ERα Gene Polymorphisms Research Articles

Efficacy of ER-α Polymorphisms and the Intrafollicular IGF System for Predicting Pregnancy in IVF-ET Patients

Aims: To evaluate the efficacies of the estrogen receptor-α (ER-α) gene polymorphisms and of the intrafollicular insulin-like growth factor (IGF) system for predicting pregnancy in in vitro fertilization and embryo transfer (IVF-ET) patients. Methods: A total of 96 patients undergoing IVF-ET were included in this study. Genotyping for the ER-α gene PvuII and XbaI polymorphisms was performed using polymerase-chain reaction and single base extension method. Follicular fluid (FF) IGF-I, IGF-II, and IGFBP-3 concentrations were measured by RIA, and IGFBP-4 by ELISA. We compared, between pregnant (n = 28) and non-pregnant groups (n = 68), the allele frequency, genotype distribution and haplotype distribution of PvuII and XbaI polymorphisms, and then FF IGF-I, IGF-II, IGFBP-3, IGFBP-4 concentrations and their ratios. Results: No significant differences were found between the two groups in terms of allele, genotype or haplotype distributions of the ER-α gene PvuII and XbaI polymorphisms between the two groups. The mean FF IGF-I/IGFBP-3 ratio was significantly higher in the pregnant group (5.9 ± 1.5 vs. 4.8 ± 1.5 ×10^–2). Conclusions: The intrafollicular IGF-I/IGFBP-3 ratio of the FF of the dominant follicle during oocyte retrieval appears to be related to the establishment of pregnancy in IVF-ET patients, whereas the ER-α gene PvuII and XbaI polymorphisms do not.

MUC1 and estrogen receptor α gene polymorphisms in dry eye patients

Dry eye syndrome is a collection of common disorders of multifactorial etiology. Although the epidemiology of dry eye has been well studied, reports of genetic patterns that might influence susceptibility to dry eye are few. We reported that the frequency of non-Sjögren's aqueous-deficient dry eye patients expressing only the MUC1/A splice variant of the mucin MUC1 may be lower than that of a normal control group [Imbert, Y., Darling, D.S., Jumblatt, M.M., Foulks, G.N., Couzin, E.G., Steele, P.S., Young, W.W., Jr., 2006. MUC1 splice variants in human ocular surface tissues: possible differences between dry eye patients and normal controls. Exp. Eye Res. 83, 493–501]. Also, He et al. [He, Y., Li, X., Bao, Y., Sun, J., Liu, J., 2006. The correlation of polymorphism of estrogen receptor gene to dry eye syndrome in postmenopausal women. Yan. Ke. Xue. Bao. 22, 233–236] reported a difference between Chinese dry eye and control groups in the frequency of a polymorphism in estrogen receptor α (ERα). In the present study we determined the statistical significance and generality of these observations and tested if the MUC1 splice variant difference between subject groups reflected a difference in the MUC1 variable number of tandem repeat (VNTR) size class. There was a perfect correlation between the MUC1/A or MUC1/B splice variant pattern and the SNP genotype frequency of the SNP (rs4072037) controlling that splicing event. In contrast, western and Southern blotting indicated that MUC1 VNTR size class corresponded to the MUC1 SNP genotype in only 80% of cases. We determined the status of the MUC1 SNP in normal and dry eye populations all of whom were female Caucasians. The MUC1 SNP genotype frequency of the normal control group was statistically different from both the non-Sjögren's aqueous-deficient dry eye group with ocular surface staining (P=0.017) and the evaporative dry eye group (P=0.015). We also tested SNP rs2234693 to analyze the polymorphism in the ERα gene and found no significant difference in the SNP genotype frequency between the control group and either of the dry eye subtypes. Thus, among Caucasians there is no evidence for an association of the ERα gene polymorphism with dry eye syndrome as previously described in a Chinese population. In conclusion, the etiologies of evaporative dry eye and non-Sjögren's aqueous-deficient dry eye are known to be different. However, our results suggest that both of these subtypes of dry eye disease may share a common mechanism or factor related to MUC1 genotypic differences that affects susceptibility to ocular surface damage. This altered susceptibility may not be related to the MUC1 VNTR size class. Therefore, mechanisms influencing protection of the ocular surface against inflammation and damage in different types of dry eye disease warrant further investigation particularly in relation to MUC1 genotype.

