Estrogen Receptor Genotypes Research Articles

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

Tamoxifen induces important changes in serum lipid profiles in some women; however, little information is available to predict which women will experience improved lipid profiles during tamoxifen therapy. As part of a multicenter prospective observational trial in 176 breast cancer patients, we tested the hypothesis that tamoxifen-induced lipid changes were associated with genetic variants in candidate target genes (CYP2D6, ESR1, and ESR2). Tamoxifen lowered low-density lipoprotein cholesterol (P<0.0001) by 23.5 mg/dl (13.5-33.5 mg/dl) and increased triglycerides (P=0.006). In postmenopausal women, the ESR1-XbaI and ESR2-02 genotypes were associated with tamoxifen-induced changes in total cholesterol (P=0.03; GG vs GA/AA) and triglycerides (P=0.01; gene-dose effect), respectively. In premenopausal women, the ESR1-XbaI genotypes were associated with tamoxifen-induced changes in triglycerides (P=0.002; gene-dose effect) and high-density lipoprotein (P=0.004; gene-dose effect). Our results suggest that estrogen receptor genotyping may be useful in predicting which women would benefit more from tamoxifen.

Tamoxifen-induced hot flashes are associated with estrogen receptor polymorphisms

501 Background: Hot flashes are the most common side effect of tamoxifen. The pharmacogenetic predictors of hot flashes are not known. We hypothesized that estrogen receptor (ER) genotypes that have been associated with clinical phenotypes may predict the frequency and composite score of tamoxifen-associated hot flashes. Methods: We conducted a prospective observational study in 3 academic centers to evaluate the associations between ER and hot flash composite scores in women with breast cancer during the first year of adjuvant tamoxifen treatment. Menopausal status and prior chemotherapy history were collected at baseline. Medication records and validated hot flash diaries were prospectively collected before and following 1, 4, 8 and 12 months of starting tamoxifen. ERa (ESR1) PvuII (rs2234693) and XbaI (rs9340799) genotypes were determined using a Restriction Fragment Length Polymorphism (RFLP) assay; and ERβ (ESR2–02; rs4986938) genotype was determined using a Taqman™ assay. The haplotype of two ESR1 SNPs and their association with the baseline hot flash score were analyzed with haplo.stat function in R. Individual SNPs and their interactions in baseline hot flash score and month 4 hot flash score change were analyzed with SAS PROC GLM. Results: Of the 298 women recruited to the trial, 286 returned their baseline diaries and 251, 239, 214, and 213 women returned their diaries 1, 4, 8, and 12 months after tamoxifen treatment. At baseline, premenopausal women who were homozygous for the ESR1 CG haplotype reported higher hot flash scores (17.2±3.7) than carriers with one or less CG allele (5.2±3.9), p=0.01. After tamoxifen treatment, postmenopausal women with ESR1 PvuII CC and ESR2–02 GG genotype had the greatest increase (p=0.0004) in hot flash score (53.9±16.4) as compared with women with other genotypes (12.5±3.6). Women who were homozygous for the ESR2–02 AA allele were significantly less likely to experience tamoxifen-induced hot flashes than women with at least one G allele (OR=4.0, P=0.0006) regardless of menopausal status and chemotherapy history. CYP2D6 analysis in underway and results will be available for the meeting. Conclusions: Menopausal status, history of prior chemotherapy, and ER genotype may be used to predict who may suffer hot flashes during tamoxifen treatment. [Table: see text]

Estrogen receptor alpha polymorphisms and fertility in populations with different reproductive patterns

The estrogen receptor (ER) plays an important role in mediating estrogen action on target tissues. ER-alpha, the most abundant, is found in all human reproductive tissues and studies on alpha-ER knockout mice have highlighted its role in reproduction. ER-alpha gene (ESR1) polymorphisms have been associated with a variety of disorders including human infertility. In this study, we examined the association of ESR1 PvuII and XbaI polymorphisms with fertility in two populations with different reproductive patterns and precisely in a sample of healthy Italian men and women (n=178) and in a sample of healthy African-Ecuadorian women (n=57). ESR1 xx and ppxx genotypes among the Italian men were found to be associated with an above-median number of children (P=0.01 and P=0.004, respectively). ESR1 pp genotype among the Italian women showed a tendency to be associated with a lower number of abortions (P=0.04), whereas ESR1 pp and ppxx genotypes among African-Ecuadorian women were associated with a higher number of children (P=0.02 and P=0.03, respectively). These results are consistent with previous observations indicating a role of ESR1 genotypes in human infertility and give insight into the complex interactions between genotypes and reproductive behaviours in human populations.

