Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation inpostmenopausal Italian women

Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component, The discovery that inactivation of es trogen receptor alpha (ER alpha) gene is associated with low BMD indicated ER alpha as a candidate gene for osteoporosis, We have investigated the rol e of three ER alpha gene polymorphisms [intron 1 PvuII and XbaI RFLPs and T A dinucleotide repeat polymorphism 5' upstream of exon 1] in 610 postmenopa usal women, There was a strong linkage disequilibrium between intron 1 poly morphic sites and also between these sites and the microsatellite (TA)(n) d inucleotide polymorphism, with a high degree of coincidence of the short TA alleles and the presence of PvuII and XbaI restriction sites, No significa nt relationship between intron 1 RFLPs and BMD was observed, A statisticall y significant correlation between (TA)(n) repeat allelic variants and lumba r BMD was observed (P = 0.04, ANCOVA), with subjects with a low number of r epeats (TA < 15) showing the lowest BMD values, We observed a statistically significant difference in the mean +/- SD number of TA repeats between ana lyzed women with a vertebral fracture (n = 73) and the non-fracture group, equivalent to 2.9 (95% CI 1.56-5.72) increased fracture risk in women with a low number of repeats (TA < 15), We conclude that in this large populatio n sample the (TA)(n) dinucleotide repeat polymorphism at the 5' end of the ER alpha gene accounts for part of the heritable component of BMD and might prove useful in the prediction of vertebral fracture risk in postmenopausa l osteoporosis.