Association between oestrogen receptor gene polymorphism and mortality in female end-stage renal disease patients

In the general population, genetic variations in the oestrogen receptor alpha (ERalpha) gene may influence lipid abnormalities, cardiovascular disease (CVD), and mortality, but this has not previously been studied in end-stage renal disease (ESRD) patients. A total of 227 ESRD (141 men and 86 women) patients starting renal replacement therapy (RRT) were genotyped for three ERalpha gene polymorphisms (Ser10Ser, PvuII and XbaI) and the associations between these polymorphisms and clinical and laboratory parameters and survival were analysed. Patients were followed for a median period of 55 months (range 1-126 months). The PvuII and XbaI polymorphisms were not associated with any of the clinical parameters. The ERalpha Ser10Ser CC genotype was present in 24 (28%) of the female and in 37 (26%) of the male patients. When comparing the CC genotype with the CT and TT genotypes, there were significant differences in lipid levels and inflammatory marker levels, especially in female patients. In female patients, the CC genotype was associated with lower prevalence of protein energy wasting (PEW) (17.4% vs 43.1%; P=0.03), lower median serum triglyceride (1.7 vs 2.1 mmol/l; P=0.001), higher median serum albumin (34.0 vs 32.5 g/l; P=0.03) and lower median high sensitivity-CRP (hsCRP) (2.2 vs 5.5 mg/l; P=0.03) levels compared with the CT plus TT genotypes. In male patients only HDL-cholesterol and ApoA levels were associated with this polymorphism. Whereas this polymorphism did not influence survival in males, the mortality was lower in female patients with the CC genotype (Kaplan-Meier; Log-rank 2.2, P=0.02). Moreover, female patients with the CT plus TT genotypes had a borderline significant increased relative risk (Cox hazard model; 6.6, 95% CI: 0.87-49.9 P=0.06) of death as compared with those with the CC genotype, even after adjustment for age and prevalence of CVD. Female, but not male ESRD patients with the ERalpha Ser10Ser CC genotype had lower prevalence of PEW, lower serum triglyceride, higher serum albumin and lower hsCRP levels. As this genotype was associated with a significantly decreased risk of all-cause death during the initial years of RRT, its protective properties need further study.

Relationship between estrogen receptor-α polymorphism and serum levels of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, C-reactive protein and homocysteine in postmenopausal women

Background and aim. Genetic variation in the estrogen receptor-α gene (ERα) may influence the risk of cardiovascular diseases in postmenopausal women. This effect, at least in part, may be dependent on the decrease in expression of injury and inflammatory markers in the vascular wall. The aim of the present study was to evaluate the relationship between ERα PvuII and XbaI polymorphisms and serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP) and homocysteine in postmenopausal women.Subjects and methods. Subjects of the study were 64 postmenopausal women. PvuII and XbaI ERα gene polymorphisms were analyzed by polymerase chain reaction–restriction fragment length polymorphism.Results. Mean sVCAM-1 level was significantly higher in pp homozygotes in comparison with PP homozygotes and Pp heterozygotes, as well as higher in xx homozygotes in comparison with XX homozygotes and Xx heterozygotes. Levels of sVCAM-1 were also significantly higher in women with px haplotype compared with PX and Px haplotypes. There were no relationships between investigated genotypes or haplotypes and levels of sICAM-1, CRP and homocysteine.Conclusion. The results of our study suggest that genetic variation in ERα gene may influence blood levels of VCAM-1 in women after the menopause.

Estrogen receptor α and β polymorphisms

A cross-sectional segregation analysis of polymorphisms in the estrogen receptor (ER) genes (Pvull and Xbal in ERalpha, and Alul in ERAbeta with bone mineral density in the lumbar spine and forearm and with lipid profile was performed in 1098 postmenopausal women. Additionally, in a subpopulation of 280 women, who completed 1 year of treatment with estrogen plus progestin, the association between genotypes and the response to treatment in both plasma lipids and bone was investigated. In another untreated subpopulation of 443 women, genotype influence on the prevalence of vertebral fractures and on annual rate of bone loss during a mean follow-up period of 11 years was estimated. Baseline plasma lipids, bone mineral density, annual rate of bone loss and prevalence of spinal fractures were not significantly associated with polymorphisms in the ERbeta gene. The ERA polymorphism was significantly associated with bone loss from the distal forearm (P = 0.04) but not with bone loss from the spine. After 1 year of treatment with hormone therapy there was also a significant association between the ERbeta polymorphism and the response in total cholesterol (P = 0.02); while the ERalpha gene polymorphisms did not significantly influence the response to hormone therapy. In a large white population of postmenopausal women, ERalpha gene polymorphisms were not associated with bone mineral density or lipid profile at baseline or after hormone therapy. Conversely, the ERbeta genotype appeared to segregate with bone loss from the forearm and to modulate the decrease in total cholesterol during hormone therapy.