Estrogen Receptor 1 gene (ESR1) variants in Alzheimer’s disease. Results of a meta-analysis

There is some disagreement between clinical and basic science as to the benefit of estrogen in preventing cognitive decline. For cardiovascular disease, estrogen effects have been shown to vary with estrogen receptor (ESR) genotype. The present study was conceived to review evidence of ESR association with Alzheimer's disease (AD) which could account for the variability observed in estrogen treatment outcome. A meta-analysis was performed on data from 8288 cases and controls, controlling for ethnicity (Asian vs European). To explore the specificity of our findings further, a second meta-analysis of association studies was then appended, addressing non-AD forms of dementia or cognitive impairment (total n=11036). A significant overall association of AD with two neighboring ESR1 variants located in a transcription-enhancing region (p=0.015) was noted. The genotypic effect was driven by the minor alleles in Asian populations, and did not reach significance in European samples (OR=1.1, p>0.267). When the phenotype was extended to other forms of dementia or cognitive impairment, the association was no longer observed. ESR1 variability was confirmed to modulate susceptibility to AD in Asian individuals, but not in Europeans. More research is required to address possible clinical implications, e.g., for hormone replacement therapy in early stages of AD.

Estrogen receptor‐1 genotype is related to coronary intima thickness in young to middle‐aged women

Objective. The incidence of coronary disease in premenopausal women is about one‐half that in men of similar age. The estrogen receptor‐1 (ESR1, c.454‐397T>C) CC variant genotype is associated with the severity of coronary artery disease (CAD) and an increased risk of myocardial infarction in men. The purpose of the present study was to investigate whether this ESR1 CC variant also disposes to atherosclerosis in women in terms of increased total coronary artery intima thickness. Material and methods. A total of 125 forensic autopsy cases of women aged 15 to 49 years were investigated. The thickness of the coronary intima, which reflects the severity of atherosclerosis, was measured by computerized image analysis. The ESR1 c.454‐397T>C genotype was determined by polymerase chain reaction (PCR). Results. The mean intima thicknesses in the three genotype groups were 428±298 µm (TT), 494±371 µm (CT) and 636±436 µm (CC). We found that, on average, women with the CC genotype had a thicker coronary intima compared with that of women with the TT genotype, even after adjusting for age and body mass index (BMI) (p = 0.030). The intermediate group (TC) did not significantly differ from either the CC or the TT genotype group in this respect. Conclusion. Our results point to the importance of ESR1 genotype in relation to cardiovascular disease susceptibility.

Genetic factors for obesity

The purpose of the present study was to identify gene polymorphisms for the reliable assessment of genetic factors for obesity. The study population comprised 3906 unrelated Japanese individuals (2286 men, 1620 women), including 1196 subjects (677 men, 519 women) with obesity (body mass index of > or = 25 kg/m2) and 2710 controls (1609 men, 1101 women). The genotypes for 147 polymorphisms of 124 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of smoking revealed that the -30Gright curved arrow A polymorphism of GCK, the -240Aright curved arrow T polymorphism of ACE, and the -482Cright curved arrow T polymorphism of APOC3 were significantly (P < 0.01) associated with the prevalence of obesity, and the -1989Tright curved arrow G polymorphism of ESR1 was almost significantly associated. A stepwise forward selection procedure demonstrated that ACE, GCK, and ESR1 genotypes significantly (P < 0.01) and independently affected the prevalence of obesity. Combined genotype analysis for these three polymorphisms yielded a lowest odds ratio of 0.45 for the combined genotypes of AT or TT for ACE, GG for GCK, and GG for ESR1 in comparison with the combined genotypes of AA for ACE, GG for GCK, and TT or TG for ESR1. Genotypes for ACE, GCK, and ESR1 may prove reliable for the assessment of genetic factors for obesity. Determination of the combined genotypes for these genes may contribute to the personalized prevention of this condition.

