Two single-nucleotide polymorphisms in the human vitamin D receptor promoter change protein–DNA complex formation and are associated with height and vitamin D status in adolescent girls

Abstract

Numerous association studies have dealt with single-nucleotide polymorphisms (SNPs) in coding and intronic regions of the human vitamin D receptor (hVDR) gene. We have hypothesized that phenotypic traits may also be associated with variations in VDR expression due to the presence of SNPs in promoter regions. In this work, we have studied two SNPs located 1521 bp (G/C) and 1012 bp (A/G) upstream of the transcriptional start site of the main human VDR gene promoter. One base-change in any of the two variant sites led to a dramatic change in protein-DNA complex formation using nuclear extracts from HEK293, Caco-2 and COS-7 cells. Genetic analysis of 185 healthy adolescent girls evidenced two major haplotypes: 1521G/1012A and 1521C/1012G and three main genotypes: homozygous for 1521G/1012A (21.1%), homozygous for 1521C/1012G (17.3%) and heterozygous 1521CG/1012GA (57.3%). On the basis of transfection data, promoter activity was nearly 2-fold higher with the 1521G/1012A haplotype, when compared with the 1521C/1012G haplotype. Clinical and biological association study in the adolescent cohort showed that girls with a CC/GG genotype had (i) lower circulating levels of 25-dihydroxyvitamin D, with no detectable consequence on calcium metabolism, (ii) lower serum IGF-1 levels and (iii) smaller height from 11 years of age up to adult height.

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

“…We have shown in gel shift assays that GATA-3 binds preferentially to the A allele of A-1012G (unpublished results) and d'Alesio et al 9 and Fang et al 10 have also shown that GATA binding occurs preferentially at the A allele. Both also showed increased promoter activity of the A allele of A-1012G in reporter assays.…”

A Prospective Nested Case-Control Study of Vitamin D Status and Pancreatic Cancer Risk in Male Smokers

“…This concept may be indirectly supported by positive associations that have been observed between height and pancreatic cancer by others (30,31), as well as in this nestedcase control study. Vitamin D receptor polymorphisms have been associated with adult stature (32)(33)(34) and adult height may be a marker for exposure to growth factors during childhood and adolescence. Alternatively, vitamin D status could be correlated to unmeasured exposures that may increase pancreatic cancer risk.…”

Association of vitamin D-related gene polymorphisms with manifestation of vitamin D deficiency in children

“…We selected polymorphisms that have been reported to be associated with serum 25(OH)D levels in either GWAS or candidate gene studies [8,9,11,12,[15][16][17][18][19][20]. Well-known VDR polymorphisms reported to be associated with bone mineral density and several vitamin D-related diseases were also included [21][22][23].…”