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Vitamin D and Its Role in Cancer and Immunity: A Prescription for Sunlight* Integrative GI Nutrition Services, Capsule Endoscopy, Division of Gastroenterology and Liver Disease, Johns Hopkins Hospital, Baltimore, Maryland Correspondence: Correspondence: Gerard E. Mullin, MD, MHS, FACP, CNSP, FACN, AGAF, Director of Integrative GI Nutrition Services, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21205. Electronic mail may be sent to gmullin1{at}jhmi.edu. Vitamin D has been recognized for more than a century as essential for the normal development and mineralization of a healthy skeleton. More extensive roles for vitamin D were suggested by the discovery of the vitamin D receptor (VDR) in tissues that are not involved in calcium and phosphate metabolism. VDR has been discovered in most tissues and cells in the body and is able to elicit a wide variety of biologic responses. These observations have been the impetus for a reevaluation of the physiologic and pharmacologic actions of vitamin D. Here, we review the role of vitamin D in regulation of the immune system and its possible role in the prevention and treatment of cancer and immune-mediated diseases.
Most humans depend on sun exposure to satisfy their requirements for vitamin D. Brief exposure to direct sunlight on a bright summer day is all the body needs to produce sufficient cholecalciferol (or vitamin D3).1 Skin exposure to ultraviolet B light (wavelength 290–315 nm) initiates the photochemical conversion of 7-dehydrocholesterol to previtamin D3 in the epidermis and dermis. Body heat then catalyzes the rapid isomerization of previtamin D3 to vitamin D3 (cholecalciferol), which binds to the vitamin-D-binding protein (VDBP) in the extracellular space.2 Vitamin D3 is transported to the liver, which uses 25-hydroxylase to produce 25-hydroxyvitamin D3, or 25(OH)D3. Although endogenous production of vitamin D typically provides most of the vitamin D requirement, vitamin D can be ingested orally as either vitamin D3 (cholecalciferol) or D2 (ergocalciferol, derived from the irradiation of plant sterols). Very few foods naturally contain vitamin D: oily fish and fish products such as cod-liver oil, salmon, mackerel, and herring contain approximately 300–500 international units (IU) of vitamin D per serving.3 Foods in the United States that are fortified with vitamin D include milk, orange juice, and some cereals, breads, yogurts, and cheeses. Most European countries permit margarine and some cereals to be fortified with vitamin D, and a few countries, including Sweden, also permit milk to be fortified with this vitamin. 25-Hydroxyvitamin D [25(OH)D] derived from endogenous production or exogenous sources is the major vitamin D metabolite in the human body's circulation system and is the best known indicator of vitamin D status. There is debate regarding cutoffs for vitamin D deficiency and insufficiency using 25(OH)D concentrations. The current thinking is that the traditional cutoff for deficiency, 10 ng/mL of 25(OH)D (above which protection from rickets or osteomalacia is conferred), is too low to indicate vitamin D adequacy. A low serum 25(OH)D concentration, often referred to as hypovitaminosis D, is not simply a biochemical abnormality. It is associated with physiologic, pathologic, and clinical evidence of vitamin D deficiency, including increased parathyroid hormone secretion, increased bone turnover, osteoporosis and mild osteomalacia, and an increased risk of hip and other fractures. To prevent more subtle or long-term effects of vitamin D insufficiency, circulating concentrations of at least 30 ng/mL 25(OH)D may be warranted.3
In the kidney, 25(OH)D is further hydroxylated to
1
More recently, VDRs were found in cells of tissues not involved in calcium
homeostasis, and extrarenal tissues were found to produce
1
Epidemiologic Studies Geography, sunlight, and cancer risk. Most of the information about vitamin D and cancer prevention has been based on observational, case-control, or cohort studies linking sunlight exposure to cancer incidence or survival. The first of these studies was documented nearly a half century ago, when it was reported that individuals living in the northeast regions of the United States had an approximately 2-fold higher risk of dying of cancer than those living in southern regions.7 Recently, several more studies found a similar association between latitude and the risk of developing prostate, breast, and colon cancer in the United States and Europe.8–10 Colon cancer mortality was subsequently found to be higher among people from the Northeastern United States compared with people living in southern states.11 It is now well established that the risk of developing and dying of prostate, breast, colon, ovarian, esophageal, non-Hodgkin's lymphoma, and a number of other lethal cancers correlated with living at higher latitudes.11–24 Several investigators have confirmed the reciprocal relationship of sunlight