Estrogen receptor gene (&amp;lt;i&amp;gt;ESR&amp;lt;/i&amp;gt;) and semen characteristics of boars

Abstract. Estrogen receptor gene (ESR) which is localized in the swine chromosome 1, has been recognized as a "candidate" gene of reproductive traits. The aim of this study was to determine the mutations in the ESR/AvaI (ESR1) and ESR/PvuII (ESR2) gene in boars kept at the AI Station and its effect on selected quantitative and qualitative characters of the semen. The study included 217 boars maintained at the AI Station. The ESR genotypes were determined with PCR-RFLP. Two alleles ESR1 were identified: A (109 and 76 bp), B (76, 62 and 47 bp) and also two alleles ESR2: C (120 bp), D (65 and 55 bp), with the frequencies: 0.79 (A), 0.21 (B), 0.83 (C) and 0.17 (D) respectively. In the studied population of boars, the genotype AA was detected with the frequency 0.69, AB-0.21, BB-0.10 of ESR1 and CC-0.72, CD-0.23, DD-0.05 of ESR2. The analysis showed statistically significant differences (P≤0,01) between boars carrying different ESR1 and ESR2 genotypes and all semen traits.

The Association of Genetic Polymorphisms in Sex Hormone Biosynthesis and Action with Insulin Sensitivity and Diabetes Mellitus in Women at Midlife

We evaluated associations of insulin sensitivity, metabolic syndrome, and diabetes mellitus with single nucleotide polymorphism (SNP) variants from sex hormone biosynthesis and action in women of 4 races/ethnicities. DNA was extracted from transformed cell samples of 1,538 women in the Study of Women’s Health Across the Nation (SWAN). African American, Caucasian, Chinese, and Japanese women in SWAN enrolled in the Sex Steroid Hormone Genetics Protocol from whom fasting glucose and insulin measures (for estimating insulin sensitivity), diabetes status, and metabolic syndrome classification were obtained. SNPs from the genes encoding aromatase ( CYP 19), 17β-hydroxysteroid dehydrogenase ( 17HSD) type 1, and the estrogen receptors–α ( ESR1) and –β ( ESR2) were measured. The prevalence of metabolic syndrome was 20% in Chinese women, 22% in Japanese women, 28% in Caucasian women, and 43% in African American women. The prevalence of diabetes was 3% in Chinese women, 4% in Japanese women, 7% in Caucasian women, and 19% in African American women. Significant associations of CYP 19 genotypes and insulin sensitivity were observed in African American, Caucasian, and Japanese women. Selected ESR1 and ESR2 genotypes were associated with insulin sensitivity and metabolic syndrome only in Japanese and Chinese women. The strongest associations related 17HSD genotypes to diabetes in Caucasian women, with odds ratios ranging from 4.4 to 7.5 and confidence intervals that excluded the null value. We observed strong associations between variations in sex hormone biosynthesis and function genes with insulin sensitivity, the metabolic syndrome, and diabetes that varied by race/ethnicity. The strong association of 17HSD and diabetes in Caucasian women has not been previously reported and should be further investigated.

The Association of Bone Mineral Density with Estrogen Receptor Gene Polymorphisms

