Prediction of bone density from vitamin D receptor alleles

Morrison, Nigel Alexander; Qi, Jian; Tokita, Akifumi; Kelly, Paul; Crofts, Linda; Nguyen, Tuan V.; Sambrook, Philip N.; Eisman, John A.

doi:10.1038/367284a0

Cited by 1,737 publications

(969 citation statements)

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“…20,21 The associations between ApaI genotype, B lymphopenia and CD8+CD57+ lymphocytosis suggests that the immunoregulatory actions of vitamin D may be modified by the expression and activity of the vitamin D receptor. Existing data suggest that the ApaI A allele is associated with higher VDR expression than the ApaI a allele, 22 and thus would enhance the immunosuppressive actions of calcitriol. This provides a plausible theoretical basis for the association data presented here, but further evidence regarding the physiological effect of the VDR polymorphisms is required.…”

Section: Discussionmentioning

confidence: 99%

Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency

et al. 1999

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Variation in clinical phenotype is a hallmark of many complex diseases. The cause of this clinical heterogeneity is unknown, but it may be determined by genetic factors distinct from those conferring disease susceptibility. Common variable immunodeficiency (CVID) is a complex disease of unknown aetiology and diverse clinical manifestations. We have developed a unified polymerase chain reaction and sequence-specific primer (PCR-SSP) method to simultaneously genotype multiple polymorphisms under identical conditions, and have used this method to test the hypothesis that the clinical phenotype of CVID is determined by immunoregulatory gene polymorphism. Twenty-three polymorphisms in 13 genes were studied in 163 CVID patients. Vitamin D receptor and IL-6 alleles were associated with immunophenotypic abnormalities characteristic of more severe disease; and tumour necrosis factor and IL-10 alleles conferred susceptibility to the granulomatous form of CVID in an interacting fashion. These findings demonstrate that different clinical features of a disease may have unique pathogenetic abnormalities, determined by multiple interacting genetic factors. The ease of application of this efficient, robust genotyping technique to polymorphisms throughout the genome will make it a powerful tool in the investigation of the genetic basis of phenotypic variability in a wide variety of diseases.

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Section: Discussionmentioning

confidence: 99%

Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency

et al. 1999

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“…Thus, polymorphisms in the 3 0 and 5 0 regions of the gene have been described and variously associated with risk of breast, prostate and colon cancer, although the functional consequences remain to be established clearly (149)(150)(151)(152)(153)(154)(155) . For example, a start codon polymorphism in exon II at the 5 0 end of the gene, determined using the fok-I restriction enzyme, results in a truncated protein (156,157) . At the 3 0 end of the gene three polymorphisms have been identified that do not lead to any change in either the transcribed mRNA or the translated protein.…”

Section: Genetic Resistancementioning

confidence: 99%

The vitamin D receptor in cancer

2008

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Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1a,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR. In vitro and in vivo dissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells display de novo and acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance the efficacy of VDR-centred therapeutics. The cancer burdenThe impact of cancer continues to be one of the greatest burdens in the developed world and is also increasingly impacting on the developing world. Approximately 1 . 5 million individuals will die from breast, colon or prostate cancer this year, and the total number of deaths from cancer accounts for 13 % of all deaths worldwide and for one in every four deaths in the UK and USA (1) . The impact is also economic; $280 · 10 9 is spent annually worldwide on the treatment of patients. Many cancers are however preventable, and through lifestyle choices such as smoking, diet and exercise the worldwide incidence of cancer could be cut by 40 % (2,3) . Major risk factors for cancer DietRecently, the appreciation of the impact of diet on cancer has come to the fore, with a number of studies establishing unequivocal relationships between diet and cancer initiation and progression. Reflecting the accumulation of these data, the WHO has now stated that diet forms the secondmost preventable cause of cancer (after smoking) (3) . This impact will rise further as a result of demographic factors, and quite possibly because of changing dietary habits worldwide, which will contribute further to the projected increase in cancer incidence in developing nations. Highprofile malignancies such as breast, prostate, and colon cancer typify this scenario, in which the aetiology of the disease reflects the cumulative impact of dietary factors over an individual's lifetime (4)(5)(6) . The relationship between diet and disease is already exploited clinically, e.g. in the Selenium and Vitamin E Cancer Prevention Trial to assess the chemoprevention potential of vitamin E ...

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“…VDR is essential for 1,25(OH) 2 D 3 to induce the calcemic and phosphatemic effects that normally result in bone mineralization and remodelling [37]. VDR genotypes increase the risk for low BMD and osteoporotic fractures [16,38] and VDR knock-out mice develop a low bone mass phenotype with hypocalcemia, hypophosphatemia, and elevated 1,25(OH) 2 D 3 levels [39]. In addition, reduced serum 25(OH)D levels might predispose young men to stress fractures [40].…”

Section: Discussionmentioning

confidence: 99%

“…Genotyping of the VDR , CTR , and IL-6 variations was performed as described previously [16,18,21,24,25]. Genes that have shown evidence of biological interactions were chosen as candidates for gene-gene interaction analysis [26,27], but only interaction combinations where sample size was large enough were evaluated.…”

Section: Methodsmentioning

confidence: 99%

“…Mutations or allelic variants in the genes leading to a variety of bone pathologies that increase bone fragility, such as collagen I, ( COL1A1 and COL1A2 ) [14,15], vitamin D receptor ( VDR ) [16], osteoprotegerin ( OPG ) [17], calcitonin receptor ( CTR ) [18], estrogen receptor ( ESR ) [19], low density lipoprotein receptor-related protein 5 ( LRP5 ) [20], and interleukin 6 ( IL-6 ) [21] may also increase the risk of stress fractures. Sequence variations in these genes are associated with a low peak bone mass, osteoporosis, osteogenesis imperfecta, osteoporosis-pseudoglioma syndrome, and high bone mass, but their role in predisposing to stress fracture is not clear [14-21].…”

Section: Introductionmentioning

confidence: 99%

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Genetic predisposition for femoral neck stress fractures in military conscripts

et al. 2010

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BackgroundStress fractures are a significant problem among athletes and soldiers and may result in devastating complications or even permanent handicap. Genetic factors may increase the risk, but no major susceptibility genes have been identified. The purpose of this study was to search for possible genetic factors predisposing military conscripts to femoral neck stress fractures.ResultsEight genes involved in bone metabolism or pathology (COL1A1, COL1A2, OPG, ESR1, VDR, CTR, LRP5, IL-6) were examined in 72 military conscripts with a femoral neck stress fracture and 120 controls. The risk of femoral neck stress fracture was significantly higher in subjects with low weight and body mass index (BMI). An interaction between the CTR (rs1801197) minor allele C and the VDR C-A haplotype was observed, and subjects lacking the C allele in CTR and/or the C-A haplotype in VDR had a 3-fold higher risk of stress fracture than subjects carrying both (OR = 3.22, 95% CI 1.38-7.49, p = 0.007). In addition, the LRP5 haplotype A-G-G-C alone and in combination with the VDR haplotype C-A was associated with stress fractures through reduced body weight and BMI.ConclusionsOur findings suggest that genetic factors play a role in the development of stress fractures in individuals subjected to heavy exercise and mechanical loading. The present results can be applied to the design of future studies that will further elucidate the genetics of stress fractures.

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Prediction of bone density from vitamin D receptor alleles

Cited by 1,737 publications

References 21 publications

Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency

Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency

The vitamin D receptor in cancer

Genetic predisposition for femoral neck stress fractures in military conscripts

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