exposure and cancer. Most recently, Grant24,25 reported that increased sun exposure decreases mortality from common cancers in both white men and women.7 Grant17 suggested that 25% of breast cancer mortality in Europe was related to living at a higher latitude and being vitamin D deficient. These observations are also supported by a report of men who had little sun exposure and developed prostate cancer 3–5 years earlier than men who had optimal sun exposure.26 Vitamin D deficiency was reported to increase the risk for prostate cancer, and sunlight exposure is inversely proportional to prostate cancer mortality. Colon cancer incidence was evaluated in California because the state has a wide range of latitudes. Living in San Diego was reported to significantly decrease the risk of developing colon cancer compared with living in San Francisco or further north.27 There has been speculation that subjects living further north synthesized less vitamin D and that therefore vitamin D seems to be protective against tumor development or growth. The sunlight effect therefore seems to attenuate the risk of numerous cancers, such as prostate, breast, colon, ovarian, non-Hodgkin's lymphoma, esophageal, stomach, pancreatic, rectal, kidney, corpus uteri, lung, and bladder. These studies, which controlled for other important variables such as smoking and lifestyle, provide indirect evidence of a possible causal relation between low vitamin D status and cancer risk.
Studies have looked more specifically at quantitative estimates of sunlight exposure and cancer risk or mortality. Men with elevated levels of sunlight exposure had a later onset of prostate cancer than those with low levels of sunlight exposure.18 Solar ultraviolet (UV)-B exposure was inversely related to the risk of dying of cancer in men and women in the United States.28
Putative mechanisms for vitamin D protection against cancer. The
original hypothesis for why exposure to sunlight decreased the risk of common
cancers was that increased production of vitamin D3 in the skin
resulted in higher circulating levels of 25(OH)D3, which could be
metabolized by the kidneys to 1
However, because the kidney's production of
1
Animal models. Although the epidemiologic evidence linking sun
exposure to cancer risk seems strong, whether vitamin D deficiency per
se promotes tumor growth remained unclear. To this end, a study evaluated
the growth of a mouse colon cancer cell line MC-26 in Balb/c mice that were
either vitamin D deficient or vitamin D
sufficient.32 The
tumors grew much more rapidly in the vitamin D–deficient mice. By the
end of the study on day 19, tumors in the vitamin D–deficient mice were
on average 80% larger than in the vitamin D–sufficient mice. The 25(OH)D
levels in the vitamin D–deficient mice at the end of the study were
<5 ng/mL, whereas the vitamin D–sufficient mice maintained a 25(OH)D
level of 35 ng/mL. This observation provides strong corroborating data
supporting the concept that vitamin D sufficiency is important for reducing
tumor cell growth. There is now emerging data that vitamin D may play a role
in altering colon cancer cell growth. Spina et
al33 performed
studies using murine models of colon cancer to demonstrate that those mice who
were sufficient in vitamin D had a significantly lower (p < .05)
tumor burden compared with vitamin D–deficient mice. Furthermore, using
Gemini analog A in the same mouse model of colon cancer, these investigators
demonstrated that the tumor burden was decreased by 50% in the treatment group
when compared with placebo or 1
Dietary intake of vitamin D and cancer risk. Aside from sun exposure, others sources of vitamin D are in the form of diet and supplements. There are several epidemiologic studies of the association between vitamin D and breast cancer risk. Studies reporting dietary and supplemental intake demonstrate inconsistent results (Table 1).20,35–38,41 Three case-controlled studies demonstrated no association between dietary vitamin D intake and breast cancer risk35,39,40; however, small sample size and selection bias may have skewed the results. On the other hand, the Nurses Health Study demonstrated an inverse association between vitamin D intake and breast cancer risk among premenopausal women but no association among postmenopausal women.41 Along these lines, the Cancer Prevention Study II Nutrition Cohort found no correlation between dietary intake of vitamin D and development of breast cancer in postmenopausal women,38 and 2 additional studies determined that the dietary intake of vitamin D in the female adolescent had no bearing in determining future breast cancer risk.36,37 However, researchers provided additional preliminary evidence demonstrating a potential role of vitamin D in decreasing breast cancer risk. In a population-based, case-controlled study in Ontario, women with breast cancer (identified through the Ontario Cancer Registry) and controls were interviewed about their past and present diets and sun exposure.