Estrogen receptor gene polymorphisms are associated with recurrence of endometriosis

The presence of gene polymorphisms of the estrogen receptors ERalpha (PvuII and XbaI) and ERbeta (AluI) in 61 women with endometriosis was investigated. A statistically significant correlation between PvuII ERalpha gene polymorphism (PvuII), both in homozygosity (PP) and in heterozygosity (Pp), and a recurrence of endometriosis was found. In conclusion, women affected by endometriosis with the ERalpha polymorphic allele, even if heterozygous, have a worse prognosis, and these results suggest that the ERalpha gene polymorphisms may be included among the genetic risk factors for endometriosis.

Estrogen receptor alpha gene polymorphisms are associated with changes in bone remodeling markers and treatment response to estrogen

Objectives Association studies between estrogen receptor α (ERα) gene polymorphisms and bone mineral density (BMD) have yielded inconsistent results. In the present study we evaluated the influence of XbaI and PvuII ERα gene polymorphisms on BMD, biochemical markers, rates of bone loss and the response to estrogen/hormone therapy (ET/HT) in elderly postmenopausal women. Methods At baseline, we measured the association between ERα genotypes and BMD and biochemical markers in 489 elderly women, mean age 71 ± 3 years. In the longitudinal study, the changes in the same measures were determined in 96 women on placebo and in 79 women receiving the ET/HT for 3 years. The XbaI and PvuII ERα polymorphisms were determined by polymerase chain reaction (PCR). BMD measurements for spine, femoral neck and total body were performed by DEXA, and biochemical indices were measured by standard methods. Results Neither the PvuII nor the XbaI ERα gene polymorphisms were associated with baseline BMD and biochemical indices. In the longitudinal study, there were trends for higher bone loss in the placebo group in the genotypes pp or xx compared to PP or XX genotypes, but the changes were not significant. However, the changes in the bone markers were significantly ( p < 0.05) higher in genotype group pp compared to PP (serum osteocalcin, 4.9 ± 7.0% versus −13.4 ± 6.7%; urine NTx:Cr ratio, 32.3 ± 10.3% versus −2.5 ± 10.3%) or xx compared to XX (serum osteocalcin, 7.5 ± 6.4% versus −15.6 ± 7.3%; urine NTx:Cr ratio, 39.4 ± 9.2% versus −8.84 ± 10.7%). At the end of 3 years, the mean urine NTx:Cr ratio was 78.7 ± 9.0 versus 44.6 ± 4.9 in pp versus PP ( p < 0.05) and 75.5 ± 10.7 versus 48.7 ± 5.4 in xx versus XX ( p < 0.05) genotypes. The response in total body BMD to ET/HT treatment was significantly higher in women with the PP genotype compared to pp genotype (2.48 ± 0.55% versus 0.66 ± 0.46%). Similar trends were seen at other skeletal sites for both XX and PP compared to pp and xx genotypes. Conclusion Women with ERα, PP and XX genotypes have lower bone remodeling, lower rates of bone loss and benefit more from hormone therapy.

