Haplotypes of intron 4 of the estrogen receptor alpha gene and hip fractures: a replication study in Caucasians

We analyzed those two SNPs and another neighbour SNP located on the exon 4 of ESR1 in 787 patients with hip fractures and 953 controls from Spain.The allelic frequencies differed markedly from those reported in Asian populations. Nevertheless, haplotypes including the rs3020314 and rs1884051 loci in intron 4 showed a significant association with hip fractures (omnibus test p = 0.006 in the whole group and 0.00005 in women). In the sex-stratified analysis, the association was significant in females, but not in males. In women, the CA haplotype appeared to have a protective influence, being present in 6.5% of the controls, but only in 3% of patients with fractures (odds ratio 0.39; 95% confidence interval 0.26-0.59; estimated population preventive fraction 3.5%). The inclusion of the rs1801132 SNP of exon 4 further increased the statistical significance of the association (odds ratio 0.17; 95% CI 0.08-0.37; p = 0.00001). Each SNP appeared to contribute independently to the association. No genotype-related differences in gene expression were found in 42 femoral bone samples.This study confirms the association of some polymorphisms in the region of exon 4/intron 4 of ESR1 and hip fractures in women. However, there are marked differences in allele frequencies between Asian and Caucasian populations.Osteoporosis has a strong genetic component, and twin and family studies have shown that the variation of skeletal traits such as bone mineral density and bone size depends on heritable factors to a large extent [1,2]. Thus, for the past 15 years many studies have been performed in order to identify the genes responsible for such hereditary influence. Sex steroids play a critical role in bone homeostasis [3]. Hence, not surprisingly, estrogen-related genes, including enzymes involved in estrogen synthesis [4,5] and the estrogen receptor alpha gene (ESR1) have been widely studied. ESR1 is located on chromosome 6q25 and comprises 8 exons [6]. After the seminal work by Kobayashi