The investigators' preliminary analysis suggests that earlier exposures to vitamin D during breast development in adolescence may be more significant for reducing breast cancer risk than recent exposures.42,43 A recent study seeking to estimate the amount of vitamin D required to reduce the incidence of breast cancer was performed via a meta-analysis of 2 large previously published studies that measured vitamin D concentrations in the blood [as serum 25(OH)D] and subsequent breast cancer development. The results demonstrated that women who consumed 1000 IU a day of vitamin D in addition to the normal background amount had a 10% reduced risk of breast cancer.43 Garland and colleagues44 plotted a dose-response gradient and found that as quintiles of serum 25(OH)D (0–11 ng/mL, 12–25 ng/mL, 26–31 ng/mL, 32–42 ng/mL, and >42 ng/mL) increased, the risk of breast cancer significantly decreased. A serum 25(OH)D concentration exceeding 52 ng/mL (which would require intake of >2700 IU/d of vitamin D3 in an individual weighing 70 kg) was associated with 50% lower risk of breast cancer compared with a serum concentration of <12 ng/mL. The authors noted that the US median intake of 320 IU/d of vitamin D is only about one-tenth of the amount found to be associated with a 50% reduction of breast cancer incidence. They concluded that increasing daily intake of vitamin D, perhaps by fortification of foods, should be considered. Studies analyzing endogenous circulating vitamin D levels and breast cancer risk are shown in Table 2.12,19,34,45,46
Biochemical indicators of vitamin D status and cancer risk. There has been considerable debate recently about concentrations of circulating 25(OH)D that can be viewed as optimal for preventing vitamin D deficiency and, in particular, promoting health. Prospective and retrospective studies have shown that circulating levels of 25(OH)D above 50 nmol/L (20 ng/mL) were associated with a 30%–50% decreased risk of developing prostate, breast, and colon cancer.47 A recent study by Dr Walter Willett's group from Harvard University found that higher serum vitamin D levels correlated with reduced risk for certain forms of cancers in a population of middle-aged to elderly men in a retrospective analysis of data from a major study of health professionals.48 Giovannucci and colleagues48 analyzed prospective data from Harvard's Health Professionals Follow-up Study, which includes >50,000 men aged 40–75 years. Higher serum levels of vitamin D were associated with a significantly lower incidence of colorectal, pancreatic, esophageal, and oral/pharyngeal cancers. An increase of 25 nmol/L in serum vitamin D level was associated with a 17% decline in overall cancer incidence and a 29% drop in total cancer deaths. For cancers involving the digestive system, a 25 nmol/L increase in vitamin D reduced cancer incidence by 43% and mortality by 45%. This study was the first to examine total cancer incidence and mortality by using a comprehensive assessment of factors that determine 25(OH)D levels. The authors estimated that cancer mortality for US men could be reduced by 29% if serum vitamin D levels were increased by 25 nmol/L throughout the male population. The findings from this cohort study are the latest of several49–52 linking vitamin D status with reduced cancer risk, and are some of the most compelling yet. The results, with lower risks of most (but not all) forms of cancer, are also some of the most broad-based, and they indicate that vitamin D may have a role in most human tumors. Factors associated with higher serum levels of vitamin D were white race, residence in the southern United States, higher intakes of vitamin D, body mass index <22 kg/m2, and more physical activity. Vitamin D supplements (as opposed to dietary vitamin D) had only a slight effect on serum vitamin D. The investigators noted that increasing one's serum vitamin D by 25 nmol/L (the basis of their relative-risk calculation) might mean adding at least 1500 IU/d of vitamin D, far exceeding the US Department of Agriculture's recommended dietary allowance (RDA) of