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VDBP, VDR Mutations and Other Factors Related With Vitamin D Metabolism May Be Associated With Type 1 Diabetes Mellitus
Corresponding Author(s) : Deniz Kirac
Cellular and Molecular Biology,
Vol. 64 No. 3: Issue 3
Abstract
Type 1 diabetes mellitus (T1DM) is an insulin dependent autoimmune disorder resulting the progressive destruction of pancreatic beta cells. Another possible factor considered to be related with T1DM is vitamin D deficiency. Therefore in this study it was aimed to investigate the associations between T1DM, vitamin D binding protein (VDBP) and vitamin D receptor (VDR) gene mutations which are related with vitamin D metabolism. Fifty five T1DM paitents and 40 healthy volunteers were recruited to the study. FokI (rs2228570), BsmI (rs1544410) mutations in VDR; rs4588 and rs7041 polymorphisms in VDBP were investigated with real-time polymerase chain reaction (RT-PCR). Other risk factors related with T1DM were also investigated. Results were evaluated statistically. Statistically significant relations were found in glucose, HbA1c, TSH, higher 25[OH]D, free vitamin D, calcium, albumin, log25[OH]D, retinopathy, higher than 30 mg/day microalbuminuria in T1DM patients. Also statistically significant association was found between C allele in Fok1 and T1DM in patients. When the relation between the risk factors and mutations were investigated, it was found that VDBP, free vitamin D and bioactive vitamin D were significantly associated with rs7041 mutation in VDBP whereas HDL was significantly associated with rs2228570 mutation in VDR. Other studies with larger data sets may demonstrate more reliable statistical results to rule out genotype–phenotype correlations of the disease.
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- Cheon CK, Nam HK, Lee KH, Kim SY, Song JS, Kim C. Vitamin D receptor gene polymorphisms and type 1 diabetes mellitus in a Korean population. Pediatr Int 2015;57(5):870-874.
- Miller KM, Hart PH, de Klerk NH, Davis EA, Lucas RM. Are low sun exposure and/or vitamin D risk factors for type 1 diabetes? Photochem Photobiol Sci 2017;16(3):381-398.
- Altieri B, Muscogiuri G, Barrea L, Mathieu C, Vallone CV, Mascitelli L, et al. Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept. Rev Endocr Metab Disord 2017.
- Grammatiki M, Rapti E, Karras S, Ajjan RA, Kotsa K. Vitamin D and diabetes mellitus: Causal or casual association? Rev Endocr Metab Disord 2017;18(2):227-241.
- Engelen L, Schalkwijk CG, Eussen SJ, Scheijen JL, Soedamah-Muthu SS, Chaturvedi N, et al. Low 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 levels are independently associated with macroalbuminuria, but not with retinopathy and macrovascular disease in type 1 diabetes: the EURODIAB prospective complications study. Cardiovasc Diabetol 2015;14:67.
- Griz LH, Bandeira F, Gabbay MA, Dib, SA, Carvalho EF. Vitamin D and diabetes mellitus: an update 2013. Arq Bras Endocrinol Metabol 2014;58(1):1-8.
- Muscogiuri G, Mitri J, Mathieu C, Badenhoop K, Tamer G, Orio F, et al. Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur J Endocrinol 2014;171(3):R101-110.
- Saccone D, Asani F, Bornman L. Regulation of the vitamin D receptor gene by environment, genetics and epigenetics. Gene 2015;561(2):171-180.
- Miettinen ME, Smart MC, Kinnunen L, Mathews C, Harjutsalo V, Surcel HM, et al. Maternal VDR variants rather than 25-hydroxyvitamin D concentration during early pregnancy are associated with type 1 diabetes in the offspring. Diabetologia 2015;58(10):2278-2283.
- Wang G, Zhang Q, Xu N, Xu K, Wang J, He W, et al. Associations between two polymorphisms (FokI and BsmI) of vitamin D receptor gene and type 1 diabetes mellitus in Asian population: a meta-analysis. PLoS One 2014;9(3):e89325.
- Mahon BD, Wittke A, Weaver V, Cantorna MT. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J Cell Biochem 2003;89(5):922-932.
- Sahin OA, Goksen D, Ozpinar A, Serdar M, Onay H. Association of vitamin D receptor polymorphisms and type 1 diabetes susceptibility in children: a meta-analysis. Endocr Connect 2017;6(3):159-171.
- Kamel MM, Fouad SA, Salaheldin O, El-Razek Ael R, El-Fatah AI. Impact of vitamin D receptor gene polymorphisms in pathogenesis of Type-1 diabetes mellitus. Int J Clin Exp Med 2014;7(12):5505-5510.
- Stakisaitis D, Lesauskaite V, Girdauskaite M, Janulionis E, Ulys A, Benetis R. Investigation of Vitamin D-Binding Protein Polymorphism Impact on Coronary Artery Disease and Relationship with Longevity: Own Data and a Review. Int J Endocrinol 2016;2016:8347379.
- Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, 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.
- Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinol Metab Clin North Am 2010;39(2):419-446, table of contents.
