Polymorphisms in the estrogen receptor beta gene but not estrogen receptor alpha gene affect the risk of developing endometriosis in a Japanese population

OBJECTIVE: To determine whether polymorphisms in the estrogen receptor (ER) alpha and beta genes are associated with endometriosis in a Japanese population. DESIGN: Association study. SETTING: University hospital. PATIENT(S): Japanese women diagnosed with endometriosis by laparotomy or laparoscopy. INTERVENTION(S): Determination of polymorphisms in the ERalpha and ERbeta genes was performed by polymerase chain reaction restriction fragment-length polymorphism analysis in 132 affected women and 182 controls. MAIN OUTCOME MEASURE(S): Frequency and distribution of AluI and RsaI polymorphisms in ERbeta gene and of PvuII and XbaI polymorphisms in ERalpha gene. RESULT(S): No significant differences in the frequency of either AluI and RsaI polymorphisms in the ERbeta gene or of XbaI and PvuII polymorphisms in the ERalpha gene were found between endometriosis patients and controls. However, a positive association was noted between the AluI polymorphism in the ERbeta gene and stage IV endometriosis patients in the population studied. CONCLUSION(S): The AluI polymorphism in the ERbeta gene is associated with an increased risk of stage IV endometriosis in a Japanese population.     

阴道前壁膨出患者阴道组织中雌激素受体α和β亚型的表达

目的 了解阴道前壁膨出（AVP）患者阴道组织中雌激素受体（ER）α、β亚型的表达情况,探讨其与盆腔器官脱垂（POP）发病的关系。方法 选取1999年7月-2004年7月在北京大学人民医院手术治疗的AVP患者40例（AVP组）,其中绝经前7例,绝经后33例。对照组为同时期手术的Ⅰb1～Ⅱb期宫颈鳞癌患者17例（无盆腔器官膨出症状）,其中绝经前9例,绝经后8例。应用免疫组化方法检测阴道前壁组织中鳞状上皮、黏膜固有层、肌层3个部位的ERa和ERβ表达水平（以阳性细胞率及阳性染色强度的评分判断ER的表达水平）,进行半定量分析及统计学检验。结果 （1）ERα、ERβ在AVP组患者阴道组织中鳞状上皮、黏膜固有层、肌层均有表达。（2）AVP组绝经前患者阴道组织中ERα表达水平分别为：鳞状上皮（5．3±0．8）分、黏膜固有层（3．2±2．1）分、肌层（3．0±1．5）分,绝经后患者分别为（4．6±1．2）、（4．1±1．2）、（3．7±1．4）分,绝经前、后患者不同部位分别比较,差异均无统计学意义（P〉0．05）;对照组患者的阴道组织中ERα表达水平在绝经前、后比较,差异也无统计学意义（P〉0．05）。（3）ERβ表达水平在绝经前、后AVP组患者阴道组织中比较,差异无统计学意义（P〉0．05）;而对照组绝经前患者阴道组织中ERB表达水平分别为：鳞状上皮（4．2±0．5）分、黏膜固有层（2．6±1．4）分、肌层（2．4±0．8）分,绝经后患者分别为（2．6±1．3）、（1．1±0．7）、（1．4±0．9）分,对照组绝经后患者阴道组织中ERB的表达水平下降（P〈0．05）。（4）AVP组绝经后患者阴道组织中ERB表达水平分别为：鳞状上皮（4．1±1．6）分、黏膜固有层（3．4±1.7）分、肌层（3．3±112）分,绝经后AVP组患者阴道组织各部位ERβ的表达水平高于绝经后对照组患者相应部位（P〈0．05）;而绝经后患者ERα在阴道组织中的表达水平,AVP组与对照组比较,差异无统计学意义（P〉0．05）。结论 无论绝经前、绝经后AVP患者,阴道组织都存在ERα、ERβ的表达。AVP患者阴道组织中ERβ表达在绝经后未下降,且较对照组绝经后患者表达增加,而ERα无明显变化。     

Estrogen receptor polymorphisms in tamoxifen-treated women with breast cancer.

In postmenopausal women with estrogen receptor (ER)-positive breast cancer, long-term tamoxifen administration has proved beneficial after surgical treatment and subsequent chemotherapy. One of the major adverse effects of tamoxifen is the development of endometrial pathology (polyps, endometrial hyperplasia and endometrial cancer). PvuII and XbaI polymorphisms of the estrogen receptor-alpha gene (ERalpha) and RsaI and AluI polymorphisms of the estrogen receptor-beta gene (ERbeta) have been associated with breast cancer. Thus the present study aimed to identify whether ER gene polymorphisms are associated with breast cancer stage or endometrial responsiveness to long-term tamoxifen treatment in 87 postmenopausal, tamoxifen-treated women with ER-positive breast cancer. The mean age of the patients was 58.7 +/- 4.7 years and the mean duration of tamoxifen treatment was 3.9 +/- 1.1 years. At diagnosis, the stage of breast cancer was determined as follows: 29 women (32%) at Stage I, 49 (58%) at Stage II and 9 (10%) at Stage III. The frequency distributions of the estrogen receptor polymorphisms in all women with breast cancer were not different from those predicted by the Hardy-Weinberg equilibrium hypothesis (p > 0.10). None of the ER polymorphisms studied was linked to either the presence of endometrial pathology or the stage of breast cancer.     

