References

(DOI is hyperlinked on-line)

1. Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child. 2008;93(6):512–7. - DOI
2. Bikle DD, Siiteri PK, Ryzen E, Haddad JG. Serum protein binding of 1,25-dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels. J Clin Endocrinol Metab. 1985;61(5):969–75. - DOI
3. Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG. Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol Metab. 1986;63(4):954–9. - DOI
4. Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell. 1999;96(4):507–515.
5. Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, et al. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci U S A. 2001;98(24):13895–900. - DOI
6. Cooke NE, Willard HF, David EV, George DL. Direct regional assignment of the gene for vitamin D binding protein (Gc-globulin) to human chromosome 4q11-q13 and identification of an associated DNA polymorphism. Hum Genet. 1986;73(3):225–9. - DOI
7. Cleve H, Constans J. The mutants of the vitamin-D-binding protein: more than 120 variants of the GC/DBP system. Vox Sang. 1988;54(4):215–25. - DOI
8. Speeckaert M, Huang G, Delanghe JR, Taes YE. Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin Chim Acta. 2006;372(1–2):33–42. - DOI
9. Braun A, Bichlmaier R, Cleve H. Molecular analysis of the gene for the human vitamin-D-binding protein (group-specific component): allelic differences of the common genetic GC types. Hum Genet 1992, 89(4):401–406. - DOI
10. Constans J, Viau M. Group-specific component: evidence for two subtypes of the Gc1 gene. Science 1977, 198(4321):1070–1071. - DOI
11. Braithwaite VS, Jones KS, Schoenmakers I, Silver M, Prentice A, Hennig BJ. Vitamin D binding protein genotype is associated with plasma 25OHD concentration in West African children. Bone 2015, 74:166–170. - DOI
12. Sinotte M, Diorio C, Berube S, Pollak M, Brisson J. Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women. Am J Clin Nutr 2009, 89(2):634–640. - DOI
13. Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum Genet 1993, 92(2):183–188. - DOI
14. Rowling MJ, Kemmis CM, Taffany DA, Welsh J. Megalin-mediated endocytosis of vitamin D binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. J Nutr 2006, 136(11):2754–2759. - DOI
15. Kamboh MI, Ferrell RE. Ethnic variation in vitamin D-binding protein (GC): a review of isoelectric focusing studies in human populations. Hum Genet 1986, 72(4):281–293. - DOI
16. Lauridsen AL, Vestergaard P, Hermann AP, Brot C, Heickendorff L, Mosekilde L, Nexo E. Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women. Calcif Tissue Int 2005, 77(1):15–22. - DOI
17. Ongagna JC, Pinget M, Belcourt A. Vitamin D-binding protein gene polymorphism association with IA-2 autoantibodies in type 1 diabetes. Clin Biochem 2005, 38(5):415–419. - DOI
18. Ongagna JC, Kaltenbacher MC, Sapin R, Pinget M, Belcourt A. The HLA-DQB alleles and amino acid variants of the vitamin D-binding protein in diabetic patients in Alsace. Clin Biochem 2001, 34(1):59–63. - DOI
19. Blanton D, Han Z, Bierschenk L, Linga-Reddy MV, Wang H, Clare-Salzler M, Haller M, Schatz D, Myhr C, She JX et al. Reduced serum vitamin D-binding protein levels are associated with type 1 diabetes. Diabetes 2011, 60(10):2566–2570. - DOI
20. Mahmoud M, Ibrahim GH, Fawzy MS, Atwa H. Lack of association of Vitamin D Binding Protein Polymorphisms in Egyptian Children with Type 1 Diabetes. Turkish Journal of Endocrinology and Metabolism 2011, 15(4):111–115.
21. Kirac D, Dincer Yazan C, Gezmis H, Yaman A, Haklar G, Sirikci O, Altunok EC, Deyneli O. VDBP, VDR Mutations and Other Factors Related With Vitamin D Metabolism May Be Associated With Type 1 Diabetes Mellitus. Cell Mol Biol (Noisy-le-grand) 2018;64(3):11–16.
22. Winters SJ, Chennubhatla R, Wang C, Miller JJ. Influence of obesity on vitamin D-binding protein and 25-hydroxy vitamin D levels in African American and white women. Metabolism 2009, 58(4):438–442. - DOI
23. Setayesh L, Casazza K, Moradi N, Mehranfar S, Yarizadeh H, Amini A, Yekaninejad MS, Mirzaei K. Association of vitamin D-binding protein and vitamin D3 with insulin and homeostatic model assessment (HOMA-IR) in overweight and obese females. BMC Res Notes 2021, 14(1):193. - DOI
24. Cooper JD, Smyth DJ, Walker NM, Stevens H, Burren OS, Wallace C, Greissl C, Ramos-Lopez E, Hypponen E, Dunger DB et al. Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 2011, 60(5):1624–1631. - DOI
