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)under bar> (the (M) under bar allele is ATG at the putative translation start site), 75 (31%) were genotype <(mm)under bar> (the (m) under bar allele is ACG at the putative translation start site), and 132 (55%) were genotype <(Mm)under bar>. 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)under bar> homozygotes than for <(MM)under bar> homozygotes, Synthesis of the proteins by the (M) under bar and (m) under bar 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) under bar 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 similar to 1.7-fold greater for the (m) under bar type VDR than for the (M) under bar type protein. These results suggest that the polymorphism at the translation start site of the VDR gene may modulate BMD in premenopausal Japanese women.