Estrogen receptor and laminin genetic polymorphism among women with pelvic organ prolapse

Objective

Laminin is a connective tissue component. The LAMC1 gene encodes for gamma-1 chain of laminin, which is associated with familial clustering of POP. The ERα gene which encodes for cellular estrogen receptor has also been associated with POP. The aim of this study was to evaluate a possible correlation between polymorphism in these genes and the risk for developing POP.

Association of angiotensin receptor 2 gene polymorphisms with pregnancy induced hypertension risk

Objectives: To investigate the association of polymorphisms and haplotypes of angiotensin receptor 2 (AT2R) gene with pregnancy induced hypertension (PIH) in Chinese Han women. Methods: A case-control study was designed with 446 cases (gestational hypertension, GH: 124; pre-eclampsia, PE + eclampsia, E: 322) and 650 controls. rs5193, rs1403543 and rs12710567 of AT2R gene were genotyped. A logistic regression approach was applied to estimate the relationship between the polymorphisms and haplotypes of AT2Rgene with PIH risk. Results: No relationship between AT2R gene polymorphisms and PIH was detected. The haplotype analysis also showed a negative result. Conclusions: rs5193, rs1403543 and rs12710567 of AT2R gene might have no effect on PIH risk among Chinese Han women.     

Haplotype analysis of VEGF gene polymorphisms in polycystic ovary syndrome

Abstract

This study evaluated the association of polymorphisms of VEGF (endothelial vascular growth factor) gene + 936C/T (rs3025039), 1154?G/A (rs 1570360) and ?2578?C/A (rs 699947) in patients with polycystic ovary syndrome (PCOS) and to perform the haplotypes formed by the alleles in the Brazilian population. A total of 110 women without PCOS and 112 women with PCOS were included in the study. Genotyping analyses were performed using the PCR-RFLP assays (rs 3025039 and rs 699947) and by allelic discrimination using the real-time PCR technique (rs 1570360). In the univariate analysis, we observed a significant difference between the groups for the polymorphism rs 1570360 and this polymorphism presented statistical differences between the groups for the recessive model (p?=?.04). The frequency of the T-G-C haplotype showed a statistically significant difference between women with PCOS and controls (p?=?.05). The ?2578?A/C polymorphism was more frequent in the control group, which may be associated with a protective characteristic for the PCOS manifestation. In the sample analysis, polymorphism rs 1570360 is associated with PCOS and the T-G-C haplotype could be associated with protective factors.     

Evidence for associations between common polymorphisms of estrogen receptor beta gene with homocysteine and nitric oxide.

BACKGROUND: Homocysteine and asymmetric dimethylarginine (ADMA) affect nitric oxide (NO) concentration, thereby contributing to cardiovascular disease (CVD). Both amino acids can be reduced in vivo by estrogen. Variation in the estrogen receptor (ER) may influence homocysteine and ADMA, yet no information is available on associations with single nucleotide polymorphisms in the estrogen receptor genes ERalpha (PvuII and XbaI) and ERbeta (1730G-->A and cx + 56 G-->A). OBJECTIVE: To find relationships between common polymorphisms associated with cardiovascular disease and cardiovascular risk factors homocysteine and ADMA. METHODS: In a cross-sectional study with healthy postmenopausal women (n = 89), homocysteine, ADMA, nitric oxide metabolites (NOx), plasma folate and ERalpha and beta polymorphisms ERalpha PvuII, ERalpha XbaI; ERbeta 1730G-->A (AluI), ERbeta cx + 56 G-->A (Tsp509I) were analyzed. RESULTS: Women who are homozygotic for ERbetacx + 56 G-->A A/A exhibited higher homocysteine (p = 0.012) and NOx (p = 0.056) levels than wildtype or heterozygotes. NOx concentration was also significantly affected by ERbeta 1730 G -->A polymorphism (p = 0.025). The ERbeta (p < 0.001) and ERalpha (p < 0.001) polymorphisms were in linkage disequilibrium. CONCLUSIONS: Women who are homozygotic for ERbetacx + 56 G-->A A/A may be at increased risk for cardiovascular disease due to higher homocysteine levels.     

