VDR Gene Polymorphisms are Overrepresented in German Patients with Type 1 Diabetes Compared to Healthy Controls without Effect on Biochemical Parameters of Bone Metabolism

Abstract

Type 1 diabetic individuals are known to develop disorders of bone metabolism resulting in osteopenia. Previous studies have suggested an influence of vitamin D receptor alleles on bone metabolism and susceptibility for type 1 diabetes mellitus. The present study was initiated to investigate the distribution of vitamin D receptor alleles in Caucasian type 1 diabetic patients and their relation to bone turnover parameters.

75 patients were included and compared to 57 healthy controls. Three vitamin D receptor alleles were examined (BsmI, TaqI and FokI); serum levels of intact osteocalcin, parathyroid hormone, bone specific alkaline phosphatase, the carboxy terminal extension peptide of type I procollagen, 25-OH-vitamin D levels, HbA1c and urinary deoxypyridinoline excretion were measured.

We observed a higher frequency of the TT genotype in diabetic patients, but no difference in markers of bone turnover between diabetics and non-diabetics in either sex. Bone turnover was different in men and in women without any association with vitamin D receptor genotype. No association was found between diabetes duration, age of onset or metabolic control and bone turnover parameters.

In summary, our results show an association between the TT genotype and diabetes in Germans, but no difference in bone turnover markers between diabetics and non-diabetics.

