A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women.
The effect of a T-C transition polymorphism at the translation initiation codon of the human vitamin D receptor (VDR) gene on the biological function of the encoded protein was investigated. Of 239 Japanese women volunteers subjected to genotype analysis for this polymorphism, 32 (13%) were genotype MM (the M allele is ATG at the putative translation start site), 75 (31%) were genotype mm (the m allele is ACG at the putative translation start site), and 132 (55%) were genotype Mm. The bone mineral density (BMD) in the lumbar spine (L2-L4) was determined for 110 healthy premenopausal women from the volunteers and was shown to be 12.0% greater (p < 0.05) for mm homozygotes than for MM homozygotes. Synthesis of the proteins by the M and m alleles from the cloned cDNAs in vitro and in transfected COS-7 cells revealed them to have a size of 50 and 49.5 kD, respectively, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is consistent with initiation of translation of the M allele-encoded protein from an ATG codon located at nucleotides +10 to +12 in the conventional open reading frame. The extent of vitamin D-dependent transcriptional activation of a reporter construct under the control of a vitamin D response element in transfected HeLa cells was approximately 1.7-fold greater for the m type VDR than for the M type protein. These results suggest that the polymorphism at the translation start site of the VDR gene may modulate BMD in premenopausal Japanese women.
Arai
H
H
Department of Clinical Nutrition, School of Medicine, Tokushima University, Japan.
Miyamoto
K
K
Taketani
Y
Y
Yamamoto
H
H
Iemori
Y
Y
Morita
K
K
Tonai
T
T
Nishisho
T
T
Mori
S
S
Takeda
E
E
D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D015519:Bone Density / Q000235:genetics*; D019556:COS Cells; D018387:Codon, Initiator / Q000235:genetics; D004247:DNA / Q000235:genetics; D005091:Exons; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007564:Japan; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D018387:Codon, Initiator; D018167:Receptors, Calcitriol; D004247:DNA