ESR2 Rs1256049 Research Articles

The role of estrogen receptor gene polymorphisms in menopausal symptoms and estradiol levels in perimenopausal women – Findings from the Swiss Perimenopause Study

ObjectivesFluctuating estradiol (E2) levels seem to be associated with menopausal symptoms, though not all women suffer from these symptoms to the same extent despite experiencing these hormonal changes. This suggests underlying, interindividual mechanisms, such as single-nucleotide polymorphisms (SNPs) influencing estrogen receptors α and β, and the g-protein-coupled estrogen receptor (GPER). As research is scarce, we aimed to address this research gap by assessing genetic traits, E2 levels, and menopausal symptoms longitudinally. Study design129 perimenopausal women (aged 40–56 years) participated in the 13-month longitudinal Swiss Perimenopause Study. Main outcome measuresMenopausal symptoms were assessed fortnightly using the Menopause Rating Scale (MRS II). Salivary E2 levels were assessed 14 times over two non-consecutive months. Blood samples were collected using the dried blood spot (DBS) technique to analyze ESR1 rs2234693, ESR1 rs9340799, ESR2 rs1256049, ESR2 rs4906938, and GPER rs3808350. Group-based trajectory modeling was performed to identify interindividual trajectories of menopausal symptoms. Multinomial logistic regression models were employed to identify factors associated with these trajectories. ResultsFour distinct trajectory groups of menopausal symptoms were identified (increase, moderate, rebound, decrease). ER gene polymorphisms and E2 fluctuation were significantly associated with group membership. Furthermore, ER gene polymorphisms modulated the effect of E2 fluctuations on menopausal symptom trajectory. ConclusionsThis study illuminates the multifaceted factors contributing to the individuality of the perimenopausal experience. ER gene polymorphisms emerged as integral factors by modulating the effect of E2 fluctuations on menopausal symptom trajectory. This underscores the intricate interplay of genetic factors, E2 fluctuations, and menopausal symptoms during perimenopause.

ESR2 polymorphisms on prostate cancer risk: A systematic review and meta-analysis.

This meta-analysis was performed to address the association of 2 ESR2 gene polymorphisms (rs1256049 and rs4986938) with susceptibility to cancer. An extensive literature search for eligible candidate gene studies published before May 10, 2022, was conducted in PubMed, Medline, and Web of Science. The search strategy was as follows: (ESR2 OR ERβ OR ER beta OR estrogen receptor beta) AND (polymorphism OR mutation OR variation OR SNP OR genotype) AND (PCa OR PC OR prostate cancer). Potential sources of heterogeneity were sought out via trial sequential analysis, subgroup, and sensitivity analysis. Overall, a total of 10 articles involving 18,064 cases and 19,556 controls for 2 polymorphisms of the ESR2 gene were enrolled. In the stratified analysis of rs1256049, we found that Caucasians might be correlated with an increased risk of prostate cancer (PCa), while less susceptibility was found in Asians. We observed that rs4986938 was not associated with PCa risk. ESR2 rs1256049 polymorphism is associated with a higher risk of PCa in the Caucasian population and a lower risk of PCa in the Asian population.

Unique ESR1 and ESR2 estrogen receptor gene variants associated with altered risk of triple-negative breast cancer: A case-control study