The purpose of this investigation was to evaluate single nucleotide polymorphism (SNP) variants of the estrogen receptor genes ESR1 and ESR2 and bone mineral density (BMD) of the lumbar spine (LS-BMD) or total hip (hip BMD) in women of 4 races/ethnicities who were premenopausal or in early perimenopause. The sample consisted of 1,301 participants from the Study of Women’s Health Across the Nation (SWAN) with measures of BMD and genotyping; of these, 295 were African American, 693 were Caucasian, 151 were Chinese, and 162 were Japanese. We evaluated the potential association of LS-BMD or hip BMD with 4 SNPs from the ESR1 gene ( ESR1 rs9340799, ESR1 rs2234693, ESR1 rs728524, and ESR1 rs3798577), and 3 SNPs from the ESR2 gene ( ESR2 rs1255998, ESR2 rs1256030, and ESR2 rs1256065). Unadjusted mean LS-BMD values ranged from 1.141 ± 0.14 g/cm 2 in African American women to 1.031 ± 0.11 g/cm 2 in Japanese women; unadjusted mean hip BMD values ranged from 1.053 ± 0.14 g/cm 2 in African American women to 0.862 ± 0.10 g/cm 2 in Chinese women. African American and Japanese women with the ESR1 rs2234693 ( PvuII) CC genotype had higher LS-BMDs than did their peers with the TT genotype ( P = 0.009 and P = 0.04, respectively). Japanese women with the ESR1 rs3798577 CC or TC genotypes had lower LS-BMD than did Japanese women with the TT genotype ( P = 0.02 and P = 0.01, respectively). Caucasian women with the TC genotype for ESR2 rs1256030 had lower LS-BMDs than did those with the CC genotype ( P = 0.02). Chinese women who were heterozygous for ESR2 rs1256030 or ESR2 rs1256065 had significantly higher LS-BMDs and hip BMDs than did the referent groups for each of these SNPs ( CC and AA, respectively). Associations between BMD and ESR1 and ESR2 genotypes varied by race/ethnicity and by bone site. Our results differ from those previously reported for 2 ESR1 genotypes ( ESR1 rs2234693 [ PvuII] and ESR1 rs9340799 [ XbaI]). Moreover, 2 ESR1 and 3 ESR2 SNPs we studied have not previously been examined with respect to BMD. Among these, ESR2 rs1256030 and ESR2 rs1256065 appear to have an effect at both the lumbar spine and hip in Chinese women and may warrant further study.

Association between breast cancer and estrogen receptor gene polymorphism PVU II

643 Background: The estrogen receptor (ER) is well acknowledged as a prognostic factor in breast cancer, and it is a prerequisite to use the predictive information for hormonal therapy. We investigated whether that the different polymorphisms of the estrogen receptor could influence its expression or functionality. Methods: DNA was extracted from white blood cells of 236 breast cancer patients and 236 healthy, matched controls. The ER genotypes were determined by polymerase chain reaction (PCR) amplification followed by restriction enzyme digestion of the PCR product. Results were shown by electrophoreses. Clinical data such as histologic types, pTNM stage and patients age were available for statistical analyses. Results: We found a statistically significant correlation between the estrogen receptor polymorphism pattern and breast cancer. The receptor type PP was detected statistically significantly more often in postmenopausal breast cancer patients (PP vs pp+Pp, p =0.03). However, there was no correlation to the histobiochemical receptor status or UICC-Stadium. Conclusions: These results show an association between the estrogen receptor polymorphism and breast cancer. It seems to be that a complete lack of the p-allel is a risk factor to develop breast cancer at postmenopausal age. There was no influence on estrogen receptor expression or clinical tumor stage. Thus, we propose that there is no clinical use for estrogen receptor polymorphism analyses at this stage. No significant financial relationships to disclose.

Association of Estrogen Receptor α (ESR1) PvuII and XbaI Polymorphisms with Sporadic Alzheimer’s Disease and Their Effect on Apolipoprotein E Concentrations

Background: Many studies have shown that estrogen replacement therapy may improve cognitive function in women and reduce the risk of Alzheimer’s disease (AD). Because most of the estrogen neuroprotective effect is mediated by receptors, we studied the associations between estrogen receptor α (ESR1) polymorphisms (PvuII and XbaI) and AD, and their interactions with apolipoprotein E (APOE) polymorphism and plasma levels. Methods: ESR1 genotypes and APOE plasma concentrations were determined in a sample of AD patients and controls. Results: ESR1 PP and XX genotypes were associated with an increased risk for AD only in males (OR = 3.6, 95% CI = 1.2–10.9) and conferred a relevant additional risk of AD to subjects also carrying APOE e*4 allele (OR = 13.3, 95% CI = 1.7–103.6). Mean APOE concentrations were lower in AD patients; the lowest levels were observed in male patients carrying PP and/or XX genotypes (p = 0.006) and in patients carrying PP and/or XX genotypes together with the e*4 allele (p = 0.003). In AD women, ESR1 PP and XX genotypes were also associated with lower MMSE values (p = 0.0007). Conclusion: The present data suggest that the involvement of ESR1 polymorphisms in AD onset is mediated by the regulation of apoE expression. ESR1 polymorphisms are also associated with a faster cognitive decline in the women AD patients.

