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

J Bone Miner Res. 2001 Jul;16(7):1256-64. doi: 10.1359/jbmr.2001.16.7.1256.

Abstract

The major physiological activity of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] 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-ATAAAAACTTAT), 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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Animals
  • Base Sequence
  • Binding Sites
  • Bone Density / genetics
  • CDX2 Transcription Factor
  • COS Cells
  • Electrophoretic Mobility Shift Assay
  • Female
  • Gene Expression Regulation
  • Genotype
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Japan
  • Menopause
  • Middle Aged
  • Osteoporosis, Postmenopausal / genetics
  • Polymorphism, Genetic / genetics*
  • Promoter Regions, Genetic / genetics
  • Receptors, Calcitriol / genetics*
  • Response Elements / genetics*
  • Spine / physiology
  • Trans-Activators
  • Transfection
  • Tumor Cells, Cultured

Substances

  • CDX2 Transcription Factor
  • Homeodomain Proteins
  • Receptors, Calcitriol
  • Trans-Activators