The unfavorable effect of the A allele of the vitamin D receptor promoter polymorphism A-1012G has different mechanisms related to susceptibility and outcome of malignant melanoma

Abstract

The A allele of the A-1012G (rs4516035) vitamin D receptor (VDR) promoter polymorphism is associated with increased susceptibility and worsened outcome in malignant melanoma (MM). The A allele contains a GATA-3 binding site. There is a second polymorphism in the same promoter region, G-1520C (rs7139166), and there is potential for another GATA binding site in the G allele. Here, we tested the hypothesis that the G -1520 A -1012 haplotype might be a greater risk factor for MM than A-1012 alone. The A allele of A-1012G was preferentially linked to G of G-1520C and was more frequent in MM patients (p = 0.011) but G of G-1520C was not (p = 0.756). The CA haplotype was a very significant risk factor for MM (p = 0.0001) while the CG haplotype was protective (p = 0.014, combined model p = 0.00002). There was no effect of GA haplotype (p = 0.931), suggesting that that the difference in frequencies of the A allele between patients and controls was accounted for by the differences in frequencies of the CA haplotype. The A allele of A-1012G was more frequent in patients with metastasis (p = 0.054) than MM patients without metastasis, as was the G allele of G-1520C (p = 0.028). The GA haplotype was more frequent in patients with metastasis (p = 0.015), while frequencies of CA were similar. We suggest that the different roles of the A allele of A-1012G in susceptibility and metastasis risk may be a function of the availability of transcription factors in the differing cellular backgrounds related to susceptibility and progression of MM.

From the bench to emerging new clinical concepts

“…Halsall et al found out that the CA haplotype was a very significant risk factor for malignant melanoma while the CG haplotype was protective. 50 There was no effect of GA haplotype. The A allele of A-1012G was more frequent in patients with metastasis than malignant melanoma patients without metastasis, as was the G allele.…”

“…Futrthermore, Halsall et al tested the hypothesis that the G(-1520)A(-1012) haplotype of the VDR promoter polymorphism might be a greater risk factor for MM than A-1012 alone. 50 The A allele of A-1012G was preferentially linked to G of G-1520C and was more frequent in malignant melanoma patients but G of G-1520C was not. Halsall et al found out that the CA haplotype was a very significant risk factor for malignant melanoma while the CG haplotype was protective.…”

“…Halsall et al suggest that the different roles of the A allele of A-1012G in susceptibility and metastasis risk may be a function of the availability of transcription factors in the differing cellular backgrounds related to susceptibility and progression of malignant melanoma. 50 In a melanoma case-control comparisons for six vitamin D receptor (VDR) gene single nucleotide polymorphisms and serum 25-hydroxyvitamin D3 levels Randerson-Moore et al found out that the FokI T allele was associated with increased melanoma risk. 51 In a meta-analysis in conjunction with published data from other smaller data sets (total 3769 cases and 3636 controls), the FokI T allele was associated with increased melanoma risk, whereas the BsmI A allele was associated with a reduced risk, in each instance under a parsimonious dominant model.…”

Relationship between vitamin D receptor (VDR) polymorphisms and the efficacy of recombinant human growth hormone (rhGH) treatment in children with idiopathic short stature

“…The A allele in position 1A-1012 (rs4516035) also contributes to different physiological processes and disorders, and may indirectly promote a GATA-3-driven T-cell switch from naive to T-helper 2 cells; this allele may influence susceptibility and metastasis under the influence of transcription factors secreted by different cellular backgrounds (Halsall et al, 2009). SNPs at the -1012 locus may be correlated with height and serum calcium concentration, in contrast with the results of our study.…”

Vitamin D-related Nutrigenetics and Cognitive Decline in an Elderly Population

“…39 Another study involving elderly subjects found significant associations between VDR-BsmI, VDR-TaqI and a low composite cognitive score (calculated by averaging the scores of other cognitive function tests) but not with a low MMSE score. 40 Additionally, a significant association was observed between VDR-ApaI and less (73) 13 (18) 138 (24) 1 (1) 16 (3) 131 ( …”