Association and haplotype analyses of the COL1A2 and ER-α gene polymorphisms with bone size and height in Chinese

Bone size (BS) is another risk factor of fracture independent of BMD in determining bone strength, and height is highly related with BS. To test the effect of the estrogen receptor-α (ER-α) and collagen type I α 2 (COL1A2) genes on the variation of BS and height, we genotyped the PvuII and XbaI polymorphisms in the intron 1 of the ER-α gene and the MspI and ( GT) n markers in the intron 47 and intron 1 of the COL1A2 gene in 400 Chinese nuclear families with a total of 1256 individuals. The BS at the hip and spine was measured using a Hologic QDR 2000 dual-energy X-ray absorptiometry (DXA) scanner. Population stratification, total-family association, and within-family association were used to test the relationship of BS (at the spine and hip) and height with the four polymorphisms. We also performed these association analyses with the haplotypes of the MspI and ( GT) n polymorphisms in the COL1A2 gene, and with the haplotypes of the PvuII and XbaI markers in the ER-α gene. Weak within-family association was found between the COL1A2- MspI ( P = 0.05) and the femoral neck BS, between the ER-α- PX ( P = 0.04) and the intertrochanter BS, and between the COL1A2-( GT) 17 ( P = 0.02), COL1A2- m( GT) 17 ( P = 0.009) and height. Subsequent permutation tests generally confirmed the suggestive within-family association. For the weak within-family association, the proportions of phenotypic variance accounted by the COL1A2- MspI, ER-α- PX, COL1A2-( GT) 17 , COL1A2- m( GT) 17 markers were 1.50%, 1.51%, 2.15%, and 2.43% for the corresponding phenotypes. The association results indicate that the ( GT) n and MspI markers of COL1A2 gene may have some influence on the variation of both BS and height, and the XbaI and PvuII markers of ER-α gene may have some effect on the variation of height in Chinese but not on the variation of BS.

Polymorphisms in ER-α Gene Interact with Estrogen Receptor Status in Breast Cancer Survival

Abstract Purpose: The effects of estrogens are mediated primarily through estrogen receptor (ER) in breast tissue, and polymorphisms in the ER genes may alter the functions of these receptors. Polymorphisms in the ER-α gene have been reported to be associated with breast cancer risk. However, to our knowledge, no study has been published on the relation between ER-α gene polymorphisms and breast cancer survival. Experimental Design: To determine whether three common polymorphisms in the ER-α gene, PvuII, XbaI, and GT dinucleotide repeats are associated with breast cancer survival, we evaluated data from a cohort of 1,069 breast cancer patients who participated in the Shanghai Breast Cancer Study between 1996 and 1998. The median follow-up time for this cohort of women was 5.2 years. Results: No overall association was observed between ER gene polymorphisms and breast cancer survival. The genotype associations, however, were modified by ER status in breast cancer tissues. Comparing those with the PP genotype to the pp genotype of the PvuII polymorphism, the hazard ratios (HR) of dying were 3.30 [95% confidence interval (95% CI), 1.42-7.69] and 0.54 (95% CI, 0.24-1.23), respectively, for participants with ER-negative breast cancer and ER-positive breast cancer. Similarly, compared with those with no (GT)23 alleles, carrying one or two (GT)23 alleles of the GT repeat polymorphism was related to a HR of 1.48 (95% CI, 0.77-2.87) for ER-negative breast cancer and a HR of 0.25 (95% CI, 0.09-0.69) for ER-positive cancer. The effect of ER on breast cancer survival was also modified by genotypes of ER-α gene. Tests for multiplicative interaction were highly significant. Conclusions: These data suggest that the ER-α gene polymorphisms and ER status may have an interactive effect on breast cancer survival.

Association of estrogen receptor-? gene polymorphisms with bone mineral density in postmenopausal Korean women

We examined the potential associations between PvuII and XbaI polymorphisms in the first intron of the estrogen receptor alpha (ER-α) gene and bone mineral density (BMD) in a population-based study of 174 postmenopausal Korean women. BMD was measured at the lumbar spine (L2–L4), right femoral neck, right trochanter, and right Ward’s triangle. ER-α gene polymorphisms were detected by PvuII and XbaI restriction endonuclease digestion of polymerase chain reaction products. Differences in BMD values between the ER-α genotypes were analyzed in a general linear model, with adjustments for age, height, weight, and smoking status. The following genotype frequencies were noted: PP, 14.9%; Pp, 46.0%; pp, 39.1%; XX, 3.5%; Xx, 29.3%; and xx, 67.2%. Both the femoral neck and Ward’s triangle BMD values in women with the Pp genotype were significantly (P < 0.05) higher than those in women with the pp genotype. No significant effect of the XbaI genotype on BMD was found at any site. Carriers of the pX haplotype were more likely to have lower BMD values at the trochanter than noncarriers, after adjustment for potentially confounding factors. Women with the pp genotype had more previous hip or spine fractures than those with other genotypes (P = 0.05). These results suggest that the PvuII polymorphism and the ER-α haplotype may be associated with the BMD at several femur sites in postmenopausal Korean women.

