Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk

Abstract

This study investigates the influence of genetic variation of the estrogen receptor alpha (ESR1) gene locus on several bone parameters in 2042 individuals of The Rotterdam Study, a prospective population-based cohort study of elderly subjects. We analysed three polymorphic sites in the 5' region of the ESR1 gene; a (TA)(n)-repeat in the promoter region, and molecular haplotypes of the PvuII and XbaI RFLPs in intron 1, and inferred long-range haplotypes (LRH) thereof. We observed only three of the possible four PvuII-XbaI haplotypes in our population. A comparison with other Caucasian populations showed similar haplotype frequencies, while in Asian and African populations these were different. Linkage disequilibrium (LD) analysis between the PvuII-XbaI haplotype and the (TA)(n) repeat showed strong LD between the two sites. Reconstruction of long range haplotypes over the entire 5' region, revealed six frequent LRH. In men, we did not observe an association between the ESR1 polymorphisms studied and bone parameters. In women, we demonstrated an allele dose effect of haplotype "px" (P=0.003) and a low number of (TA)(n) repeats (P=0.008) with decreased lumbar spine bone mineral density (BMD) (4.8% lower BMD in women homozygous for haplotype "px", representing 28% of the population, compared with homozygous non-carriers) and decreased vertebral bone area (2.3% difference between extreme genotypes; P=0.016). Most importantly, we found an increased vertebral fracture risk with evidence for an allele dose effect with an odds ratio of 2.2 (95%CI 1.3-3.5) for haplotype "px", and 2.0 (1.5-3.2) for a low number of (TA)(n) repeats. The ESR1 genotype dependent fracture risk is largely independent of BMD and bone area. Combination of risk alleles at both loci by long-range haplotyping improved the associations slightly, but because of the strong LD between the two polymorphic sites, we were unable to determine if any particular polymorphic site is driving the associations found. We conclude that ESR1 polymorphism in the 5' (promoter) region is associated with vertebral fracture risk, lumbar spine BMD and vertebral bone area in postmenopausal women, but not in men. The molecular mechanism underlying this association needs further study.

Evaluation of in vitro fertilization parameters and estrogen receptor alpha gene polymorphisms for women with unexplained infertility

“…3). This polymorphism showed a bimodal distribution, with two peaks at 13 repeats (35.3% of alleles) and 21 repeats (10.9% of alleles), and a breakpoint at 18 TA repeats as reported previously [17][18][19]. This cutoff point was used to divide alleles into categories of either short (S<18 TA repeats) or long alleles (L≥18 TA repeats).…”

Hypercoagulability in adolescent girls on oral contraceptives‐global coagulation profile and estrogen receptor polymorphisms

“…Estrogenic actions are thought to decrease when the number of receptors decreases. Others have reported an association between ER-a T > C polymorphism and phenotypes with low estrogen levels and activity, such as osteoporosis, early menopause, and hysterectomy [11]. Indeed, some women appear more sensitive to the effects of estrogen than others.…”

“…The biological effects of estrogen are mediated primarily through estrogen receptor a (ER-a), which is a ligand-activated transcription factor, composed of several domains important for hormone binding [11]. ER-a single nucleotide polymorphisms (SNPs) act by modulating the estrogen receptors and estrogen levels, and have been shown to be independent risk factors for VTE [12].…”

Active and passive smoking, IL6, ESR1, and breast cancer risk

“…The 351A > G XbaI polymorphism of the ESR1 gene was evaluated by PCR amplifying as previously described [32]. The 'X' or A allele was cut yielding bands of 148 bp and 198 bp, whereas the 'X' or G allele remained uncut and resulted in a band of 346 bp as modified from van Meurs et al [19].…”

“…The three most widely studied polymorphisms of the ESR1, the PvuII 397T > C, the XbaI (351A > G) restriction fragment length polymorphisms, both located in intron 1, and the TA repeat within the promoter region of the gene, are in linkage disequilibrium [18,19]. These polymorphisms have been examined with breast cancer risk [20][21][22][23] as well as with other conditions that have been linked to estrogen [19,24,25] with mixed results.…”