25. Klupa T, Malecki M, Hanna L, Sieradzka J, Frey J, Warram JH, Sieradzki J, Krolewski AS. Amino acid variants of the vitamin D-binding protein and risk of diabetes in white Americans of European origin. Eur J Endocrinol 1999, 141(5):490–493. - DOI
26. Carpenter TO, Zhang JH, Parra E, Ellis BK, Simpson C, Lee WM, Balko J, Fu L, Wong BY, Cole DE. Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers. J Bone Miner Res 2013, 28(1):213–221. - DOI
27. Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, Tamez H, Zhang D, Bhan I, Karumanchi SA et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013, 369(21):1991–2000. - DOI
28. Rivera-Paredez B, Hidalgo-Bravo A, León-Reyes G, Antuna-Puente B, Flores YN, Salmerón J, Velázquez-Cruz R. Association of GC Variants with Bone Mineral Density and Serum VDBP Concentrations in Mexican Population. 2021;12(8):1176.
29. Kim HY, Lee YA, Jung HW, Gu MJ, Kim JY, Lee GM, Lee J, Yoon JY, Yang SW, Shin CH. A lack of association between vitamin D-binding protein and 25-hydroxyvitamin D concentrations in pediatric type 1 diabetes without microalbuminuria. Ann Pediatr Endocrinol Metab 2017, 22(4):247–252. - DOI
30. Thrailkill KM, Jo CH, Cockrell GE, Moreau CS, Fowlkes JL. Enhanced excretion of vitamin D binding protein in type 1 diabetes: a role in vitamin D deficiency? J Clin Endocrinol Metab 2011, 96(1):142–149. - DOI
31. Binder R, Kress A, Kan G, Herrmann K, Kirschfink M. Neutrophil priming by cytokines and vitamin D binding protein (Gc-globulin): impact on C5a-mediated chemotaxis, degranulation and respiratory burst. Mol Immunol 1999, 36(13–14):885–892. - DOI
32. Yamamoto N, Homma S. Vitamin D3 binding protein (group-specific component) is a precursor for the macrophage-activating signal factor from lysophosphatidylcholine-treated lymphocytes. Proc Natl Acad Sci U S A 1991, 88(19):8539–8543. - DOI
33. Vecchio F, Lo Buono N, Stabilini A, Nigi L, Dufort MJ, Geyer S, Rancoita PM, Cugnata F, Mandelli A, Valle A, et al. Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes. JCI Insight. 2018;3(18):e122146. https://doi.org/10.1172/jci.insight.122146 .
34. Wan J, Ren Y, Yang X, Li X, Xia L, Lu N. The Role of Neutrophils and Neutrophil Extracellular Traps in Acute Pancreatitis. Front Cell Dev Biol 2020, 8:565758. - DOI
35. Kongsbak M, Levring T, Geisler C, von Essen M: The Vitamin D Receptor and T Cell Function. 2013;4(148). https://doi.org/10.3389/fimmu.2013.00148 .
36. Larcombe L, Mookherjee N, Slater J, Slivinski C, Singer M, Whaley C, Denechezhe L, Matyas S, Turner-Brannen E, Nickerson P et al. Vitamin D in a northern Canadian first nation population: dietary intake, serum concentrations and functional gene polymorphisms. PLoS One 2012, 7(11):e49872. - DOI
37. Bouillon R, van Baelen H, de Moor P. The measurement of the vitamin D-binding protein in human serum. J Clin Endocrinol Metab 1977, 45(2):225–231. - DOI
38. George JA, Norris SA, van Deventer HE, Pettifor JM, Crowther NJ. Effect of adiposity, season, diet and calcium or vitamin D supplementation on the vitamin D status of healthy urban African and Asian-Indian adults. Br J Nutr 2014, 112(4):590–599. - DOI
39. Pop LC, Shapses SA, Chang B, Sun W, Wang X. Vitamin D-Binding Protein in Healthy Pre- and Postmenopausal Women: Relationship with Estradiol Concentrations. Endocr Pract 2015, 21(8):936–942. - DOI
40. Alexandraki KI, Piperi C, Ziakas PD, Apostolopoulos NV, Makrilakis K, Syriou V, Diamanti-Kandarakis E, Kaltsas G, Kalofoutis A. Cytokine secretion in long-standing diabetes mellitus type 1 and 2: associations with low-grade systemic inflammation. J Clin Immunol 2008, 28(4):314–321. - DOI
41. Guha C, Osawa M, Werner PA, Galbraith RM, Paddock GV. Regulation of human Gc (vitamin D–binding) protein levels: hormonal and cytokine control of gene expression in vitro. Hepatology 1995, 21(6):1675–1681. - PubMed
42. Wegner M, Araszkiewicz A, Piorunska-Stolzmann M, Wierusz-Wysocka B, Zozulinska-Ziolkiewicz D: Association between IL-6 concentration and diabetes-related variables in DM1 patients with and without microvascular complications. Inflammation 2013, 36(3):723–728. - DOI
43. Schram MT, Chaturvedi N, Schalkwijk CG, Fuller JH, Stehouwer CD, Group EPCS. Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes–the EURODIAB Prospective Complications Study. Diabetologia 2005, 48(2):370–378. - DOI
44. Purohit S, Sharma A, Zhi W, Bai S, Hopkins D, Steed L, Bode B, Anderson SW, Reed JC, Steed RD et al. Proteins of TNF-alpha and IL6 Pathways Are Elevated in Serum of Type-1 Diabetes Patients with Microalbuminuria. Front Immunol 2018, 9:154. - DOI