vitamin D currently set at 200–400 IU for people aged 1–70 years. A glass of milk contains only 100 IU and would increase serum vitamin D by only 2–3 nmol/L, they noted, but "a fair-skinned individual can produce 20,000 IU of vitamin D in the skin through 20–30 minutes of sun exposure." A recent editorial also noted that "the amount of sun needed to produce adequate levels of vitamin D, at least for bone health, is modest and can be obtained in a light-skinned person by a brief summertime afternoon stroll."53 Other previous reports support a role for vitamin D in the prevention of colorectal cancer.15,22,54 Giovannucci55 has recently published a review of the data on colon cancer risk and vitamin D. Other cancers where vitamin D plays a protective role. Polesel et al56 reported that vitamin D also serves a protective role against the development of non-Hodgkin's lymphoma. Vitamin D (chiefly contained in fish) provided protection against non-Hodgkin's lymphoma that was stronger in women, whereas no differences emerged according to age (odds ratio [OR] = 0.4; 95% confidence interval [CI], 0.2–0.9). Vitamin D also seems to play a protective role in pancreatic cancer.57 In 2 US cohorts, increased intakes of vitamin D were associated with reduced risks for pancreatic cancer, suggesting a potential role for vitamin D in the pathogenesis and prevention of this malignancy. Melanoma, on the other hand, has been linked to sun exposure. Thus, the risk of excessive sun exposure needs to be weighed against the benefit of sun-derived vitamin D. Li et al58 reported that genetic variants (ie, TaqI t protective allele and FokI f risk allele) in VDR may alter risk of cutaneous melanoma. Thus, genetic alternations in VDRs may in part determine the risk for developing cutaneous melanoma from sun exposure.
Over the past quarter century, evidence for the anticancer properties of vitamin D and its analogs has been emerging in the literature. The volume of data supports a multipronged attack that involves growth arrest at the G1 phase of the cell cycle, apoptosis, tumor-cell differentiation, disruption of growth-factor-mediated cell survival signals, and inhibition of angiogenesis and cell adhesion (Figure 2). Processes involved in the tumor suppressive activity of vitamin D analogues include inhibition of cell proliferation, induction of apoptosis, inhibition of cell adhesion, G1-phase cell-cycle arrest, promotion of cell differentiation, inhibition of angiogenesis, alteration of growth factors, and inhibition of metastasis.59,60 Thus, VDR-mediated pathways constitute potential therapeutic targets for cancer prevention and treatment.
Proposed Cellular Mechanisms
1  ,25(OH)2D3 regulates proliferation and
differentiation of different kinds of cells, including keratinocytes,
osteoblasts, and hematopoietic
cells.2
1,25(OH)2D3 has been shown to inhibit cellular
growth and induced differentiation of M-1 leukemic cells and HL-60 leukemic
cells expressing
VDR.62
1,25(OH)2D3 inhibits proliferation and induces
differentiated function in osteoblasts, keratinocytes, and hematopoietic
cells.63
1,25(OH)2D3 is generally associated with
inhibiting proliferation and inducing differentiation. The growth inhibition
of cancer cells by 1,25(OH)2D3 is associated with
growth factor signaling through transforming growth factor-β
(TGF-β), which is a potent inhibitor of proliferation of many cell types
and is involved in cell cycle control and apoptosis. Vitamin D analogs induce
an autocrine TGF-β activity through increasing expression of TGF-β
isoforms or TGF-β receptors in nonmalignant and malignant
cells.64
Insulin-like growth factor (IGF)-binding protein 3 induction by
1,25(OH)2D3 seems to contribute to its
antiproliferative and proapoptotic actions in primary cancer
cells.65–67
Recent microarray studies of gene expression profiles in cancer cells have
further highlighted the capacity of 1,25(OH)2D3
analogs to drive malignant cells to a more differentiated
state.68
1 ,25(OH)2D3-induced apoptosis is an important
contributor to its growth-suppressing and anticancer properties.
