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 initiat ion codon of the human vitamin D receptor (VDR) gene on the biological function of the encoded protein was investigated, Of 239 Japanese wom en 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)u nder bar> (the (m) under bar allele is ACG at the putative translation start site), and 132 (55%) were genotype <(Mm)under bar>. The bone mi neral density (BMD) in the lumbar spine (L2-L4) was determined for 110 healthy premenopausal women from the volunteers and was shown to be 1 2.0% 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 trans fected COS-7 cells revealed them to have a size of 50 and 49.5 kD, res pectively, 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 c odon located at nucleotides +10 to +12 in the conventional open readin g frame. The extent of vitamin D-dependent transcriptional activation of a reporter construct under the control of a vitamin D response elem ent 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.