Estrogen receptor genotype is associated with platelet inhibition after tamoxifen treatment

Backgroud Tamoxifen therapy can cause a ~ 4% decrease in platelet count. We hypothesized that this decrease may lead to changes in platelet function, and that estrogen receptor (ESR) genotype may influence tamoxifen-induced changes in platelet function. METHODS Platelet aggregation tests were performed on blood drawn from 19 women before and after 4 months of tamoxifen treatment. ESR1 PvuII and XbaI and ESR2-02 genotypes were also determined. Differences in platelet aggregation were tested using student’s t test (SPSS, v12). Data expressed as mean ± SD. RESULTS Tamoxifen therapy led to a significant decrease in ADP (13.3±3.4 vs 11.5±2.0, P = 0.012) and collagen (15.0±5.7 vs 12.2±6.1, P=0.04) induced platelet aggregation. ESR1 PvuII genotype was associated with differences in baseline ADP-induced platelet aggregation and the change in ADP-induced platelet aggregation (table 1). CONCLUSION Platelet aggregation was inhibited after 4 months of tamoxifen treatment. ESR1 PvuII genotype was associated with changes in platelet aggregation after tamoxifen treatment. Table 1.. ADP-induced Platelet aggregation based on ESR1 PvuII genotype

Association Between an Eestrogen Receptor Alpha Gene Polymorphism and the Risk of Prostate Cancer in Black Men

Studies suggest that SNPs within ESR1 may be associated with an increased risk of prostate cancer. We evaluated the association of the XbaI and PvuII ESR1 SNPs and prostate cancer risk in 3 different racial/ethnic populations. A total of 1,603 volunteers from the SABOR study (285 black, 876 white and 442 Hispanic men) were genotyped to assess allelic frequencies of the ESR1 SNPs. Case-control analysis was performed on 598 prostate cancer cases and 1,098 controls (260 black men, 1,013 non-Hispanic white men and 423 Hispanic white men) to assess the association between these polymorphisms and prostate cancer risk. Allelic frequency was significantly different across ethnic/racial groups for both SNPs. Logistic regression analysis adjusted for age and stratified by race and ethnicity demonstrated an association between the AG genotype or presence of the G allele (GG or AG genotype) in the XbaI SNP and prostate cancer risk within black men (OR 2.25, 95% CI 1.07-4.70, p = 0.031; OR 2.14, 95% CI 1.05-4.35, p = 0.035, respectively). No association was observed among Hispanic and non-Hispanic white men for this SNP. Furthermore, there was no association between the PvuII SNP and prostate cancer risk across all groups. Our study demonstrates an association between the AG genotype, as well as presence of the G allele within the XbaI ESR1 SNP and prostate cancer risk among black men.

Tu-P8:302 Coronary intima thickness in relation to estrogen receptor genotype in women younger than 50 years of age

Tu-P8:302 Coronary intima thickness in relation to estrogen receptor genotype in women younger than 50 years of age

Distinct association of gene polymorphisms of estrogen receptor and vitamin D receptor with lumbar spondylosis in post-menopausal women

Contribution of genetic backgrounds to the etiology of lumbar spondylosis has been suggested by epidemiological studies. This study was designed to determine the association of restriction fragment length polymorphisms (RFLPs) of estrogen receptor (ER), vitamin D receptor (VDR), parathyroid hormone (PTH) and interleukin-1beta (IL-1beta) genes with the radiological severity of lumbar spondylosis at the disk level from L1/2 to L5/S1 in Japanese post-menopausal women. ER and VDR RFLP haplotypes were associated with the severity of spondylosis in the upper levels (L1/2 and L2/3) more than in the lower levels. Association of ER genotype was more pronounced in the group younger than average than in the older group, while that of VDR genotype was more significant in the older group. Neither PTH nor IL1-beta RFLP was associated with the severity at any levels in either stratified group. We thus conclude that ER and VDR genes may contribute to lumbar spondylosis in a distinct manner: estrogen sensitivity influences the severity in the early phase after menopause while vitamin D plays an important role at older ages when the contribution of estrogen loss is weaker.

