The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene

The major physiological activity of 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] is the regulation of calcium absorption in the small intestine, and the level of vitamin D receptor (VDR) is an important factor in this regulation. In a previous study, we indicated that the caudal-related homeodomain Cdx-2 played an important role in the intestine-specific transcription of the human VDR gene, In this study, the polymorphism was identified in the core sequence 5 ' -ATAAAAACTTAT-3 ' in the Cdx-2 binding site in the VDR gene promoter. In 261 Japanese women with genotyped VDR polymorphisms, 48 were genotype Cdx-A (adenine at -3731 nucleotides [nt] relative to the transcription start site of human VDR gene 5-ATAABBACTTAT), 82 were genotype Cdx-G (guanine at -3731 nt, 5 ' -GTAAAAACTTAT-3 '), and 131 were genotype Cdx-A/G (heterozygote). In postmenopausal Japanese women, the bone mineral density (BMD) in the lumbar spine (L2-L4) with the Cdx-G homozygote was 12% lower than that with the Cdx-A homozygote (p < 0.05), In electrophoretic gel mobility shift assay (ER;ISA), the oligonucleotide with Cdx-G allele markedly decreased the binding to Cdx-2 compared with that in the Cdx-A allele, The transcriptional activity of the VDR promoter with Cdx-G allele was decreased to 70% of the Cdx-A allele, In addition, in the herpes simplex virus thymidine kinase promoter, the Cdx-2 binding element with the G allele showed significantly lower transcriptional activity than that of the A allele. Thus, the polymorphism in the Cdx-2 binding site of the VDR gene (Cdx-polymorphism) would affect the expression of VDR in the small intestine. In addition, this polymorphism may modulate BMD in postmenopausal Japanese women.