Research Projects

Vitamin D receptor research – Prof Liza Bornman

Vitamin D receptor research – Prof Liza Bornman

Prof Liza Bornman

Prof Liza Bornman

Prof Liza Bornman

Title of project

Functional impact of genetic and epigenetic variants of the vitamin D receptor gene (VDR).

Project description

Vitamin D status is implicated in susceptibility to several cancers, while polymorphisms in the gene coding for its  receptor is associated most significantly with breast, skin and prostate cancer. The vitamin D receptor (VDR) is a ligand-activated transcription factor mediating the pleotropic actions of vitamin D including its anti-proliferative and pro-differentiation actions. This association between VDR polymorphisms and cancer is complex and involves interaction with vitamin D status as influenced by diet and sunlight exposure. Epigenetic variation imposed by the environment through mechanisms such as DNA methylation, histone modification and RNA interference further  regulates VDR expression. Genetic and epigenetic diversity of the VDR and its functional impact in South African populations is largely unknown. The proposed molecular epidemiology project aims to establish a profile for genetic and epigenetic diversity of the VDR to answer from a molecular perspective epidemiological questions relating to cause, frequency, interrelationship and population-specific effects regarding the vitamin D signalling pathway to verify its potential role in cancer in the South African context.

Objectives of Project (What hypothesis will this project test?)

The most significant highlight/milestone is summarised in the summary below. This work had been accepted for publication in PLOS ONE.

Polymorphisms of the vitamin D receptor gene (VDR) have been associated inconsistently with various diseases, across populations of diverse origin. The T(f) allele of the functional SNP FokI, in exon 2 of VDR, results in a longer vitamin D receptor protein (VDR) isoform, proposed to be less active. Genetic association of VDR with disease is likely confounded by ethnicity and environmental factors such as plasma 25(OH)D3 status. We hypothesized that VDR expression, VDR level and transactivation of target genes, CAMP and CYP24A1, depend on vitamin D, ethnicity and FokI genotype. Healthy volunteers participated in the study (African, n = 40 and White, n = 20). Plasma 25(OH)D3 levels were quantified by LC-MS and monocytes cultured, with or without 1,25(OH)2D3. Gene expression and protein level was quantified using qRT-PCR and flow cytometry, respectively. Mean plasma 25(OH)D3 status was normal and not significantly different between ethnicities. Neither 25(OH)D3 status nor  1,25(OH)2D3 supplementation significantly influenced expression or level of VDR. Africans had significantly higher mean VDR protein levels (P <0.050), nonetheless transactivated less CAMP expression than Whites. Genotyping the FokI polymorphism by pyrosequencing together with HapMap data, showed a significantly higher (P < 0.050) frequency of the CC genotype in Africans than in Whites. FokI genotype, however, did not influence VDR expression or VDR level, but influenced overall transactivation of CAMP and 1,25(OH)2D3-elicited CYP24A1 induction; the latter, interacting with ethnicity. In conclusion, differential VDR expression relates to ethnicity, rather than 25(OH)D3 status and FokI genotype. Instead, VDR transactivation of CAMP is influenced by FokI genotype and, together with ethnicity, influence 1,25(OH)2D3-elicited CYP24A1 expression. Thus, the expression and role of VDR to transactivate target genes is determined not only by genetics, but also by ethnicity and environment involving complex interactions which may confound disease association.

Our preliminary findings suggest ethnicity-based differences in the expression and function of the vitamin D receptor (VDR). This has implications for an individual’s ability to activate the expression of critical target genes, regulated by the VDR, central in combating cancer and infectious diseases. This knowledge may find application in cancer prevention strategies in southern Africa.

Peer-reviewed publications


Preliminary report on findings from the epidemiological study conducted in collaboration with the NCR.


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