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VitaminDWiki - Vitamin D Binding Protein category listing has 178 items and contains

Vitamin D Binding Protein (GC) gene can decrease the bio-available Vitamin D that can get to cells,

• GC is not the only such gene - there are 3 others, all invisible to standard Vitamin D tests
• The bio-available calculation does not notice the effect of GC, CYP27B1, CYP24A1, and VDR
• The actual D getting to the cells is a function of measured D and all 4 genes
• There is >2X increase in 8+ health problems if have poor VDBP (GC)
• It appears that VDBP only blocks oral vitamin D,
  • but NOT Vitamin D from sun, UV, topical or inhaled (tissue activated)
  • A clue: - Vitamin D from UV is 2X better for MS than oral Vitamin D

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VitaminDWiki - Vitamin D Binding Protein has a list of health problems

Increased Risk	Health Problem
11 X	Preeclampsia
6.5X	T1D in SA Blacks
6 X	Food Allergy
5 X	PTSD
4 X, 5X	Kidney Cancer
4 X	Poor Response to Oral Vitamin D
3 X	Ear infection
2.8 X	MS
2.5 X	Severe Autism
2 X	Colorectal Cancer
2 X	Prostate Cancer -in those with dark skins
1.3 X	Infertility

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VitaminDWiki - 5 studies in both categories VDBP and Diabetes (both kinds)

This list is automatically updated

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VitaminDWiki - 24 studies in both categories Skin-Dark and Diabetes (both kinds)

This list is automatically updated