BackgroundWe previously reported on the association between ESR1 and ESR2 gene variants and heightened risk of breast cancer (BC). Here we investigated the association of common ESR1 and ESR2 gene variants with triple negative BC (TNBC). MethodsThis retrospective case-control study involved 488 BC patients (130 TNBC, 358 non-TNBC patients). ESR1 (rs2234693, rs9340799, rs3020314, rs3798577) and ESR2 (rs928554, rs944459, rs4986938, rs1256049, rs1256030, rs1271572) genotyping was done by real-time PCR. ResultsWhile minor allele frequencies (MAF) of ESR1 variants were comparable between TNBC and non-TNBC subjects, significantly higher ESR2 rs1256049 MAF was seen in TNBC patients. Significantly higher frequency of ESR1 rs3798577 T/C and C/C genotypes were noted in TNBC cases, and significant differences were seen in ESR2 rs928554, rs1256049, and rs1271572 genotype distribution. Increased TNBC risk was associated with ESR1 rs3798577 T/C and C/C genotypes according to codominant and dominant models, while positive association of ESR2 rs928554 with TNBC was seen according to codominant and recessive models, and positive association of ESR2 rs1256049 with TNBC was seen according to codominant and dominant models. Positive interactions were noted between ESR2 rs1271572-ESR1 rs3020314, ESR2 rs1271572-ESR1 rs9340799, and ESR2 rs1271572-ESR1 rs2234693, ESR2 rs4986938-ESR1 rs2234693, and ESR2 rs928554-ESR1 rs9340799. Haplotype analysis confirmed the positive association of ESR1 CATT with TNBC, while ACGGCTC and ACGGTT ESR2 haplotypes were positively associated with TNBC. ConclusionResults of this study confirmed the association of unique ESR1 and ESR2 genetic variants with altered risk of TNBC. This suggests possible diagnostic and prognostic role of these variants with TNBC independent of their association with BC.

Differential association of ESR1 and ESR2 gene variants with the risk of breast cancer and associated features: A case-control study

BackgroundEstrogen is key to breast cancer pathogenesis, and acts by binding its receptor (ER), which exists as ERα and ERβ, encoded by ESR1 and ESR2 genes, respectively. Studies that investigated the association of ESR1 and ESR2 variants with breast cancer yielded mixed outcome, and ethnic contribution was proposed. We evaluated the association between ESR1 and ESR2 variants and breast cancer and associated features in Tunisian women. MethodsRetrospective case-control study involving 207 female breast cancer patients, and 284 control women. Genotyping was done by real-time PCR. ResultsMinor allele frequencies (MAF) of tagging SNPs rs2234693 and rs3798577 (ESR1) were significantly higher, while MAF of rs1256049 (ESR2) was significantly lower in breast cancer patients vs. controls. Patients carrying rs3798577 genotypes had higher risk, while rs1256049 genotype carriers had reduced risk of breast cancer. The association of ESR1 and ESR2 gene variants with breast cancer depended on ER and Her-2 status. ESR1 rs3798577 and ESR2 rs1256049 were associated with breast cancer in ER-positive cases, and ESR1 rs2234693, and rs3798577 were associated with breast cancer in Her-2-negative cases, while the association of ESR2 rs1256049 with breast cancer was seen in Her-2 positive cases. Haploview analysis identified 4-locus ESR1 haplotypes that were positively (CGTT, TACC, and TACT), and negatively (CGTC) associated with breast cancer. No ESR2 haplotypes associated with breast cancer were identified. ConclusionESR1 alleles and genotypes, and specific 3-locus ESR1 haplotypes are related with increased breast cancer susceptibility in Tunisian women. However, ESR2 variant and specific 1-locus ESR1 haplotype have a protective effect.

Associations between estrogen receptor genetic polymorphisms, smoking status, and prostate cancer risk: a case-control study in Japanese men.

Prostate cancer (PCa) is one of the major causes of death among men. Our study investigated the association of ESR1 and ESR2 genotypes with susceptibility to PCa in relation to smoking status in Japanese. A case-control study was performed with 750 Japanese prostate cancer patients and 870 healthy controls. After age-matching in case-controls, 352 controls and 352 cases were enrolled in this study. By using logistic regression analysis, the different genotypes from ESR1 and ESR2 were analyzed according to case/control status. ESR2 rs4986938 AG and AG+AA genotypes were associated with significantly decreased risk of PCa (AG: OR=0.68, 95% CI 0.47-0.97, P<0.05 and AG+AA: OR=0.67, 95% CI 0.47-0.94, P<0.05). However, there was no significant association between ESR1 rs2234693 and PCa risk. When patients were grouped according to smoking status, the ESR2 rs1256049 AA genotype (OR=0.48, 95% CI 0.25-0.95, P<0.05) and ESR2 rs4986938 AG+AA genotype (OR=0.64, 95% CI 0.41-1.00, P<0.05) showed significantly decreased PCa risk in the ever-smoker group. Our results suggest that the estrogen receptor ESR2 has a very important function to predict PCa and that different SNPs have different predictive values. Smoking may influence estrogenic activity and may influence PCa together with the estrogen receptor.

