Genetics and biology of vitamin D receptor polymorphisms

Abstract

The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently in the population, are referred to as "polymorphisms" and can have modest and subtle but true biological effects. Their abundance in the human genome as well as their high frequencies in the human population have made them targets to explain variation in risk of common diseases. Recent studies have indicated many polymorphisms to exist in the vitamin D receptor (VDR) gene, but the influence of VDR gene polymorphisms on VDR protein function and signaling is largely unknown. So far, three adjacent restriction fragment length polymorphisms for BsmI, ApaI, and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied. Because these polymorphisms are probably nonfunctional, linkage disequilibrium with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis and on trying to understand the functional consequences of the variations. Substantial progress has been made that will deepen our understanding of variability in the vitamin D endocrine system and might find applications in risk assessment of disease and in predicting response-to-treatment.

Immunomodulatory Effect of Vitamin D in Children with Allergic Diseases

“…It can also be found in other tissues (brain, placenta, and lungs); however, calbindin-D genes have not been shown to be regulated by 1,25-(OH) 2 D 3 [14], suggesting that the regulation of calbindin-D gene expression by 1,25-(OH) 2 D 3 involves tissue-specific factors.…”

“…In vitro experiments demonstrate that the induction of renal calbindin-D28k by 1,25-(OH) 2 D 3 is enhanced by high levels of extracellular calcium [12][13][14]. In vivo studies of the receptor-dependent actions of 1,25-(OH)2D3 on calbindin-D gene expression have been complicated by the inability to differentiate the effects of hormone deficiency from those of hypocalcemia.…”

“…Vitamin D response elements have been found in both the murine calbindin-D9k and calbindin-28k genes [12,14]; however, Chun Li et al demonstrated that the VDR dependence of calbindin-D28k gene expression varies among the tissues examined. Consistent with the observation that the kidney and lung express the VDR, calbindin-D28k mRNA levels in these tissues were induced in the control mice treated with 1,25…”

“…This is due to the influence of variations in the DNA sequence of important proteins of this system [14]. For example, different mutations in VDR gene may cause obesity, 1,25-dihydroxyresistant rickets, or cancer [14][15][16].…”

“…This is due to the influence of variations in the DNA sequence of important proteins of this system [14]. For example, different mutations in VDR gene may cause obesity, 1,25-dihydroxyresistant rickets, or cancer [14][15][16]. The interpretation of VDR polymorphic variations is quite difficult, because the VDR gene is a large one, and the most of these are anonymous restriction fragment length polymorphisms (RLFP) that have unknown functional effect.…”