Association of Estrogen Receptor α Gene Polymorphisms with Neurofibrillary Tangles

Estrogen receptor α (ERα) may be implicated in the pathogenesis of Alzheimer’s disease (AD). The aim of this study was to clarify the association between ERα gene polymorphisms and AD-related pathologic changes. The staging of neurofibrillary tangles (NFT) and senile plaques (SP) was performed according to the method by Braak and Braak and two polymorphisms, PvuII (P or p) and XbaI (X or x), of the ERα gene were typed in 551 Japanese cadavers (294 men and 257 women; mean age, 80.8 years). Distributions of the NFT and SP stages significantly correlated with age (NFT: r = 0.306, p < 0.0001; SP: r = 0.237, p < 0.0001) and were significantly higher in patients with the apolipoprotein E Ε4 allele (p < 0.0001). Possession of the P allele showed a trend to be associated with a more serious NFT stage, but had no relationship with the SP stage. In men, a significant association between PvuII polymorphism and the NFT stage (p = 0.002) was found, revealing a gene- dose effect of the P allele. Similar results were obtained in the men without the Ε4 allele (p = 0.011). Multiple regression analyses demonstrated that age was the strongest determinant of the NFT stage, possession of the Ε4 allele was the next strongest, and PvuII polymorphism was the third strongest (p < 0.0001, R² = 0.144). The XbaI polymorphism did affect neither the NFT stage nor the SP stage. In conclusion, the PvuII polymorphism of the ERα gene is associated with Braak NFT stages and possession of the P allele may act as a risk factor for AD in Japanese men, especially in those without the Ε4 allele.

Estrogen receptor-α gene haplotype is associated with primary knee osteoarthritis in Korean population

Estrogen and estrogen receptors (ERs) are known to play important roles in the pathophysiology of osteoarthritis (OA). To investigate ER-α gene polymorphisms for its associations with primary knee OA, we conducted a case–control association study in patients with primary knee OA (n = 151) and healthy individuals (n = 397) in the Korean population. Haplotyping analysis was used to determine the relationship between three polymorphisms in the ER-α gene (intron 1 T/C, intron 1 A/G and exon 8 G/A) and primary knee OA. Genotypes of the ER-α gene polymorphism were determined by PCR followed by restriction enzyme digestion (PvuII for intron 1 T/C, XbaI for intron 1 A/G, and BtgI for exon 8 G/A polymorphism). There was no significant difference between primary knee OA patients and healthy control individuals in the distribution of any of the genotypes evaluated. However, we found that the allele frequency for the exon 8 G/A BtgI polymorphism (codon 594) was significantly different between primary knee OA patients and control individuals (odds ratio = 1.38, 95% confidence interval = 1.01–1.88; P = 0.044). In haplotype frequency estimation analysis, there was a significant difference between primary knee OA patients and control individuals (degrees of freedom = 7, χ2 = 21.48; P = 0.003). Although the number OA patients studied is small, the present study shows that ER-α gene haplotype may be associated with primary knee OA, and genetic variations in the ER-α gene may be involved in OA.

Estrogen receptor alpha gene polymorphisms and peak bone density in Chinese nuclear families.

PBD is an important determinant of osteoporotic fractures. Few studies were performed to search for genes underlying PBD variation in Chinese populations. We tested linkage and/or association of the estrogen receptor alpha gene polymorphism with PBD in 401 Chinese nuclear families. This study suggests the ER-alpha gene may have some minor effects on PBM variation in the Chinese population. Low peak bone density (PBD) in adulthood is an important determinant of osteoporotic fractures in the elderly. PBD variation is mainly regulated by genetic factors. Extensive molecular genetics studies have been performed to search for genes underlying PBD variation, largely in whites. Few studies were performed in Chinese populations. In this study, we simultaneously test linkage and/or association of the estrogen receptor alpha (ER-alpha) gene polymorphism with PBD in 401 Chinese nuclear families (both parents plus their female children) of 1260 subjects, with the 458 children generally between 20 and 40 years of age. All the subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) at polymorphic PvuII and XbaI sites inside the ER-alpha gene. Bone mineral density was measured at the lumbar spine (L1-L4) and hip (femoral neck, trochanter, and intertrochanteric region). Raw bone mineral density values were adjusted by age, height, and weight as covariates. We detected marginally significant results for within-family association (transmission disequilibrium; p = 0.054) between the spine bone mineral density variation and the ER-alpha XbaI genotypes. For the hip bone mineral density variation, significant (p < 0.05) linkage results were generally found for the two intragenic markers. Analyses of the haplotypes defined by the two markers confer further evidence for linkage of the ER-alpha with the hip PBD variation. In conclusion, this study suggests that the ER-alpha gene may have minor effects on PBD variation in our Chinese population.