Key words

Bone Metabolism - Genetics - Osteopenia - Hormone Receptor - Autoimmune

References

• 1 Lampeter E F, Signore A, Gale E A, Pozzilli P. Lessons from the NOD mouse for the pathogenesis and immunotherapy of human type 1 (insulin-dependent) diabetes mellitus.  Diabetologia. 1989;  32 703-708
• 2 Gamble D R. The epidemiology of insulin dependent diabetes, with particular reference to the relationship of virus infection to its aetiology.  Epidemiol Rev. 1980;  2 49-70
• 3 Christau B, Kromann H, Andersen O O. et al . Incidence, seasonal and geographical patterns of juvenile-onset insulin-dependent diabetes mellitus in Denmark.  Diabetologia. 1977;  13 281-284
• 4 Hitman G A, Tarn A C, Winter R M. et al . Type 1 (insulin dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11.  Diabetologia. 1985;  28 218-222
• 5 Bell G I, Horta S, Karam J H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus.  Diabetes. 1984;  33 176-183
• 6 Cordell H J, Todd J A. Multifactorial inheritance in type 1 diabetes.  Trends Genet. 1995;  11 499-503
• 7 McDermott M F, Ramachandran A, Ogunkolade B W. et al . Allelic variation in the vitamin D receptor influences susceptibility of IDDM in Indian Asians.  Diabetologia. 1997;  40 971-975
• 8 Chang T J, Lei H H, Yeh J I. et al . Vitamin receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population.  Clinical Endocrinology. 2000;  52 575-580
• 9 Mathieu C, Laureys J, Sobis H, Vandeputte M, Waer M, Bouillon R. 1,25-dihydroxyvitamin D3 prevents insulitis in NOD mice.  Diabetes. 1992;  41 1491-1495
• 10 The EURODIAB Substudy 2 Study Group .Vitamin D supplement in early childhood and risk for type I (insulin-dependent) diabetes mellitus. Diabetologia 1999 42: 51-54
• 11 Kayath M J, Dib S A, Vieira J GH. Prevalence and magnitude of osteopenia associated with insulin-dependent diabetes mellitus.  J Diabetes Complications. 1994;  8 97-104
• 12 Kelly P J, Hopper J L, Macaskill G T. et al . Genetic factors in bone turnover.  J Clin Endocrinol Metab. 1991;  72 808-813
• 13 Issa L L, Leong G M, Eisman J A. Molecular mechanism of vitamin D receptor action.  Inflamm Res. 1998;  47 451-475
• 14 Morrison N A, Qi J C, Tokita A. et al . Prediction of bone density from vitamin D receptor alleles.  Nature (London). 1994;  367 284-287
• 15 Hauache O M, Lazaretti-Castro M, Andreoni S. et al . Vitamin D receptor gene polymorphism: Correlation with bone mineral density in a Brazilian population with insulin-dependent diabetes mellitus.  Osteoporos Int. 1998;  8 204-210
• 16 Alberti K GMM, Zimmet P Z. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Part 1: Diagnosis and Classification of Diabetes Mellitus. Provisional Report of a WHO Consultation.  Diabet Med. 1998;  15 539-553
• 17 Garnero P, Delmas P D. Assessment of the serum levels of bone alkaline phosphatase with a new immunoradiometric assay in patients with metabolic bone disease.  J Clin Endocrinol Metab. 1993;  77 1046-1053
• 18 Garnero P, Grimaux M, Seguin P, Delmas P D. Characterisation of immunoreactive forms of human osteocalcin generated in vivo and in vitro.  J Bone Miner Res. 1994;  9 255-264
• 19 Melkko J, Niemi S, Risteli L. et al . Radioimmunoassay of the carboxy terminal propeptide of human type I procollagen.  Clin Chem. 1990;  36 1328-1332
• 20 Haddad J G, Chyu K J. Competitive protein-binding radioimmunoassay for 25-hydroxycholecalciferol.  J Clin Endocrinol Metab. 1971;  33 992-995
• 21 Kao P C, Jiang N-S, Klee G G. et al . Development and validation of a New Radioimmunoassay for Parathyrin (PTH).  Clin Chem. 1982;  28 69-74
• 22 Seibel M J, Cosman V, Shen V, Ratcliffe A, Lindsay R. Urinary hydroxy-pyridinium crosslinks of collagen as markers of bone resorption and estrogen efficacy in postmenopausal osteoporosis.  J Bone Min Res. 1993;  8 881-889
• 23 Carling T, Ridefelt P, Hellmann P, Rastadt J, Akerström G. Vitamin D Receptor Polymorphism Correlate to Parathyroid Cell Function in Primary Hyperparathyroidism.  J Clin Endocrinol Metab. 1997;  82 1772-1775
