A specific haplotype in the 3' end of estrogen-receptor alpha gene is associated with low bone mineral density in premenopausal women and increased risk of postmenopausal osteoporosis.

It is well established that the development of postmenopausal osteoporosis is under genetic influence. We have recently identified a synonymous single nucleotide polymorphism (SNP) in exon 8 of estrogen receptor-alpha (ERalpha) gene in the vicinity of the stop codon (G2014A) that is associated with an increased risk of postmenopausal osteoporosis. In the present study, we attempted to locate SNPs in the 3'-unstranslated region (3'UTR) of the ERalpha gene that are in linkage disequilibrium with the exon 8 SNP and assessed their utilization in the risk assessment of postmenopausal osteoporosis in 352 Thai postmenopausal women. The association with bone mineral density (BMD) in premenopausal women was also investigated in 202 premenopausal women. A C to A SNP 1,748 nucleotides distal to the end of the stop codon (C3768A) was identified. The C3768A SNP was not overrepresented in subjects with osteoporosis. However, the presence of the A-C haplotype allele based on the A2014 and C3768 alleles was significantly related to the risk of osteoporosis independently of age, body weight, the G2014A and C3768A SNPs (odds ratio 2.36, 95% CI 1.42-3.91). Moreover, the presence of the A-C haplotype allele was associated with lower femoral neck BMD in premenopausal women ( P =0.05). We concluded that a specific haplotype in the 3' end of the ERalpha gene is associated with lower BMD in premenopausal women and is associated with a higher risk of osteoporosis in postmenopausal women. It is likely that the haplotype allele exerts its influence on bone as early as during young adulthood to increase the risk of osteoporosis later in life.