Multidrug resistance 3 gene mutation 1712delT and estrogen receptor α gene polymorphisms in Finnish women with obstetric cholestasis

Objective: To investigate the contribution of the estrogen receptor α (ERα) polymorphism in the development of obstetric cholestasis and to determine whether multidrug resistance 3 ( MDR3) gene 1712delT mutation detected in French patients is also present in Finnish women with obstetric cholestasis. Study design: In a retrospective case–control study, two ERα polymorphisms and MDR3 gene mutation 1712delT were investigated in healthy control women ( N=47) and in women with diagnosis of obstetric cholestasis ( N=57). PvuII and XbaI polymorphisms in ERα gene were evaluated in genomic DNA by using the polymerase chain reaction (PCR). In addition, the frequencies in the general population in our area are presented for comparison. Results: None of the ERα genotypes or alleles was significantly over-represented in obstetric cholestasis. When the two ERα gene polymorphisms were analyzed in parallel, six genotype combinations were recognized, and the distribution of these genotype combinations did not reveal statistically significant differences between the cases and controls ( P=0.612). No patient or control was heterozygous or homozygous for the mutant allele in the MDR3 gene. Conclusion: The present data indicate that polymorphism of the ERα and MDR3 genes 1712delT mutation are unlikely to play any significant role in obstetric cholestasis in affected Finnish women. Further work to identify explanatory factors is of particular interest.

Multidrug resistance 3 gene mutation 1712delT and estrogen receptor α gene polymorphisms in Finnish women with obstetric cholestasis

Objective: To investigate the contribution of the estrogen receptor α ( ERα) polymorphism in the development of obstetric cholestasis and to determine whether multidrug resistance 3 ( MDR3) gene 1712delT mutation detected in French patients is also present in Finnish women with obstetric cholestasis. Study design: In a retrospective case-control study, two ERα polymorphisms and MDR3 gene mutation 1712delT were investigated in healthy control women ( N=47) and in women with diagnosis of obsteric cholestasis ( N=57). PvuII and XbaI polymorphisms in ERα gene were evaluated in genomic DNA by using the polymerase chain reaction (PCR). In addition, the frequencies in the general population in our area are presented for comparison. Results: None of the ERα genotypes or alleles was significantly over-represented in obstetric cholestasis. When the two ERα gene polymorphisms were analyzed in parallel, six genotype combinations were recognized, and the distribution of these genotype combinations did not reveal statistically significant differences between the cases and controls ( P=0.612). No patient or control was heterozygous or homozygous for the mutant allele in the MDR3 gene. Conclusion: The present data indicate that polymorphism of the ERα gene and MDR3 gene 1712delT mutation are unlikely to play any significant role in obstetric cholestasis in affected Finnish women. Further work to identify explanatory factors is of particular interest.

Relation of estrogen receptor-α gene polymorphism and hormone replacement therapy to fall risk and muscle strength in early postmenopausal women