1,25(OH)2D3 analogs have been shown to induce
apoptosis in cancer cells by modulating B-cell leukemia/lymphoma-2 genes
(Bcl-2) and Bax proteins (which is a proapoptotic member of the Bcl-2 protein
family), tumor necrosis factor (TNF)-, and caspase-dependent and
independent
mechanisms.69
Aside from growth inhibition, vitamin D and its analogs decrease the invasiveness of several cell lines in vitro, and they inhibit angiogenesis and metastasis in xenograft and transgenic mouse models in vivo.70 In cultured malignant cells, 1 ,25(OH)2D3 and its
analogs down-regulate cell-invasion-associated proteases, including matrix
metalloproteinases 2 and 9 and serine
proteinases.71 In
prostate and colon cells, 1,25(OH)2D3 and its
analogs increase the expression of E-cadherin, a tumor suppressor associated
with the metastatic potential of cells, and inhibit the oncogenic
β-catenin
signaling.72
1,25(OH)2D3 and its analogs inhibit the
proliferation of some tumor-derived endothelial cells, inhibit the expression
of vascular endothelial cell growth factor that induces angiogenesis in
tumors, and suppress tenascin-C, which promotes growth, invasion, and
angiogenesis during
tumorigenesis.73
Breast, colon, prostate, skin, lung, and a variety of other cell lines,
when exposed to 1
As discussed earlier, the nuclear VDR has been isolated from a variety of target cells and tissues (Table 3), suggesting that vitamin D compounds may have therapeutic potential throughout several body systems. The major drawback of 1 ,25(OH)2D3, however, is its effect on calcium
metabolism, which results in hypocalcaemia and hypercalciuria. Newly developed
vitamin D analogs with lower calcemic activity have been shown to retain many
therapeutic properties of
1,25(OH)2D3.75–106
MC 903 is a vitamin D analog with low (2/0.05) ratio of cell growth inhibition
to calcemic activity. In contrast, CB 966 (6/0.2), CB 1093 (160/0.27) and KH
1060 (1000/1.3) have much higher ratios making them potentially effective
therapeutic agents without the potential risk of
toxicity.75 More
than 2000 synthetic analogs of the biologic form of vitamin D
(1,25(OH)2D3) are presently known. These analogs
interfere with the molecular switch of nuclear
1,25(OH)2D3 signaling.