Polymorphisms in the Estrogen Receptor α Gene and Mammographic Density

AbstractThe presence of the PvuII or the XbaI polymorphism in the estrogen receptor α gene (ESR1, 6q25) has been related to breast cancer risk; however, results are not fully consistent. To further elucidate this relation, we examined these polymorphisms in relation with mammographic density, a measure of dense tissue in the breast, which is strongly associated with breast cancer risk. For this study, 620 participants aged 49 to 68 years were selected from the Prospect-European Prospective Investigation into Cancer and Nutrition cohort. Blood samples, lifestyle– and medical questionnaire data and mammograms were available for these women. Genotyping was done using the TaqMan PCR assay and mammographic density was assessed using a computer-assisted method. Means of mammographic density were compared by ESR1 genotypes and haplotypes. The percentage density was higher in women with one or two copies of the PvuII p allele (means for Pp and pp are 37% and 36%, respectively) than in those with the PP genotype (32%, Ptrend = 0.09). Women with one or two copies of the XbaI x allele had higher mean percentage density (Xx and xx, 36% and 37%, respectively) than those with the XX genotype (31%, Ptrend &amp;lt; 0.01). Haplotype 1 (px) was associated with increased density, whereas haplotype 2 (PX) was associated with decreased density, both suggesting an allele-dose effect (Ptrend = 0.08 and &amp;lt;0.01, respectively). Similar associations were found with absolute density (Ptrend &amp;lt; 0.01). The findings of this study support the view that ESR1 polymorphisms may affect breast cancer risk through differences in breast density.

ESR1 and APOE gene polymorphisms, serum lipids, and hormonal replacement therapy

Objectives The risks and benefits of hormone replacement therapy (HRT) are, at least in part, mediated by the metabolic individuality of women. Therefore, we investigated the association between polymorphisms at the estrogen receptor 1 gene ( ESR1) and at the apolipoprotein E gene ( APOE) with lipid and lipoprotein levels in order to verify whether these concentrations are modulated by these gene variants in women with different hormonal status. Methods One hundred and eighteen postmenopausal women using oral HRT with estrogen or estrogen plus progestagen (HRT+, mean age = 56 ± 6.7 years, 39–75 years) and 167 postmenopausal women that were not on HRT (HRT−, mean age = 58 ± 9.8 years, 38–85 years) participated in the study. The polymorphisms were genotyped by PCR-RFLP methods. Results No significant effect of ESR1 genotypes or haplotypes and ESR1*HRT interactions were detected on lipid levels in two-way analysis of variance. Postmenopausal women HRT nonusers carriers of the APOE*4 allele had higher T-chol and LDL-C levels than postmenopausal women HRT nonusers carriers of the APOE*3 and APOE*2 allele. T-chol and LDL-C concentrations in postmenopausal users of HRT that were APOE*4 carriers were similar to those in postmenopausal women nonusers of HRT homozygotes for APOE*3 and APOE*2 carriers. A significant APOE*4/HRT interaction was detected on T-chol and LDL-C levels by multiple regression analysis. Conclusion The results from this study suggest that the HRT influence on T-chol and LDL-C levels is modulated by APOE isoforms but not by ESR1 polymorphisms.