Are polymorphisms in oestrogen receptors genes associated with lipid levels in response to hormone therapy?

Background: Polymorphisms in the oestrogen receptor 1 (ESR1) and oestrogen receptor 2 (ESR2) genes are associated with intermediate or endpoint markers of cardiovascular disease and with the efficacy of postmenopausal hormone therapy (HT). Contradictory findings have been described in the past and the role of these genetics variants remains unclear. Methods: A cross-sectional study was carried out with 266 postmenopausal women, of whom 115 received oral HT (HT+) and 151 did not receive any HT (HT−). We analysed three single-nucleotide polymorphisms (SNPs) in ESR1 (rs1801132, rs7757956 and rs2813544) and two in ESR2 (rs3020450 and rs7154455) and derived haplotypes with three additional polymorphisms that had been previously investigated by our group (ESR1 rs2234693 and ESR2 rs1256049 and rs4986938). Results: The ESR1 rs2813544 polymorphism was associated with low-density lipoprotein cholesterol (LDL-C) in HT+ postmenopausal women (p = 0.044; pC = 0.388), while one ESR2 gene haplotype was associated with total cholesterol (T-chol) (p = 0.015; pC = 0.090) and LDL-C in HT+ postmenopausal women (p = 0.021; pC = 0.126). Conclusion: Our findings suggest that, in HT+ postmenopausal women, the rs2813544 polymorphism may influence LDL-C levels and, as previously described, ESR2 rs1256049 is associated with T-chol and LDL-C. No previous study has investigated the association of this SNP set with lipoprotein levels in women while taking into account the hormonal status of the patients.

Estrogen receptor gene variants are associated with anxiety disorders in older women

Estrogen is thought to play a key role in anxiety, but it remains unknown whether genetic variants in the estrogen receptors (ERs) can influence the risk of anxiety. This study investigated whether ESR1 and ESR2 gene variants were associated with specific anxiety disorders in postmenopausal women and evaluated the potential modifying effect of hormone treatment (HT) on these associations. One thousand and ninety-two community-dwelling women aged 65 years and older were recruited as part of the ESPRIT Study in Montpellier, France. Anxiety was assessed using the Mini-International Neuropsychiatry Interview (MINI), according to DSM-IV criteria. Two ESR1 and three ESR2 polymorphisms were genotyped. The most common anxiety disorders were phobia (14.2%) and generalised anxiety disorder (GAD, 8%). The A allele of ESR2 rs1256049 was associated with an increased risk of GAD [OR: 2.06, 95% CI: 1.09-3.87], while both ESR1 polymorphisms were specifically associated with phobia. The C allele of ESR1 rs2234693 decreased the risk of phobia by 42% [95% CI: 0.41-0.83], and this remained significant even after Bonferroni correction. The G allele of ESR1 rs9340799 was associated with a 31% decreased phobia risk [95% CI: 0.49-0.96]. There was also evidence of a significant gene-environment interaction, where only women who were currently using HT had a reduced risk of phobia with these ESR1 gene variants. This study confirms earlier findings of an association between ESR1 and global anxiety in older women, however these associations varied depending on the anxiety syndrome and the use of HT. The results also suggest that the ESR2 may contribute to the genetic vulnerability to GAD, but these findings require further confirmation.

Estrogen Receptor 2 Polymorphism and Carotid Intima-Media Thickness

The present study was designed to investigate the effects of estrogen receptor 2 gene (ESR2) rs1256049 polymorphism to carotid artery intima-media thickness (CIMT), as part of the Cardiovascular Risk in Young Finns Study. The frequencies of ESR2 genotypes G/G, G/A, and A/A were 85.1%, 14.3%, and 0.7%, respectively, in the whole study population (n = 2211). Compared with subjects with genotype GG, those with the A allele had higher mean CIMT (p = 0.004) and maximal CIMT (p = 0.005). In a Finnish population, the ESR2 rs1256049 polymorphism A allele is associated with preclinical atherosclerosis in young adulthood. Our results and those of others also suggest that some effects of this genetic variation may be population specific.