Most 1
Five vitamin D analogs have been approved for clinical use in a variety of
disorders: calcipotriol (Dovonex; Leo Pharmaceuticals, Copenhagen, Denmark)
for the treatment of psoriasis, 19-nor-1,25(OH)2D2
(Zemplar; Abbott Laboratories, Abbott Park, IL) for secondary
hyperparathyroidism, doxercalciferol (Hectorol; Bone Care Int, Madison, WI)
for reduction of elevated parathyroid hormone levels, 22-oxacalcitriol
(Maxacalcitol; Chugai Pharmaceuticals, Tokyo, Japan), and alfacalcidol. Thus,
these synthetic analogs which maintain antiproliferative effects but do not
have strong calcemic activity have been developed and show promising results
(Table 4). Studies using the
human osteosarcoma cell line MG-63 demonstrated that 3 of these analogs
(KH1060, EB1089, and CB1093), have a greater antiproliferative effect than
1,25(OH)2D3. Treatment with these analogs increases p27
protein levels by increasing expression and decreasing degradation. The
analogs cause decreased levels of cyclin E, decreased CDK2 kinase activity and
hypophosphorylation of Rb, and inhibition of the G1-to-S phase
transition.105
Similar results have been seen in neuroblastoma cell lines treated with a
20-epi-1
Several other analogs are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis, as well as immunosuppression.80 Vitamin D analogs are effective treatments and are widely used as drugs for hyperproliferative skin disorders such as psoriasis, and in suppression of secondary hyperparathyroidism and parathyroid hyperplasia resulting from chronic renal insufficiency.107–109 For instance, Gemini analogs have been recently found to be 100–1000 times more potent in their antiproliferative activity than the natural hormone. Studies in mice suggest that they may be useful in the treatment of some cancers, including colon cancer.27 Understanding how analogs exert their selective actions may allow for the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders. The promising vitamin D analogs under development for the treatment of cancer are shown in Table 476–88; the in vivo effects of vitamin D analogs in animal models for breast cancer, prostate cancer, and colon cancer are shown in Table 589–106; and the molecular targets for vitamin D compounds in cancer are shown in Table 6. Optimal administration of vitamin D analogs is only being realized, with high-dose intermittent administration overcoming bioavailability and hypercalcemic problems. Combination therapy with cytotoxic agents (taxols and cisplatins), anti-resportive agents (biphosphonates), agents blocking vitamin D metabolism (ketoconazole), ionizing radiation, antiproliferative agents (retinoic acids), antihypercalcemic agents (dexamethasone), histone deacetylase inhibitors, or cytochrome P450 inhibitors may achieve better results through synergy, as shown in vitro.110–115 Understanding how analogs exert their tissue-specific selective actions may allow for the design of more effective and safer vitamin D compounds for the treatment of hyperproliferative disorders, including cancer.
T Cells as the Main Target 1,25(OH)2D3 seems to modulate immunity principally via regulating T-cell function. VDR has been found to be expressed on virtually every type of cell involved in immunity (Table 3).110–113 The immunomodulatory actions of vitamin D are elicited through its direct action on T-cell and antigen-presenting cell (APC) functions. Thus, 1,25(OH)2D3 may have an important physiologic role in immunoregulation and therapeutic target in immune-mediated diseases.
Effects on T Cells and T Helper 1 Cytokine Profiles: Relevance to Autoimmunity
Vitamin D regulates T cells both directly and indirectly via
APCs.120,121
When vitamin D is deficient or signals through the VDR are weakened, Th1 cell
actions are intensified, whereas regulatory T cells and Th2 cells are
diminished, thus favoring an autoimmune Th1
response.122,123
1
Because vitamin D deficiency favors a proinflammatory Th1 immune response,
does supplementation rebalance immunity? In vitro addition of
1
Thus, the action of 1
Effects on APCs
Autoimmune Disease Vitamin D from sunlight exposure is lower in areas where IBD occurs most often, as IBD is most prevalent in northern climates such as North America and Northern Europe.134,135 Vitamin D deficiency is common in patients with IBD even when the disease is in remission.136,137 Why vitamin D deficiency occurs more frequently in IBD is unclear. It is probably due to the combined effects of low vitamin D intake, malabsorption of many nutrients including vitamin D, and decreased outdoor activities in climates that are not optimal for vitamin D synthesis in the skin.
