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′‐ATCTTAT‐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‐ A TCTTAT), 82 were genotype Cdx‐G (guanine at −3731 nt, 5′‐ G TCTTAT‐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 (EMSA), 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.