Estrogen receptor beta polymorphisms predict risks of osteoporosis in men and women: A linkage and association study

Abstract

Estrogen receptor beta is expressed in both osteoblast and osteoclast and estrogen receptor beta gene (ESR2) is likely to play a role in bone mass determination. We previously reported a weak association between a dinucleotide CA repeat polymorphism (D14S1046) in the intronic region of ESR2 with bone mineral density (BMD) in women. To evaluate the role of ESR2 in BMD determination and osteoporosis risk prediction in men and women, linkage and association approach were utilized by evaluating 1484 subjects from 306 extended southern Chinese pedigrees and 770 pairs of population-based case-control subjects. The cases were subjects with BMD Z score <-1.3 at either the spine or total hip region (equivalent to the lowest 10th percentile of the population) and the controls were subjects with BMD Z score > +1. Out of 11 SNPs, a SNP in the promoter region (nt -1068T→C) was in significant linkage diseqilibrium with 21 CA repeats of D14S1046. Using Merlin program, 6 tagged SNPs were in linkage with spine BMD (LOD 1.50 to 1.67, p=0.003) and femoral neck BMD (LOD 1.21, p=0.009). Using quantitative trait disequilibrium test (QTDT), nt -1068T→C was found to be associated with hip BMD in women (p=0.005) but not in men in both total family association and within-family association testing. In the population-based study, nt -1068T→C was associated with 10% reduction in spine and hip BMD in men, 4% reduction in spine BMD in premenopausal women and 4--6% reduction in spine and hip BMD in postmenopausal women. Furthermore, this SNP was associated with higher risk of osteoporosis at the lumbar spine (male: odds ratio 3.4, female: odds ratio 2.8) and at the hip (male: odds ratio 1.9, female: odds ratio 2.9). SNP haplotype analysis provided similar results as individual SNP analysis. In conclusion, nt -1068T→C polymorphism of the ESR2 gene is associated with lower BMD and higher risk of osteoporosis in both males and females. This SNP may serve as a potential marker for assessing the risk of osteoporosis and identification of at risk subjects.