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

Background Despite their great impact, few genetic association studies have used hip fractures as an endpoint. However, the association of two polymorphisms on intron 4 of estrogen receptor alpha ( ESR1 ) with hip fractures was recently reported in a Chinese population. The aim of this study was to investigate whether such association is also present in Caucasians. Methods 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. Results 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. Conclusions 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.