The strongest evidence that the VDR and its ligand have important roles in
the pathogenesis of IBD comes from studies in mouse models. IL-10 knockout
mice, model for the Crohn's disease form of IBD, spontaneously develop
enterocolitis within 5–8 weeks of birth due to an uncontrolled immune
response to resident intestinal flora in conventional animal
facilities.138
Approximately 30% of mice die subsequent to the development of severe anemia
and weight loss. By contrast, IL-10 knockout mice raised in pathogen-free
facilities develop a milder form of enterocolitis that does not result in
death. Experimental IBD is induced by TNF-
A large epidemiologic study showed an inverse relationship between vitamin
D status and the development of MS. The study showed that women with the
highest vitamin D intakes (including supplements) had a 40% reduction in the
risk of developing
disease.139 Like
IBD, vitamin D deficiency is common in patients with
MS.122 The cause
of low vitamin D levels in MS patients is also likely to be due to a
combination of low vitamin intakes and decreased outdoor activities in
climates that are not optimal for vitamin D synthesis in the skin. In
vivo, the immune targets of vitamin D have been defined primarily in
Th1-driven autoimmune diseases. Vitamin D deficiency accelerates the
development of experimental MS and type-1
diabetes.139–142
Conversely, 1,25(OH)2D3 treatment suppressed the
development of these Th1-mediated autoimmune
diseases.143 In
addition, 1
Vitamin D may also play a role in preventing type I diabetes mellitus.
Autoimmune type 1 diabetes can be prevented in nonobese diabetic mice by
1
Other effects on the immune system of NOD mice have been described, the
most important being a restoration of the defective apoptosis sensitivity of
lymphocytes, leading to a more efficient elimination of potentially dangerous
autoimmune effector
cells.148 This
increased apoptosis induced by 1
Besides preventing the onset of autoimmune diseases,
1 Development of noncalcemic vitamin D analogs could permit sustained systemic administration without causing significant hypercalcemia, thus allowing wider clinical applications in the future. Vitamin D supplementation, which is an inexpensive and efficient way to prevent vitamin D deficiency, might also help reduce the risk of autoimmune disease.
Most of the biologic activities of 1 ,25(OH)2D3
are mediated by a high-affinity receptor that acts as a ligand-activated
transcription factor. The major steps involved in the control of gene
transcription by the VDR include ligand binding, heterodimerization with
retinoid X receptor (RXR), binding of the heterodimer to VDREs, and
recruitment of other nuclear proteins into the transcriptional preinitiation
complex. Thus, genetic alterations of the VDR gene could lead to important
defects on gene activation, affecting calcium metabolism, cell proliferation,
and immune function. For example, VDR gene mutations cause vitamin
D–resistant rickets, a rare monogenetic
disease.152 A
polymorphism is a genetic variant that appears in at least 1% of the
population. These changes can occur in noncoding parts of the gene (introns),
so they would not be seen in the protein product. Changes in these regulatory
parts of the gene would then affect the degree of expression of the gene and
thus the levels of the protein. The discovery of genetic variants linked with
susceptibility of diseases can be the key to advances in preventive medicine.
In general, association studies can be used to test whether a polymorphism
occurs more frequently in the cases studied than in the controls. If a
relationship with the disease emerges from association studies, this finding
would strongly support the idea that the candidate gene is in some way
involved in the disease. The diseases associated with VDR polymorphisms are
summarized in Table
7.153
Carling et al154 reported a relationship between the BsmI polymorphism and primary hyperparathyroidism. Recently, 2 meta-analyses performed by Thakkinstian et al155,156 demonstrated a positive association between the b allele and bone mass density. Furthermore, it was shown that the haplotypes Bat and BAt were significantly associated with osteoporosis.
