ESR1 Variants Research Articles

Endogenous Estradiol and Its Association with Estrogen Receptor Gene Polymorphisms

We evaluated potential associations between single nucleotide polymorphism (SNP) variants of the estrogen receptor genes ESR1 and ESR2 and circulating estradiol (E 2) concentrations in women of 4 races/ethnicities. The study population was drawn from participants in the Study of Women’s Health Across the Nation (SWAN). A total of 1,538 African American, Caucasian, Chinese, and Japanese women from SWAN participated in the Sex Steroid Hormone Genetics Protocol by providing blood for sex steroid hormone analyses and consenting to lymphocyte transformation from which DNA was extracted and genotyped. We evaluated 4 ESR1 SNPs ( ESR1 rs9340799, ESR1 rs2234693, ESR1 rs728524, and ESR1 rs3798577), and 3 ESR2 SNPs ( ESR2 rs1255998, ESR2 rs1256030, and ESR2 rs1256065). Mean E 2 level was 196.0 ± 4.0 pmol/L in women who were premenopausal and perimenopausal (with blood drawn on days 2 through 5 of the menstrual cycle follicular phase); however, mean E 2 levels in Chinese and Japanese women were lower (155.7 ± 10.6 pmol/L and 170.0 ± 10.3 pmol/L, respectively) than in African American (196.4 ± 8.1 pmol/L, P <0.05) or Caucasian women (210.7 ± 5.9 pmol/L, P <0.002). The ESR1 rs3798577 CC genotype was associated with lower circulating E 2 concentrations in African American women ( P <0.07) and explained about 1% of the variation in circulating E 2 concentrations. In Japanese women, the GC genotype of ESR2 rs1255998 was associated with significantly lower circulating E 2 concentrations that explained about 4% of the variation. Circulating E 2 concentrations were not strongly or consistently associated with selected polymorphisms for the estrogen receptor genes. The 2 strongest associations explained <4% of the total variation in the circulating E 2 concentrations.

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.

Sex Steroid Hormone Polymorphisms, High-Density Lipoprotein Cholesterol, and Apolipoprotein A-1 from the Study of Women’s Health Across the Nation (SWAN)

We evaluated potential associations between single nucleotide polymorphism (SNP) variants in estrogen receptor (ERα and ERβ) genes, high-density lipoprotein (HDL) cholesterol, and apolipoprotein A-1 (apoA-1) concentrations in women of 4 races/ethnicities. Participants included 1,520 African American, Caucasian, Chinese, and Japanese women from the Study of Women’s Health Across the Nation (SWAN) who were premenopausal or perimenopausal and who were also enrolled in the SWAN Genetics Study, which collected blood for lipid analyses and carried out lymphocyte transformation from which DNA was extracted and genotyped. We evaluated SNPs from ERα and ERβ genes ( ESR1 and ESR2, respectively), including ESR1 rs9340799, ESR1 rs2234693, ESR1 rs728524, ESR1 rs3798577, ESR2 rs1255998, ESR2 rs1256065, and ESR2 rs1256030. The mean HDL cholesterol and apoA-1 values for these women were 1.47 mmol/L and 1.51 g/L, respectively. Japanese women with the ESR1 rs3798577 TC genotype had significantly lower apoA-1 ( P = 0.02) and HDL cholesterol levels ( P = 0.03) than did those with the TT genotype. African American women with the ESR1 rs728524 GG genotype had higher HDL cholesterol levels than did women with the AA or AG genotypes ( P = 0.05). ESR2 rs1256030 and ESR2 rs1256065 genotypes were associated with HDL cholesterol concentrations in Chinese women ( P = 0.05). Although associations were identified between the ESR1 and ESR2 SNP variants and lipids in these women, these associations were not consistently observed across the 4 racial/ethnic groups, nor were the associations consistently inclusive of both HDL cholesterol and apoA-1. These genetic variants provide limited evidence of associations with lipids that may help explain the cardioprotective effect of premenopausal status in women.

Estrogen and progesterone receptor gene polymorphisms and sporadic breast cancer risk: A Spanish case‐control study

Estrogens, and to a lesser extent progesterones, influence the proliferation, differentiation and physiology of breast tissue as well as the development and progression of breast cancer. Genetic variants in the steroid hormone receptor genes ESR1 and PGR (belonging to the nuclear receptor superfamily) could therefore modify sporadic breast cancer susceptibility. Two studies have shown a protective effect associated with variants in ESR1 in 2 distinct populations. We studied 4 single nucleotide polymorphisms (SNPs) in ESR1 and 4 in PGR in 550 consecutive and unrelated sporadic Spanish breast cancer patients and 564 healthy Spanish controls. We observed a dominant protective effect for the S10S variant in ESR1, with an estimated odds ratio (OR) of 0.75 (95% CI = 0.58-0.97; p = 0.03) although functional studies did not show changes in the RNA stability. A small subset of individuals carried a haplotype combination that corroborates this protection. No other SNP considered in either gene was found to be associated with sporadic breast cancer. Our results obtained in a European population confirm the protective role of the S10S variant in ESR1, previously reported in an Asian and a European-American population.

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.

Expression of Estrogen Receptor ESR1 and Its 46-kDa Variant in the Gubernaculum Testis1

Testicular descent corresponds to migration of the testis from the abdominal cavity to the scrotum and is essential for proper functioning of the testis. Recent advances in the characterization of estrogen receptor (ESR) subtypes and isoforms in various tissues prompted us to study ESRs within the gubernaculum testis, a structure involved in testicular descent. In the rat gubernaculum, we searched for ESR alpha (Esr1) and beta (Esr2) and for the androgen receptor (Ar), androgens being known to regulate testicular descent. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that Esr1, Esr2, and Ar mRNAs were all expressed in the gubernaculum. Using PEETA (Primer extension, Electrophoresis, Elution, Tailing, and Amplification), we established that all Esr1 leader exons, previously identified in other organs, such as the uterus and pituitary, were transcribed in the gubernaculum, with the major form being O/B. The RNA protection assays, RT-PCR, and Western blot experiments revealed that isoform-specific mRNA transcripts generated by alternative splicing of the C-leader sequence on coding exons 1 and 2 of the Esr1 gene gave the 46- and 66-kDa ESR1 proteins. The ESR1 and AR proteins were found to colocalize in the parenchymal cells of the gubernaculum early in development, whereas AR also was strongly expressed in the muscular cells, both during fetal and postnatal life. The ESR2 protein was weakly expressed, principally in the muscular cells, but only once testicular descent had occurred. The levels of the 46-kDa ESR1 variant (ER46) exceeded those of the 66-kDa ESR1 form (ER66) at periods when the gubernaculum developed. Conversely, the 66-kDa form appears to predominate clearly when the gubernaculum growth was low or completed. The possible role of estrogens on the modulation of the androgen-dependent growth of the gubernaculum and, more widely, on testicular descent is discussed.