BONE-MINERAL DENSITY AND ITS CHANGE IN WHITE WOMEN - ESTROGEN AND VITAMIN-D-RECEPTOR GENOTYPES AND THEIR INTERACTION

Low bone mineral density (BMD) is a major risk factor for development of osteoporosis; increasing evidence suggests that attainment and main tenance of peak bone mass as well as bone turnover and bone loss have strong genetic determinants. We examined the association of BMD levels and their change over a 3-year period, and polymorphisms of the estro gen receptor (ER), vitamin D receptor (VDR), type I collagen, osteonec tin, osteopontin, and osteocalcin genes in pre-and perimenopausal wome n who were part of the Michigan Bone Health Study, a population-based longitudinal study of BMD. Body composition measurements, reproductive hormone profiles, bone-related serum protein measurements, and life-s tyle characteristics were also available on each woman. Based on evalu ation of women, ER genotypes (identified by PvuII [rr = 253] and XbaI [n = 248]) were significantly predictive of both lumbar spine (p < 0.0 5) and total body BMD level, but not their change over the 3-year peri od examined. The VDR BsmI restriction fragment length polymorphism was not associated with baseline BMD, change in BMD over time, or any of the bone-related serum and body composition measurements in the 372 wo men in whom it was evaluated. Likewise, none of the other polymorphic markers was associated with BMD measurements. However, we identified a significant gene x gene interaction effect (p < 0.05) for the VDR loc us and PvuII (p < 0.005) and XbaI (p < 0.05) polymorphisms, which impa cted BMD levels. Women who had the (-/-) PvuII ER and bb VDR genotype combination had a very high average BMD, while individuals with the (- /-) PvuII ER and BE VDR genotype had significantly lower BMD levels. T his contrast was not explained by differences in serum levels of osteo calcin, parathyroid hormone, 1,25-dihydroxyvitamin D, or 25-dihydroxyv itamin D. These data suggest that genetic variation at the ER locus, s ingly and in relation to the vitamin D receptor gene, influences attai nment and maintenance of peak bone mass in younger women, which in tur n may render some individuals more susceptible to osteoporosis than ot hers.