- Setty-Shah N, Maranda L, Nwosu BU. Increased risk for vitamin d deficiency in obese children with both celiac disease and type 1 diabetes. Gastroenterol Res Pract 2014;2014:561351.
- Abd-Allah SH, Pasha HF, Hagrass HA, Alghobashy AA. Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Egyptian children. Gene 2014;536(2):430-434.
- Reis JP, Michos ED, Selvin E, Pankow JS, Lutsey PL. Race, vitamin D-binding protein gene polymorphisms, 25-hydroxyvitamin D, and incident diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 2015;101(6):1232-1240.
- Blanton D, Han Z, Bierschenk L, Linga-Reddy MV, Wang H, Clare-Salzler, M, et al. Reduced serum vitamin D-binding protein levels are associated with type 1 diabetes. Diabetes 2011;60(10):2566-2570.
- Alam U, Amjad Y, Chan AW, Asghar O, Petropoulos IN, Malik RA. Vitamin D Deficiency Is Not Associated with Diabetic Retinopathy or Maculopathy. J Diabetes Res 2016;2016:6156217.
- Cagliero E, Levina EV, Nathan DM. Immediate feedback of HbA1c levels improves glycemic control in type 1 and insulin-treated type 2 diabetic patients. Diabetes Care 1999;22(11):1785-1789.
- Kesavadev J, Sadikot S, Wangnoo S, Kannampilly J, Saboo B, Aravind SR, et al. Consensus guidelines for glycemic monitoring in type 1/type 2 & GDM. Diabetes Metab Syndr 2014;8(3):187-195.
- Hafez M, Hassan M, Musa N, Abdel Atty S, Azim SA. Vitamin D status in Egyptian children with type 1 diabetes and the role of vitamin D replacement in glycemic control. J Pediatr Endocrinol Metab 2017;30(4):389-394.
- Taverna MJ, Selam JL, Slama G. Association between a protein polymorphism in the start codon of the vitamin D receptor gene and severe diabetic retinopathy in C-peptide-negative type 1 diabetes. J Clin Endocrinol Metab 2005;90(8):4803-4808.
- Joergensen C, Tarnow L, Goetze JP, Rossing P. Vitamin D analogue therapy, cardiovascular risk and kidney function in people with Type 1 diabetes mellitus and diabetic nephropathy: a randomized trial. Diabet Med 2015;32(3):374-381.
- Kaur H, Donaghue KC, Chan AK, Benitez-Aguirre P, Hing S, Lloyd M, et al. Vitamin D deficiency is associated with retinopathy in children and adolescents with type 1 diabetes. Diabetes Care 2011;34(6):1400-1402.
- Chun RF. New perspectives on the vitamin D binding protein. Cell Biochem Funct 2012;30(6):445-456.
- Jemielita TO, Leonard MB, Baker J, Sayed S, Zemel BS, Shults J, et al. Association of 25-hydroxyvitamin D with areal and volumetric measures of bone mineral density and parathyroid hormone: impact of vitamin D-binding protein and its assays. Osteoporos Int 2016;27(2):617-626.
- Perros P, McCrimmon RJ, Shaw G, Frier BM. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 1995;12(7):622-627.
- He L, Wang M. Association of vitamin d receptor-a gene polymorphisms with coronary heart disease in Han Chinese. Int J Clin Exp Med 2015;8(4):6224-6229.
References
Cheon CK, Nam HK, Lee KH, Kim SY, Song JS, Kim C. Vitamin D receptor gene polymorphisms and type 1 diabetes mellitus in a Korean population. Pediatr Int 2015;57(5):870-874.
Miller KM, Hart PH, de Klerk NH, Davis EA, Lucas RM. Are low sun exposure and/or vitamin D risk factors for type 1 diabetes? Photochem Photobiol Sci 2017;16(3):381-398.
Altieri B, Muscogiuri G, Barrea L, Mathieu C, Vallone CV, Mascitelli L, et al. Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept. Rev Endocr Metab Disord 2017.
Grammatiki M, Rapti E, Karras S, Ajjan RA, Kotsa K. Vitamin D and diabetes mellitus: Causal or casual association? Rev Endocr Metab Disord 2017;18(2):227-241.
Engelen L, Schalkwijk CG, Eussen SJ, Scheijen JL, Soedamah-Muthu SS, Chaturvedi N, et al. Low 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 levels are independently associated with macroalbuminuria, but not with retinopathy and macrovascular disease in type 1 diabetes: the EURODIAB prospective complications study. Cardiovasc Diabetol 2015;14:67.
Griz LH, Bandeira F, Gabbay MA, Dib, SA, Carvalho EF. Vitamin D and diabetes mellitus: an update 2013. Arq Bras Endocrinol Metabol 2014;58(1):1-8.
Muscogiuri G, Mitri J, Mathieu C, Badenhoop K, Tamer G, Orio F, et al. Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur J Endocrinol 2014;171(3):R101-110.