Tobacco smoking, estrogen receptor α gene variation and small low density lipoprotein level

High levels of small low density lipoprotein (LDL) particles are a major risk factor for cardiovascular morbidity and mortality. Both estrogens and smoking, with known anti-estrogenic effects, alter the atherogenic lipid profile. We tested for a role of interaction between smoking and estrogen receptor alpha gene (ESR1) variation in association with plasma concentration of atherogenic small LDL particles and LDL particle size. We studied 1727 unrelated subjects, 854 women and 873 men, mean age 51 years (SD 10), from the population-based Framingham Heart Study. After covariate adjustment, women who smoked and had the common ESR1 c.454-397 TT genotype (in 30% of women, T was present on both chromosomes at position 397 prior to the start of exon 2) had >1.7-fold higher levels of small LDL particles than women with the alternative genotypes (P-value for smoking-genotype interaction was 0.001). Similar results were obtained for three other ESR1 variants including c.454-351A > G, in the same linkage disequilibrium block. A similar substantial gender-specific result was also evident with a fifth variant, in a separate linkage disequilibrium block, in exon 4 (P = 0.003). Women who smoked and had specific, common ESR1 genotypes had a substantially higher plasma concentration of atherogenic small LDL particles. Significant results revealed a dose-dependent effect of smoking and were evident in both pre- and postmenopausal women. The reported association has the potential to explain the risks associated with estrogen use in certain women and a recent report of association between an ESR1 haplotype comprised of c.454-397 T and c.454-351 A alleles with increased myocardial infarction and ischaemic heart disease, independent of the standard, established cardiovascular risk factors.

Association between bone mineral density and polymorphisms of the VDR, ERα, COL1A1 and CTR genes in Spanish postmenopausal women

Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component, and several candidate gene polymorphisms have been implicated in the regulation of this process. In view of the reported associations between the BMD and polymorphisms in the collagen type I alpha 1 gene (COL1A1), vitamin D receptor (VDR), estrogen receptor (ER)alpha and calcitonin receptor (CTR) genes, an association study was performed between VDR, COL1A1, CTR and ER genotypes and lumbar spine, femoral neck and Ward's triangle BMD in postmenopausal Spanish women. We statistically controlled for many confounding factors, such as height, weight, age, years since menopause, use of hormone replacement therapy (HRT), tobacco consumption, use of oral contraceptives, calcium dietary intake or exercise practice. No association between COL1A1 or ER genotypes and BMD was detected. However, we described a statistically significant association between a personal history of fractures and COL1A1 genotype. The ss genotype was found to be over-represented between those women who had a personal history of fractures. The analyses of the VDR polymorphisms showed that FF subjects reached the highest values of BMD at the three measured sites, whereas Ff individuals had an intermediate BMD and ff women had the lowest values. However, the VDR-BsmI gene polymorphism was not found to be associated with adjusted BMD. For the CTR polymorphisms, our study showed that women with the aa genotype had a lower adjusted BMD at the femoral neck. In conclusion, in our postmenopausal Spanish women cohort we found a statistically significant association beteween the VDR and CTR gene polymorphisms and the BMD. However, we did not find any association between the ER and COL1A1 gene and the BMD. The COL1A1 gene was found to be associated with the prevalence of osteoporotic fractures. Of all the studied gene polymorphisms, the FokI VDR gene polymorphism seems to be the strongest BMD genetic determinant of postmenopausal Spanish women.

Menopausal status and estrogen receptor genotypes influenced the severity of hot flashes after tamoxifen treatment

Background/Aims Hot flashes are the most common side effect of tamoxifen treatment. We conducted a prospective observational trial to evaluate factors that influenced hot flash severity after tamoxifen treatment. Methods Hot flashes frequency and severity were recorded in 7-day hot flashes diaries before, and 1, 4, 8, 12 months after tamoxifen treatment in 122 subjects. Hot flashes composit scores were calculated. Demographic information was collected at baseline, and estrogen receptor (ESR1 & 2) genotyping was also performed. Results Pre-menopausal women showed the biggest increase in hot flashes severity, from 5.2±10.5 at baseline to 28.5±51.6 at 4 month (P<0.0001), whereas there was no significant change in peri- or postmenopausal women. Twenty-two of the 122 women did not develop hot flashes. G allele carriers of the ESR2-02 SNP were 4.2 times more likely to develop hot flashes than homozygotes with AA genotype (P=0.008). Conclusion Pre-menopausal women were most likely to develop hot flashes after tamoxifen treatment. ESR2-02 genotype may also influence the risk of developing hot flashes after tamoxifen treatment. Clinical Pharmacology & Therapeutics (2005) 77, P4–P4; doi: 10.1016/j.clpt.2004.11.017