Association of CYP1A1 and CYP1B1 polymorphisms with bone mineral density variations in postmenopausal Mexican-Mestizo women

Herein, we investigated potential associations between polymorphisms of genes related to estrogen metabolism and bone mineral density (BMD) in postmenopausal women. This was a cross-sectional study, in which two hundred and ninety postmenopausal Mexican-Mestizo women were studied. The BMD of the lumbar spine (LS), total hip (TH), and femoral neck (FN) was measured. The distribution of the genetic polymorphisms, including rs1799814 and rs1048943 at CYP1A1 as well as rs1056836 at CYP1B1, were analyzed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP), single-stranded conformational polymorphism (SSCP), and DNA sequencing. Deviations from Hardy–Weinberg equilibrium (HWE) were tested, and linkage disequilibrium (LD) was calculated by direct correlation (r²). Moreover, haplotype analysis was performed. All polymorphisms were in HWE. The genotype and allele distributions of the three single nucleotide polymorphisms (SNPs) studied showed no significant differences. However, statistical significance was reached when constructing haplotypes. The CG haplotype in CYP1A1 was associated with variations in LS and FN BMD after adjustment for covariates (p?=?0.021 and 0.045, respectively), but the association with TH BMD was not significant. These results suggested that the CG haplotype in CYP1A1 may play an important role in the mechanism of osteoporosis and may be useful as a genetic marker.     

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.     

Collagen type 3 alpha 1 polymorphism and risk of pelvic organ prolapse

Objective

To investigate whether pelvic organ prolapse (POP) is associated with collagen 3 alpha 1 (COL3A1) polymorphisms and other factors.

Methods

A case-control association study was conducted with 84 women affected with POP and 147 controls. The genotypes of nucleotides COL3A1 rs1800255 and COL3A1 rs1801184 polymorphisms were ascertained by polymerase chain reaction and restriction fragment length polymorphism analysis.

Results

The distribution of the COL3A1 rs1800255 genotypes was significantly different among affected women and controls. Older age and incidence of COL3A1 rs1800255 genotype AA were significantly associated with risk of POP.

Conclusion

There may be an association between COL3A1 genotype and risk of POP.     

Fat mass and obesity-associated gene polymorphisms do not affect metabolic response to hormone therapy in healthy postmenopausal women

Objective

To determine whether fat mass and obesity-associated gene polymorphisms rs9939609 T>A and rs8050136 A>C or their haplotypes influence anthropometric and metabolic variables in recently postmenopausal women receiving hormone therapy.

Study design

In this randomized crossover study carried out in a university clinic, 86 postmenopausal women consulting for symptoms of estrogen deficiency were genotyped by real-time polymerase chain reaction for single nucleotide polymorphisms rs9939609 T>A and rs8050136 A>C of the fat mass and obesity-associated gene. Haplotypes were constructed from the combination of polymorphisms rs9939609 and rs8050136, and their frequencies were inferred using the PHASE 2.1.1 program. Participants were clinically evaluated before and after 6 months of hormone therapy to determine body mass index (current kg/m²) and waist circumference, blood pressure, lipid profile (total cholesterol, HDL cholesterol and triglycerides) plasma glucose (oral glucose tolerance test), and insulin. Blood samples were also drawn for ultra sensitive C reactive protein. The lipid accumulation product index was calculated as (waist [cm] – 58) × triglyceride concentration (mmol/L). Non-normally distributed parameters were log10 transformed before statistical analysis. Measurements at baseline and at follow-up were compared with ANOVA for repeated measures. Data were considered significant at P < 0.05.

Results

In women with the homozygous polymorphic AA genotype of the single nucleotide polymorphisms rs9939609 and the wild AA genotype of the single nucleotide polymorphisms rs8050136, lipid accumulation product index and ultra sensitive C reactive protein were higher before hormone therapy in comparison with women with other genotypes from the same single nucleotide polymorphisms group. There was no worsening of any of the anthropometric or metabolic variables, and lipid accumulation product index improved slightly after hormone therapy in SNP rs9939609 (P = 0.03) and haplotype AAAA. No changes were observed after hormone therapy in SNP rs8050136.

Conclusions

The presence of fat mass and obesity-associated gene risk variants in healthy early postmenopausal women does not adversely affect their response to hormone therapy.     