Saccone D, Asani F, Bornman L. Regulation of the vitamin D receptor gene by environment, genetics and epigenetics. Gene 2015;561(2):171-180.
Miettinen ME, Smart MC, Kinnunen L, Mathews C, Harjutsalo V, Surcel HM, et al. Maternal VDR variants rather than 25-hydroxyvitamin D concentration during early pregnancy are associated with type 1 diabetes in the offspring. Diabetologia 2015;58(10):2278-2283.
Wang G, Zhang Q, Xu N, Xu K, Wang J, He W, et al. Associations between two polymorphisms (FokI and BsmI) of vitamin D receptor gene and type 1 diabetes mellitus in Asian population: a meta-analysis. PLoS One 2014;9(3):e89325.
Mahon BD, Wittke A, Weaver V, Cantorna MT. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J Cell Biochem 2003;89(5):922-932.
Sahin OA, Goksen D, Ozpinar A, Serdar M, Onay H. Association of vitamin D receptor polymorphisms and type 1 diabetes susceptibility in children: a meta-analysis. Endocr Connect 2017;6(3):159-171.
Kamel MM, Fouad SA, Salaheldin O, El-Razek Ael R, El-Fatah AI. Impact of vitamin D receptor gene polymorphisms in pathogenesis of Type-1 diabetes mellitus. Int J Clin Exp Med 2014;7(12):5505-5510.
Stakisaitis D, Lesauskaite V, Girdauskaite M, Janulionis E, Ulys A, Benetis R. Investigation of Vitamin D-Binding Protein Polymorphism Impact on Coronary Artery Disease and Relationship with Longevity: Own Data and a Review. Int J Endocrinol 2016;2016:8347379.
Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, 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.
Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinol Metab Clin North Am 2010;39(2):419-446, table of contents.
Setty-Shah N, Maranda L, Nwosu BU. Increased risk for vitamin d deficiency in obese children with both celiac disease and type 1 diabetes. Gastroenterol Res Pract 2014;2014:561351.
Abd-Allah SH, Pasha HF, Hagrass HA, Alghobashy AA. Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Egyptian children. Gene 2014;536(2):430-434.
Reis JP, Michos ED, Selvin E, Pankow JS, Lutsey PL. Race, vitamin D-binding protein gene polymorphisms, 25-hydroxyvitamin D, and incident diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 2015;101(6):1232-1240.
Blanton D, Han Z, Bierschenk L, Linga-Reddy MV, Wang H, Clare-Salzler, M, et al. Reduced serum vitamin D-binding protein levels are associated with type 1 diabetes. Diabetes 2011;60(10):2566-2570.
Alam U, Amjad Y, Chan AW, Asghar O, Petropoulos IN, Malik RA. Vitamin D Deficiency Is Not Associated with Diabetic Retinopathy or Maculopathy. J Diabetes Res 2016;2016:6156217.
Cagliero E, Levina EV, Nathan DM. Immediate feedback of HbA1c levels improves glycemic control in type 1 and insulin-treated type 2 diabetic patients. Diabetes Care 1999;22(11):1785-1789.
Kesavadev J, Sadikot S, Wangnoo S, Kannampilly J, Saboo B, Aravind SR, et al. Consensus guidelines for glycemic monitoring in type 1/type 2 & GDM. Diabetes Metab Syndr 2014;8(3):187-195.
Hafez M, Hassan M, Musa N, Abdel Atty S, Azim SA. Vitamin D status in Egyptian children with type 1 diabetes and the role of vitamin D replacement in glycemic control. J Pediatr Endocrinol Metab 2017;30(4):389-394.
Taverna MJ, Selam JL, Slama G. Association between a protein polymorphism in the start codon of the vitamin D receptor gene and severe diabetic retinopathy in C-peptide-negative type 1 diabetes. J Clin Endocrinol Metab 2005;90(8):4803-4808.
Joergensen C, Tarnow L, Goetze JP, Rossing P. Vitamin D analogue therapy, cardiovascular risk and kidney function in people with Type 1 diabetes mellitus and diabetic nephropathy: a randomized trial. Diabet Med 2015;32(3):374-381.
Kaur H, Donaghue KC, Chan AK, Benitez-Aguirre P, Hing S, Lloyd M, et al. Vitamin D deficiency is associated with retinopathy in children and adolescents with type 1 diabetes. Diabetes Care 2011;34(6):1400-1402.
Chun RF. New perspectives on the vitamin D binding protein. Cell Biochem Funct 2012;30(6):445-456.
Jemielita TO, Leonard MB, Baker J, Sayed S, Zemel BS, Shults J, et al. Association of 25-hydroxyvitamin D with areal and volumetric measures of bone mineral density and parathyroid hormone: impact of vitamin D-binding protein and its assays. Osteoporos Int 2016;27(2):617-626.
Perros P, McCrimmon RJ, Shaw G, Frier BM. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 1995;12(7):622-627.
He L, Wang M. Association of vitamin d receptor-a gene polymorphisms with coronary heart disease in Han Chinese. Int J Clin Exp Med 2015;8(4):6224-6229.