Functional genetic variation of the vitamin D receptor in malignant melanoma and psoriasis

The vitamin D receptor (VDR) is the nuclear receptor for 1\alpha,25-dihydroxyvitamin D_3(1,25(OH)_2D_3), the active form of vitamin D. Classically involved in the regulation of calcium and phosphate homeostasis and bone mineralisation, 1,25(OH)_2D_3 has recently been demonstrated to suppress proliferation and promote differentiation in a number of cell types. This has led to the study of the 1,25(OH)_2D_3 pathway in malignancies such as melanoma and hyperproliferative disorders such as psoriasis. Genetic variation of the VDR has previously been associated with prognosis in malignant melanoma and occurrence and treatment response in psoriasis. Here, the major promoter region of the VDR, the 1a promoter region, was screened for variation. The novel polymorphism, A- 1012G, was discovered and was predicted to lie within a GATA-3 binding site, such that the site is only present in the case of the A allele. GATA-3 is a T-cell specific transcription factor involved in polarising the T-cell response to a type 2 (Th2) response and suppressing Th1 responses. It was hypothesised that the A allele would be a risk factor in malignant melanoma, due to decreased immunosurveillance but beneficial in psoriasis, due to a reduction in Th1-mediated inflammation and keratinocyte hyperproliferation. The affect of this polymorphism was studied in 191 malignant melanoma patients, 206 psoriasis patients and 80 controls. AA genotype were associated with increased risk of both occurrence (P=0.015) and metastasis (P=0.008) in melanoma. The A allele was under-represented in psoriasis patients with no family history compared to those with a family history (P=0.01), and associated with response to the vitamin D analogue Dovonex (P=0.04). GATA-3 was shown to bind at the A but not the G allele of A-1012G in gel-shift assays. In vitro studies demonstrated that T cells with AA and AG genotypes were more sensitive to 1,25(OH)_2D_3 treatment than those with GG genotype.