ASSOCIATION OF VDBP RS4701 VARIANT, BUT NOT VDR/RXR-? OVER-EXPRESSION WITH BONE MINERAL DENSITY IN PEDIATRIC ?-THALASSEMIA PATIENTS Vitamin D metabolic axis and BMD in ?-thalassemia
Main Article Content
Keywords
Bone mineral density; Gene expression; Genotyping; Real-Time PCR; RXRA; Single nucleotide polymorphism; Thalassemia; VDBP; VDR
Abstract
Introduction: The reduced rate of bone formation despite the availability of vitamin D has been reported in ?-thalassemia. This suggests genetic factors together with environmental one can be implicated in this condition. Since vitamin D binding protein (VDBP) maintains bioavailability of vitamin D which binds to vitamin D receptor (VDR)-retinoid X receptor alpha (RXRA) heterodimer to exert its molecular actions, we speculated that vitamin D metabolic-axis expression signature and variants could be potential molecular candidates for bone turnover/disease in thalassemia. To this end, this study aims to analyze VDR/RXRA expression signature, and two VDBP variants in a pilot sample of Egyptian ?-thalassemia children in correlation with bone mineral density (BMD).
Patients and methods: Forty-four ?-thalassemia children and 40 unrelated controls were enrolled. The serum bone chemistry profile was measured. Peripheral blood mononuclear cells (PBMN) VDR/RXRA expression levels were quantified by Real-Time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). VDBP rs7041 and rs4588 variants were identified by Real-Time allelic discrimination assay. All patients were subjected to lumbar-spine Dual-energy X-ray absorptiometry (DEXA).
Results: VDR/RXRA expressions were significantly higher in ?-thalassemia children compared to controls (P = 0.001 and <0.001, respectively) and showed higher values in ?-thalassemia major relative to ?-thalassemia intermedia. Expression levels of both genes were not associated with sex or BMD. However, VDBP rs4701 genotyping revealed lower BMD-L4 and a higher frequency of osteoporosis.
Conclusions: ?-Thalassemia children had higher expression levels of PBMN VDR/RXRA. VDBP rs4701 variant was associated with osteoporosis in our ?-thalassemia patients on vitamin D supplementation. Further large-scale studies in other ethnic populations are warranted.
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15. 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. Epub 2006/05/16. doi: 10.1016/j.cca.2006.03.011. PubMed PMID: 16697362.
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17. Carpenter TO, Zhang JH, Parra E, Ellis BK, Simpson C, Lee WM, et al. Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers. J Bone Miner Res. 2013;28(1):213-21. Epub 2012/08/14. doi: 10.1002/jbmr.1735. PubMed PMID: 22887780; PubMed Central PMCID: PMCPMC3511814.
18. Fu L, Yun F, Oczak M, Wong BY, Vieth R, Cole DE. Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation. Clin Biochem. 2009;42(10-11):1174-7. Epub 2009/03/24. doi: 10.1016/j.clinbiochem.2009.03.008. PubMed PMID: 19302999.
19. Barsony J, Prufer K. Vitamin D receptor and retinoid X receptor interactions in motion. Vitam Horm. 2002;65:345-76. Epub 2002/12/17. doi: 10.1016/s0083-6729(02)65071-x. PubMed PMID: 12481554.
20. Huang P, Chandra V, Rastinejad F. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol. 2010;72:247-72. Epub 2010/02/13. doi: 10.1146/annurev-physiol-021909-135917. PubMed PMID: 20148675; PubMed Central PMCID: PMCPMC3677810.
21. Elhoseiny SM, Morgan DS, Rabie AM, Bishay ST. Vitamin D Receptor (VDR) Gene Polymorphisms (FokI, BsmI) and their Relation to Vitamin D Status in Pediatrics betaeta Thalassemia Major. Indian J Hematol Blood Transfus. 2016;32(2):228-38. Epub 2016/04/12. doi: 10.1007/s12288-015-0552-z. PubMed PMID: 27065588; PubMed Central PMCID: PMCPMC4789011.
22. Braegger C, Campoy C, Colomb V, Decsi T, Domellof M, Fewtrell M, et al. Vitamin D in the healthy European paediatric population. J Pediatr Gastroenterol Nutr. 2013;56(6):692-701. Epub 2013/05/28. doi: 10.1097/MPG.0b013e31828f3c05. PubMed PMID: 23708639.
23. Bianchi ML, Baim S, Bishop NJ, Gordon CM, Hans DB, Langman CB, et al. Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents. Pediatr Nephrol. 2010;25(1):37-47. Epub 2009/07/16. doi: 10.1007/s00467-009-1249-z. PubMed PMID: 19603190.
24. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8. Epub 2002/02/16. doi: 10.1006/meth.2001.1262. PubMed PMID: 11846609.
25. Toraih EA, Fawzy MS, Mohammed EA, Hussein MH, El-Labban MM. MicroRNA-196a2 Biomarker and Targetome Network Analysis in Solid Tumors. Mol Diagn Ther. 2016;20(6):559-77. Epub 2016/06/28. doi: 10.1007/s40291-016-0223-2. PubMed PMID: 27342110.
26. Hussein MH, Sobhy KE, Sabry IM, El Serafi AT, Toraih EA. Beta2-adrenergic receptor gene haplotypes and bronchodilator response in Egyptian patients with chronic obstructive pulmonary disease. Adv Med Sci. 2017;62(1):193-201. Epub 2017/03/23. doi: 10.1016/j.advms.2016.07.008. PubMed PMID: 28327457.
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