Elsevier

Gene

Volume 338, Issue 2, 1 September 2004, Pages 143-156
Gene

Review
Genetics and biology of vitamin D receptor polymorphisms

https://doi.org/10.1016/j.gene.2004.05.014Get rights and content

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.

Introduction

The secosteroid hormone vitamin D, its receptor (VDR), and the metabolizing enzymes involved in the formation of the biologically active form of the hormone together are major players in the vitamin D endocrine system. This system plays an important role in skeletal metabolism, including intestinal calcium absorption, but has also been shown to play an important role in other metabolic pathways, such as those involved in the immune response and cancer (Haussler et al., 1998). In the immune system, for example, vitamin D promotes monocyte differentiation and inhibits lymphocyte proliferation and secretion of cytokines, such as interleukin 2 (IL2), interferon-γ, and IL12. In several different types of cancer cells, vitamin D has been shown to have antiproliferative effects.

At the same time, it is also widely known that large interindividual differences exist. One approach to understand interindividual differences in the vitamin D endocrine system is to study the influence of variations in the DNA sequence of important proteins of this system. For example, deleterious mutations in the VDR gene cause 1,25-dihydroxyvitamin D resistant rickets, a rare monogenetic disease. More subtle sequence variations (polymorphisms) in the VDR gene occur much more frequently in the population, but they have not been systematically analysed and their effects on VDR function are poorly understood. Their influence on the vitamin D endocrine system is currently under scrutiny in relation to a number of so-called complex diseases and traits, such as osteoporosis. This so-called candidate gene approach in the genetic dissection of complex traits is currently gaining increased importance over genome search approaches using linkage analysis (Risch and Merikangas, 1996).

The interpretation of polymorphic variations in the VDR gene is severely hindered by the fact that until now, only few polymorphisms in this large gene have been studied, and that most of these are anonymous restriction fragment length polymorphisms (RFLP), i.e., have an unknown functional effect. One expects them to be linked to truly functional polymorphisms elsewhere in the VDR gene [or in nearby gene(s)] which can then explain the associations observed. Thus, to understand the mechanisms underlying the associations, one has to analyse the genomic organization of the VDR locus, to identify which genes are present in the chromosomal area, to categorize all relevant VDR polymorphisms, to determine the haplotypes across the gene, to determine their relationship with the RFLP markers used so far, and—finally—to perform association analyses with relevant phenotypic endpoints such as disease.

Below we present a more detailed description of the genomic organization of the VDR gene including discussion on polymorphisms, linkage disequilibrium, and haplotypes. Historically speaking, studies of VDR polymorphisms in relation to bone endpoints, including osteoporosis in particular, have received most attention, while the analysis of VDR polymorphisms in relation to other diseases, including breast and prostate cancer and immune-related disorders, has reached the literature somewhat later on. This allows studies on associations with bone endpoints to be compared to a certain extent and to illustrate some of the difficulties in interpreting the results. This is much less possible for VDR polymorphism studies in relation to other disease endpoints, although similar interpretation problems exist. Essentially, these interpretation problems find their origin in the lack of knowledge on which polymorphisms are present in the VDR gene area and not knowing what the functional relevance is of these polymorphisms. Therefore, most attention in this review will be focussed on these aspects rather than providing an exhaustive review on which studies have found their way to the literature on VDR polymorphisms and association with one or other disease endpoint.

Section snippets

Genomic structure of the 12q13 locus

After cloning the human VDR cDNA in 1988 by Baker et al. (1988), it took almost 10 years before major parts of the genomic structure of the human VDR gene became clear as described by Miyamoto et al. (1997). All of this happened of course before the Human Genome Project became to bear fruit in the form of easily accessible databases where genomic sequences can be found. Yet, these databases are still not complete and for particular genes, efforts have to be made to determine their genomic

VDR polymorphisms

Information on the existence of VDR polymorphisms so far has come from analysis of only limited areas in the gene and by using rather insensitive techniques to find polymorphisms, such as screening with different restriction enzymes for polymorphic banding patterns in Southern blot hybridization experiments. Examples of this include the ApaI- (Faraco et al., 1989), EcoRV- (Morrison et al., 1992), BsmI- (Morrison et al., 1992), TaqI- (Morrison et al., 1994), and Tru9I- (Ye et al., 2000)

Linkage disequilibrium and haplotypes

Linkage disequilibrium (LD) measures describe the association (or co-occurrence) of alleles of adjacent polymorphisms with each other (Wall and Pritchard, 2003). This means, in practice, that one polymorphism can predict the other adjacent “linked” one because very little recombination has occurred between them over the time of evolution and population history. High levels of LD in a certain area will coincide with a limited number of “haplotypes” in that area. Haplotypes are blocks of linked

Ethnic variation in polymorphisms

VDR polymorphisms have been identified and analysed so far mostly in Caucasians and, to a lesser extent, in other ethnic groups. For example, the Cdx2 polymorphism was discovered in Japanese (Arai et al., 2001) and has only recently been analysed in Caucasians (Fang et al., 2003). For the most widely studied VDR polymorphisms, sometimes substantial differences have been noted between races and/or ethnic groups (see Table 1 and Zmuda et al., 2000). For example, the f or T allele of the FokI

Functionality of polymorphisms

The interpretation of the association studies using VDR polymorphisms is severely hindered by the fact that most of the polymorphisms used are anonymous. The likely explanation for any observed association is then to assume the presence of a truly functional sequence variation elsewhere in the gene which is—to a certain extent—in linkage with an allele of the anonymous polymorphism used. As can be understood from the complex organization of the VDR gene (see Fig. 2), the identification of these

Conclusion

Since the first publications on polymorphisms in the VDR in 1992, considerable progress has been made in unraveling the VDR in genetic terms as exemplified by the elucidation of the genomic localization, structure, and polymorphisms. A next important phase that is currently in progress and which is strongly facilitated by the data from the Human Genome Project is the establishment of LD and construction of haplotype maps. A most challenging and demanding area is the assessment of consequences

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