Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation in postmenopausal Italian women

Abstract

Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component. The discovery that inactivation of estrogen receptor alpha (ERalpha) gene is associated with low BMD indicated ERalpha as a candidate gene for osteoporosis. We have investigated the role of three ERalpha gene polymorphisms [intron 1 PVU:II and XBA:I RFLPs and TA dinucleotide repeat polymorphism 5' upstream of exon 1] in 610 postmenopausal women. There was a strong linkage disequilibrium between intron 1 polymorphic sites and also between these sites and the microsatellite (TA)(n) dinucleotide polymorphism, with a high degree of coincidence of the short TA alleles and the presence of PVU:II and XBA:I restriction sites. No significant relationship between intron 1 RFLPs and BMD was observed. A statistically significant correlation between (TA)(n) repeat allelic variants and lumbar BMD was observed (P = 0.04, ANCOVA), with subjects with a low number of repeats (TA < 15) showing the lowest BMD values. We observed a statistically significant difference in the mean +/- SD number of TA repeats between analyzed women with a vertebral fracture (n = 73) and the non-fracture group, equivalent to 2.9 (95% CI 1.56-5.72) increased fracture risk in women with a low number of repeats (TA < 15). We conclude that in this large population sample the (TA)(n) dinucleotide repeat polymorphism at the 5' end of the ERalpha gene accounts for part of the heritable component of BMD and might prove useful in the prediction of vertebral fracture risk in postmenopausal osteoporosis.

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).…”

“…It contains multiple promoter regions with alternative splice sites, resulting in expression of alternative first exons and different estrogen protein transcripts [22]. Thus (TA)n dinucleotide repeat lenght may affect alternative promoter and first exon usage resulting in different expression patterns [17]. Different expression patterns may affect the function of ESR protein and also the amounts of ESR1 protein that is produced.…”

Association of estrogen receptor ? polymorphisms with susceptibility to chronic hepatitis B virus infection

“…14,15 The level of estrogen receptor in the cytosol of peripheral blood mononuclear cells is significantly lower in asymptomatic HBV carriers and patients with chronic hepatitis than in healthy controls, and administration of IFN-␣ increases its level in a dose-dependent manner in vitro and in vivo. 16,17 Together with the genetic effect of ESR1 polymorphism on several other clinical phenotypes, including breast cancer, 33 bone mineral density, 34 hypertension, 35 lipid levels, 36 coronary atherosclerosis, 37,38 and spontaneous abortion, 39 these illustrate the pleiotropic nature of the ESR1 protein. The estrogen/estrogen receptors axis can be simultaneously involved in several different metabolic pathways, including the reproductive system, bone, cardiovascular function, immune regulation, 40,41 liver function, 42,43 and HBV replication.…”

Association of estrogen receptor α polymorphisms with breast cancer risk in older Caucasian women

“…25 In addition, increased bone mineral density, a potential surrogate marker of cumulative estrogen exposure and a predictor of breast cancer risk, 26 has also been associated with these SNP, 27,28 although not consistently. 29 These data suggest that the ESR1 2401 T/C and 2354 A/G polymorphisms may act as susceptibility or risk-modifying alleles for breast cancer. A study of 1,069 breast cancer cases and 1,166 controls in China recently reported a significant but modest increase in risk associated with the 2401 C allele (odds ratio [OR] 5 1.3 and 1.4 for heterozygotes and homozygotes, respectively).…”