• 24 Gross C, Krishnan A V, Malloy P J, Eccleshall T R, Zhao X Y, Feldman D. The Vitamin D Receptor Gene Start Codon Polymorphism: A Functional Analysis of FokI Variants.  J Bone Miner Res. 1998;  13 1691-1699
• 25 Müller K, Brendtzen K. Inhibition of Human T Lymphocyte Proliferation and Cytokine Production by 1,25 Dihydroxyvitamin D₃. Differential effects on CD45RA+ and CD45RO+ cells.  Autoimmunity. 1992;  14 37-43
• 26 Chofflon M, Gonzalez V, Weiner H L, Hafler D A. Inflammatory cerebrospinal fluid T cells have activation requirements characteristic of CD4+CD45RA^- T cells.  Eur J Immunol. 1989;  19 1791-1795
• 27 Cippiteli M, Santoni A. Vitamin D3: a transcriptional modulator of the interferon-gamma gene.  Eur J immunol. 1998;  28 3017-3030
• 28 Tsoukas C D, Provvedini D M, Manolagas S C. 1,25-Dihydroxyvitamin D3: A Novel Immunomodulatory Hormone.  Science. 1984;  224 1438-1440
• 29 Reichel H, Koepffler H P, Tobler A, Norman A. 1α,25-Dihydroxyvitamin D₃ inhibits γ-interferon synthesis by normal human peripheral blood lymphocytes.  Proc Natl Acad Sci USA. 1987;  84 3385-3389
• 30 D’Ambrosio D, Cippitelli M, Cocciolo M G. et al . Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3.  J Clin Invest. 1998;  101 252-262
• 31 Nashold F E, Miller D J, Hayes C E. 1,25-dihydroxyvitamin D3 treatment decreases macrophage accumulation in the CNS of mice with experimental autoimmune encephalomyelitis.  J Neuroimmunol. 2000;  103 171-179
• 32 Fournier C, Gepner P, Sadouk M, Charreire J. In vivo beneficial effects of cyclosporine A and 1,25-dihydroxyvitamin D3 on the induction of experimental autoimmune thyreoiditis.  Clin Immunol Immunopathol. 1990;  54 53-63
• 33 Lemire J M, Ince A, Takashima M. 1,25 Dihydroxyvitamin D₃ attenuates the expression of experimental murine lupus of MRL/I mice.  Autoimmunity. 1992;  12 143-148
• 34 Lemire J M, Archer D. 1,25 Dihydroxyvitamin D₃ prevents the In vivo induction of mourn experimental autoimmune encephalomyelitis.  J Clin Invest. 1991;  87 1103-1107
• 35 Fukazawa T, Yabe I, Kikuchi S, Sasaki H, Hamada T, Miyasaka K, Tashiro K. Association of vitamin D receptor gene polymorphism with multiple sclerosis in Japanese.  J Neurol Sci. 1999;  166 47-52
• 36 Ingles S A, Haile R W, Henderson B E. et al . Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications or association studies.  Cancer Epidemiol Biomarkers Prev. 1997;  6 93-98
• 37 Beelman C A, Parker R. Degradation of mRNA in Eukaryotes.  Cell. 1995;  81 179-183
• 38 Verbeek W, Gombart A F, Shiohara M, Campbell M, Koeffles H P. Vitamin D receptor: no evidence for allele-specific mRNA stability in cells which are heterozygous for the TaqI restriction enzyme polymorphism.  Biochem Biophys Res Commun. 1997;  238 77-80
• 39 Durrin L K, Haile R W, Ingles S A, Coetzee G A. Vitamin D receptor 3’-untranslated region polymorphisms: lack of effect on RNA stability.  Biochim Biophys Acta. 1999;  1453 311-320
• 40 Pani M A, Knapp M, Donner H. et al . Vitamin D Receptor Allele Combinations Influence Genetic Susceptibility to type 1 Diabetes in Germans.  Diabetes. 2000;  49 504-507
• 41 Serjeantson S, Ranford P, Kirk R L. et al . HLA-DR and -DQ DNA genotyping in insulin-dependent diabetes patients in South India.  Dis Markers. 1987;  5 101-108
• 42 Gross C, Eccleshall T R, Malloy P J, Villa M L, Marcus R, Feldman D. The presence of a polymorphism in the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women.  J Bone Miner Res. 1996;  11 1850-1855
• 43 Arai H, Miyamoto H I, Taketani Y. A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women.  J Bone Miner Res. 1997;  12 915-921
• 44 Jurutka P W, Remus L S, Whitfield G K. et al . The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB.  Mol Endocrinol. 2000;  14 401-420
• 45 Yamagata M, Nakajima S, Tokita A. et al . Analysis of the stable levels of messenger mRNA derived from different polymorphic alleles in the vitamin D receptor gene.  J Bone Miner Metab. 1999;  17 164-170
• 46 Bouillon R, Bex M, van Herck E, Laureys J, Doom L, Lesaffre E, Ravussin E. Influence of age, sex and insulin on osteoblast function: osteoblast dysfunction in diabetes mellitus.  J Clin Endocrinol Metab. 1995;  80 1194-1202
