Dinucleotide CA repeat polymorphisms in ESR1 gene are associated with increased risk of low BMD and osteoporotic fractures

Abstract

Studies of PvuII and XbaI polymorphisms of the estrogen receptor alpha (ESR1) gene have shown that these intronic polymorphisms may be associated with fracture risk, but their relation with bone mineral density (BMD) is controversial. We postulated that other polymorphic sites of ESR1 may be of importance in determining osteoporosis and fracture risk, such as the dinucleotide CA repeats polymorphism (D6S440) in intron 5 of the gene. To assess the role of D6S440 as a marker for predicting risk of low BMD and osteoporotic fractures, we studied 770 Southern Chinese case-control pairs (93 male, 677 female pairs). Cases were subjects with BMD Z scores <-1.28 at either the spine or hip (equivalent to lowest 10th percentile of the population), and controls were subjects with BMD T scores >+1. Among them, 88 perimenopausal women (aged 45--55years) were studied at 18 months to determine the association between the CA repeat and rate of bone loss. All subjects were followed prospectively for incidence of osteoporotic fractures. The results showed that allele size shorter than 18 CA repeats (CA<18) were associated with 6% reduction in hip BMD (p<0.01) and 3% reduction in lumbar spine BMD (p<0.05) in female but not male subjects. During the 18 month study period, peri-menopausal women carrying CA<18 demonstrated greater bone loss at the hip than those with CA>18. (2.65% vs 0.468%, p=0.01). Postmenopausal women with CA<18 had a 5-fold increase in osteoporosis risk and a 2-fold increase in fracture risk at both the spine and hip (p<0.01) These results indicate that ESR1 CA repeats may be a useful diagnostic marker for osteoporosis and fracture risk assessment in peri- and postmenopausal women.