ESR1 CA(n) repeat polymorphism is associated with increased risk of osteoporotic fractures and estrogen receptor alpha: mrna expression in bone

Abstract

Introduction: Recent studies have shown that intronic CA dinucleotide repeat polymorphisms may be associated with disease risk by modulating mRNA splicing efficiency. D6S440 is a newly identified intronic CA repeat polymorphism located downstream of the 5’-splicing site of exon 5 of estrogen receptor alpha gene (ESR1). Methods: To evaluate the role of D6S440 in bone mineral density (BMD) determination and osteoporosis outcomes prediction, 281 pairs of premenopausal and 395 pairs of postmenopausal Chinese female case-control subjects were studied. The functional significance of D6S440 in determining estrogen receptor (ER ) gene expression was examined in human bone. Results: Post- but not premenopausal women with less CA repeats had lower BMD at both spine and hip. A linear relationship was seen between the number of CA repeats and hip BMD in postmenopausal women (;=0.008; p=0.004). Postmenopausal women with less than 18 CA repeats had higher risks of osteoporosis at the spine (odds ratio (OR) 2.46, 95% confidence interval (CI) 1.30–4.65; p=0.0006) and hip (OR 3.79(1.64–8.74), p=0.0002), and also increased risk of spine and hip fractures (OR 2.31(1.29–4.14), p=0.005). Perimenopausal women with CA repeat size <18 had significantly greater bone loss at the hip (-1.96%) than those with CA repeat size R18 (-1.61%; p=0.029) during 18 months of observation. Subjects with fewer CA repeats had reduced ER mRNA expression in their bone cells. Conclusions: ESR1 CA repeat polymorphism is associated with multiple osteoporosis outcomes and mRNA expression in bone, and this may be a useful genetic marker for fracture risk assessment.