BACKGROUND. Several factors may increase fracture risk, among them reduced bone mineral density (BMD), increased bone resorption, microarchitectural deterioration of bone, increased fall risk, and decreased muscle strength. We have previously reported that PvuII polymorphism of the estrogen receptor-α (ER α) gene is associated with bone loss rate, fracture risk, and response to hormone replacement therapy (HRT) in early postmenopausal Finnish women.METHOD. We studied the influence of the ERα genotype on fall risk and muscle strength in a 5-year randomized HRT trial of 331 early postmenopausal women (subgroup of the population-based OSTPRE study, Kuopio, Finland). A 5-year postal inquiry in May 1994 included questions on falls during the previous 12 months. Grip strength was measured with dynamometer. The ERα gene polymorphism was analysed using PCR and PvuII restriction enzyme digestion. RESULTS. In all, 97 out of the 331 women reported falls. Half of those (56%) were slip falls, mostly during the winter season. In the HRT group, the ERα genotype was associated with fall risk (P = 0.002, logistic regression). The risk of falls (RR) was higher in women with the PP genotype than in those with the Pp (RR = 5.26, 95% CI 1.98-13.94, P = 0.001) or the pp (RR = 3.84, 95% CI 1.46-10.12, P = 0.007) genotype. When the falls were divided into slip (environment-related) and non-slip (endogenous) falls, the non-slip falls were associated with the genotype (P = 0.004), but the slip falls were not so clearly (P = 0.061). When all falls and non-slip falls were adjusted to the number of chronic health disorders and the variable time-since-menopause, the difference between the genotypes persisted (P = 0.003 and P = 0.010, respectively). In the non-HRT group, the ERα genotype was not associated with fall risk. The baseline or the 5-year grip strength values were not influenced by the ERα genotype. In conclusion, ER α polymorphism is associated with fall risk, especially with non-slip falls, in early postmenopausal Finnish women during the HRT. We have previously reported that, during HRT, women with the P allele have decreased fracture risk and that they may preferentially derive benefit from the positive effect of HRT on BMD. This suggests that the influence of ERα polymorphism may depend on the target tissue (bone versus the nervous system). CONCLUSIONS. In these early postmenopausal, non-osteoporotic and relatively healthy women, the increased fall risk associated with the PP genotype was not associated with increased fracture risk, possibly due to improved bone strength during the HRT although falls generally predispose to fractures.

Genotype distribution of estrogen receptor-α gene polymorphisms in italian women with surgical uterine leiomyomas

Objective: To explore a possible association between estrogen receptor-α (ER-α) gene polymorphisms and development of uterine leiomyomas. Design: Case–control study. Setting: University teaching hospital. Patient(s): 119 women with clinically and surgically diagnosed uterine leiomyomas. Intervention(s): Therapeutic hysterectomy. Main Outcome Measure(s): Frequency and distribution of ER-α gene polymorphisms. Result(s): No statistically significant differences between controls and patients in the allele frequency and genotype distribution were found when Pvu II and Xba I restriction polymorphism sites were analyzed separately. When the two ER-α gene polymorphisms were analyzed in combination, five major genotypes were recognized in controls or patients; the frequency differed slightly but not significantly between groups. Conclusion(s): The Pvu II and Xba I polymorphisms in the ER-α gene do not produce different risks of developing uterine leiomyomas.

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

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.

Association of the Estrogen Receptor α Gene Polymorphisms with Sporadic Alzheimer's Disease

Alzheimer's disease (AD) is a multifactorial disorder determined by the interaction of genetic, metabolic, and environmental factors. In the common late-onset familial and sporadic forms of AD apolipoprotein E type 4 allele (APOE-ε4) is now widely accepted as a major risk factor. The association of estrogen treatment with a reduction in the risk of AD together with the modulation by estrogen of the secretory metabolism of the amyloid precursor protein offers new possibilities for identification of other AD susceptibility genes, as those encoding for the estrogen receptors (ERs). A total of 193 patients with sporadic late-onset AD, meeting the NINCDS-ADRDA criteria, and a total of 202 control subjects, age and education matched, were included in this study. PvuII and XbaI ERα and HhaI APOE gene polymorphisms were evaluated in genomic DNA by Polymerase Chain Reaction (PCR). The frequency of the various ERα genotypes by the combination of P, p and X, x was calculated for controls and AD patients stratified based on ApoE typing. When the two ERα gene polymorphisms were analyzed in combination, 7 genotypes were recognized, with a significantly increased prevalence of PPXX genotype in AD patients compared to controls (P = 0.0001). Risk of AD increased by a factor of 7.6 (CI [1.10-62.3]) in homozygous APOE-ε4 individuals with PPXX ERα genotype. These results are consistent with a segregation of PPXX ERα genotype with a higher risk of developing late-onset sporadic AD in the Italian population. The ERα gene appears to interact with the APOE-ε4 genotype in determining AD susceptibility.