• 47 Patel S R, Xu Y, Koenig R J. et al . Effect of glucose on the function of the calcitriol receptor and vitamin D metabolism.  Kidney Inter. 1997;  52 79-86
• 48 Inaba M, Terada M, Koyama H. et al . Influence of high glucose on 1,25-Dihydroxyvitamin D₃-induced effect on human osteoblast-like MG-63 cells.  J Bone Miner Res. 1995;  10 1050-1056
• 49 Pedrazzoni M, Ciotti G, Piolo G. et al . Osteocalcin levels in diabetic subjects.  Calcif Tissue Int. 1989;  45 331-336
• 50 Rico H, Hernandez E R, Cabranes J A. et al . Suggestion of a deficient osteoblastic function in diabetes mellitus: The possible cause of osteopenia in diabetics.  Calcif Tissue Int. 1989;  45 71-73
• 51 Pietschmann P, Schernthaner G, Woloszuk W. Serum osteocalcin levels in diabetes mellitus: analysis of the type diabetes and microvascular complications.  Diabetologia. 1988;  31 892-895
• 52 Burkhardt R, Moser W, Bartl R. et al . Is diabetic osteoporosis due to microangiopathy?.  Lancet. 1981;  1 844
• 53 Takeshita N, Yoshino T, Mutoh S. Possible involvement of corticosterone in bone loss of genetically diabetic db/db mice.  Horm Metab Res. 2000;  32 147-151
• 54 Fassbender W J, Steinhauer B, Stracke H, Schumm-Draeger P-M, Usadel K-H. Validation of a new automated immunoassay for measurement of intact osteocalcin. Clin Lab 2002 in press
• 55 Kemink S A, Hermus A R, Swinkels L M, Luttermann J A, Smals A G. Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology.  J Endocrinol Invest. 2000;  23 295-303
• 56 Inukai T, Fujiwara Y, Tayama K, Aso Y, Takemura Y. Alterations in serum levels of 1 alpha, 25(OH)2 D3 and osteocalcin in patients with early diabetic nephropathy.  Diabetes Res Clin Pract. 1997;  38 53-59
• 57 Miazgowski T, Czekalski S. A 2-year follow-up study on bone mineral density and markers of bone turnover in patients with long-standing insulin-dependent diabetes mellitus.  Osteoporos Int. 1998;  8 399-403
• 58 Henry Y. Ethnic and gender differences in bone mineral density and bone turnover in young adults: effect of size.  Osteoporosis Int. 2000;  11 512-517
• 59 Dahl E, Nordal K O, Halse J, Attramadal A. Histomorphometric analysis of normal bone from the iliac crest of Norwegian subjects.  Bone and Mineral. 1988;  3 369-377
• 60 Dawson-Hughes B, Harris S S, Finneran S. Calcium absorption on high and low calcium intakes in relation to vitamin D receptor genotype.  J Bone Miner Res. 1995;  10 S162
• 61 Fleet J C, Harris S S, Wood R J, Dawson-Hughes B. The BsmI vitamin D receptor restriction fragment length polymorphism (BB) predicts low bone density in premenopausal black and white women.  J Bone Miner Res. 1995;  10 985-990
• 62 Tokita A, Matsumoto H, Morrison N A. et al . Vitamin D receptor alleles, bone mineral density and turnover in premenopausal Japanese women.  J Bone Miner Res. 1996;  11 1003-1009
• 63 Krall E A, Parry P, Lichter J B. et al . Vitamin D receptor alleles and rates of bone loss: Influences of years since menopause and calcium intake.  J Bone Miner Res. 1995;  10 978-984
• 64 Houston L A, Grant S F, Reid D M, Ralston S H. Vitamin D receptor polymorphism, bone mineral density, and osteoporotic vertebral fracture. Studies in a UK population.  Bone. 1995;  18 249-252
• 65 Uitterlinden A G, Pols H A, Burger H. et al . A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density.  J Bone Miner Res. 1996;  11 1241-1248
• 66 Looney J E, Yoon H K, Fischer M. et al . Lack of prevalence of the BB vitamin D receptor genotype in severely osteoporotic women.  J Clin Endocrinol Metab. 1995;  80 2158-2162
• 67 Garnero P, Borel O, Sornay-Rendu E, Arlot M E, Delmas P D. Vitamin D Receptor Gene Polymorphisms Are Not Related to Bone Turnover, Rate of Bone Loss, and Bone Mass in Postmenopausal Women: The OFELY Study.  J Bone Miner Res. 1996;  11 827-834
• 68 Morrison N A, Yeoman R, Kelly P J, Eisman J A. Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin.  Proc Natl Acad Sci USA. 1992;  89 6665-6669