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 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.
Arai
H
H
Department of Clinical Nutrition, School of Medicine, University of Tokushima, Japan.
Miyamoto
K I
KI
Yoshida
M
M
Yamamoto
H
H
Taketani
Y
Y
Morita
K
K
Kubota
M
M
Yoshida
S
S
Ikeda
M
M
Watabe
F
F
Kanemasa
Y
Y
Takeda
E
E
D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015519:Bone Density / Q000235:genetics; D000071616:CDX2 Transcription Factor; D019556:COS Cells; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007564:Japan; D008593:Menopause; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics*; D020218:Response Elements / Q000235:genetics*; D013131:Spine / Q000502:physiology; D015534:Trans-Activators; D014162:Transfection; D014407:Tumor Cells, Cultured
D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; D018167:Receptors, Calcitriol; D015534:Trans-Activators