An association has been described between VDR polymorphisms and
susceptibility to and outcome of some cancers, like breast, prostate, and
colon cancers. In 1997, Ingles et
al157 published
one of the first reports finding a relationship between the polyA polymorphism
of the VDR gene and prostate cancer in the US population. Taylor et
al158 showed the
relationship between the TaqI polymorphism and an increased risk of
prostate cancer, whereas the restriction site (tt) was associated
with a lower risk with higher levels of
1 As with prostate cancer, conflicting results have been reported regarding the possible relationship between breast cancer and VDR polymorphisms. The majority of the reports present in the literature found no relationship between the risk of breast cancer and TaqI polymorphism, but some of them presented a link between TaqI polymorphism and risk of metastases.167–171 The BsmI shows an opposite pattern, with a relationship detected in 3 reports.172–174 In the case of FokI the consensus is higher, and most of the reports showed no association with increased risk of breast cancer.171,173,174 To date, studies investigating the relationship between polyA or ApaI170,171 and the risk of breast cancer showed a link between these VDR polymorphisms and the possibility of presenting a tumor. The number of papers analyzing VDR polymorphisms in other cancer types is significantly lower. Regarding colon carcinoma, there are reports showing an association with BsmI polymorphism,175,176 whereas conflicting results are found regarding FokI.177,178 VDR polymorphisms have been described in a number of autoimmune diseases. A positive relationship between the B allele of the BsmI polymorphism and a lack of a relationship between the FokI polymorphism and the incidence of systemic lupus erythematosus has been observed.179–181 In the case of Crohn's disease, a link has been suggested between the TaqI, ApaI and FokI polymorphisms and disease susceptibility.182 Furthermore, a link between BsmI and FokI with primary biliary cirrhosis and autoimmune hepatitis has also been found.183,184 In MS patients, a higher presence of the bA haplotype has been detected,185,186 whereas TaqI187 and FokI188 polymorphisms were observed. In summary, a vast amount of information has been collected through the years regarding the association of vitamin D polymorphisms with susceptibility to contract different diseases. Unfortunately, the results obtained so far are conflicting, and the role of VDR polymorphisms remains obscure. Therefore, the use of VDR polymorphisms as diagnostic tools, or even as markers for a higher propensity toward some diseases, is still a matter of debate.
Vitamin D deficiency is a common clinical problem in the United States.189–194 Because most patients with mild deficiency are asymptomatic, physicians should have a high index of suspicion in populations at highest risk for deficiency. Identification and treatment of patients with vitamin D deficiency are important for optimal bone development and muscle strength. The major source of vitamin D for both children and adults comes from reasonable sun exposure. In the absence of sun exposure, most experts now agree that 1000 IU of vitamin D is needed daily in the absence of sun exposure to maintain a healthy blood level of 25(OH)D of between 75 and 125 nmol/L (30–50 ng/mL).194–200 However, vitamin D supplementation is not widely practiced and most supplements only contain 400 IU of vitamin D. As reviewed in this manuscript, in addition to bone health, there is mounting scientific evidence that implicates vitamin D deficiency with an increased risk of autoimmune disease and many common deadly cancers. Children over the age of 1 year and all adults should receive 1000 IU of vitamin D per day, or have judicious sun exposure to satisfy their vitamin D requirement. Measurement of 25(OH)D should be encouraged. The risks and potential benefits of vitamin D supplementation should be further studied for use in patients who either have or are at high risk for breast, colon, and prostate cancer and autoimmune diseases. The authors acknowledge Kerry Schulze, PhD, Johns Hopkins School of Public Health, Department of Human Nutrition, and Susan Kreimer, MS, a freelance medical writer in New York, for their editorial contributions. The work was supported in part by grant number AT00437 from the National Center for Complementary & Alternative Medicine of the National Institutes of Health (Adrian S. Dobs, MD, MHS, principal investigator). 1 Holick MF. Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health. Curr Opin Endocrinol Diabetes. 2002;9:87 –98.[CrossRef] 2 Holick MF. Vitamin D: importance for bone health, cellular health and cancer prevention. In: Holick MF, ed. Biologic Effects of Light 2001: Proceedings of a Symposium, Boston, MA. Boston, MA: Kluwer Academic Publishing; 2002:155 –173. 3 Calvo MS, Whiting SJ, Barton CN. Vitamin D intake: a global
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Nutrition in Clinical Practice, Vol. 22, No. 3,
305-322 (2007) This article has been cited by other articles:
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Vitamin D Overview
Vitamin D and Cancer...
) at the site of pathology, which drives the
disease process. In general, if a treatment for Th1-mediated autoimmunity
works, it suppresses the number or activity of Th1 cells or antagonizes the
cytokines (TNF-
B in macrophages. Ag, antigen; IFN, interferon; IL,
interleukin; TNF, tumor necrosis factor.
