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

Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component. The discovery that inactivation of estrogen receptor alpha (ERalpha) gene is associated with low BMD indicated ERalpha as a candidate gene for osteoporosis. We have investigated the role of three ERalpha gene polymorphisms [intron 1 PVU:II and XBA:I RFLPs and TA dinucleotide repeat polymorphism 5' upstream of exon 1] in 610 postmenopausal women. There was a strong linkage disequilibrium between intron 1 polymorphic sites and also between these sites and the microsatellite (TA)(n) dinucleotide polymorphism, with a high degree of coincidence of the short TA alleles and the presence of PVU:II and XBA:I restriction sites. No significant relationship between intron 1 RFLPs and BMD was observed. A statistically significant correlation between (TA)(n) repeat allelic variants and lumbar BMD was observed (P = 0.04, ANCOVA), with subjects with a low number of repeats (TA < 15) showing the lowest BMD values. We observed a statistically significant difference in the mean +/- SD number of TA repeats between analyzed 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 population sample the (TA)(n) dinucleotide repeat polymorphism at the 5' end of the ERalpha gene accounts for part of the heritable component of BMD and might prove useful in the prediction of vertebral fracture risk in postmenopausal osteoporosis.