白细胞介素6与雌激素受体基因对绝经后妇女骨密度的联合效应

目的：探讨白细胞介素（IL）6基因和雄激素受体（ER）基因多态性对绝经后妇女骨密度的联合效应。方法：应用双能X吸收测量法检测205例绝经后妇女的腰椎和股骨颈骨密度;以聚合酶链反应（PCR）扩增IL-6基因多态性区域、产物行7％聚丙酰胺凝胶电泳,根据条带位置,以A-F等位基因命名;ER基因的PCR扩增产物经PvuII和XbaI内切酶酶切后,行1.5％琼脂糖凝胶电泳,其多态性分别用P和p(PvuII)及X和x(XbaI)表示。结果：12位绝经后妇女的IL-6基因型为C/D、C/C和E/E型。193例妇女的IL-6基因为D/D和D/E型,腰椎、股骨颈骨密度和骨生化指标等没有差异,ER基因为pp型妇女股骨颈骨密度显著高于Pp型（P=0.036）;XX型妇女的腰椎骨密度显著高于Xx型（P=0.005）和xx型妇女（P=0.031）,无Pz单倍型（PPXX、ppxx）妇女的腰椎骨密度明显高于有Px单倍型者（PPxx、PPXx、Ppxx、PpXx（P=0.029）。合并IL-6基因D/D、D/E型和ER基因Px单倍型妇女,DD*无Px单倍型者腰椎骨密度显著高于DE*有Px单倍型者（P=0.036）。结论：同时检测ER基因Px单倍型和IL-6基因型,有助于准确发现绝经后妇女骨密度低者。     

Low-activity haplotype of the microsomal epoxide hydrolase gene is protective against placental abruption

OBJECTIVE: We wanted to determine whether genetic variability in the gene encoding microsomal epoxide hydrolase (EPHX) contributes to individual differences in susceptibility to the occurrence of placental abruption. METHODS: The study involved 117 women with placental abruption and 115 healthy control pregnant women who were genotyped for two single nucleotide polymorphisms (SNPs), T-->C (Tyr113His) in exon 3 and A-->G (His139Arg) in exon 4, in the EPHX gene. Chi-square analysis was used to assess genotype and allele frequency differences between the women with placental abruption and the control group. In addition, single-point analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, among the women with placental abruption and the control group. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization algorithm. RESULTS: Single-point allele and genotype distributions in exons 3 and 4 of the EPHX gene were not statistically different between the groups. However, in the haplotype estimation analysis we observed a significantly decreased frequency of haplotype C-A (His113-His139) among the placental abruption group compared with the control group (P = .007). The odds ratio for placental abruption associated with the low-activity haplotype C-A (His113-His139) was 0.552 (95% confidence interval, 0.358 to 0.851). CONCLUSIONS: The use of two intragenic SNPs jointly in haplotype analysis of association demonstrated that the genetically determined low-activity haplotype C-A (His113-His139) was significantly less frequent in women with placental abruption.     

Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are associated with polycystic ovary syndrome

OBJECTIVE: To determine whether genetic variability in the gene encoding microsomal epoxide hydrolase (EPHX) contributes to individual differences in susceptibility to the development of polycystic ovary syndrome (PCOS). DESIGN: Retrospective case-control study. SETTING: University-based clinic. PATIENT(S): One hundred twelve white women with PCOS and 115 healthy controls. INTERVENTION(S): None. MAIN OUTCOME MEASURES: The presence of two single nucleotide polymorphisms (SNPs), T-->C (Tyr113His) in exon 3 and A-->G (His139Arg) in exon 4, in the EPHX gene. Single point analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, in the PCOS and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, using an expectation-maximization algorithm. RESULT(S): Single point allele and genotype distributions in exon 3 and exon 4 of the EPHX gene were not statistically different between the groups. However, according to the haplotype estimation analysis, we observed a significantly elevated frequency of haplotype C-G (His113-Arg139) in the PCOS group versus the control group. The odds ratio for PCOS associated with the low activity haplotype C-G (His113-Arg139) was 2.28 (95% confidence interval 1.1-4.8). CONCLUSION(S): The use of two intragenic single nucleotide polymorphisms jointly in haplotype analysis of association demonstrated that the genetically determined low activity haplotype C-G (His113-Arg139) was significantly associated with PCOS.     

Matrix metalloproteinase-9 polymorphism and risk of pelvic organ prolapse in Taiwanese women

Objective

Matrix metalloproteinase-9 is known to play an important role in the pathophysiology of pelvic organ prolapse. We investigated whether the matrix metalloproteinase-9 gene polymorphisms were associated with pelvic organ prolapse by conducting a case–control association study in 92 women with pelvic organ prolapse and 152 women without pelvic organ prolapse.

Study design

Genotypes of the matrix metalloproteinase-9 gene polymorphisms (rs3918242, rs17576, and rs2250889) were determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis.

Results

There was significant difference between women with and without pelvic organ prolapse in the distribution of the matrix metalloproteinase-9 rs17576 genotypes evaluated. Using multivariable logistic regression, menopausal status, matrix metalloproteinase-9 rs17576 genotype AG, and matrix metalloproteinase-9 rs17576 genotype GG were significantly associated with pelvic organ prolapse.

Conclusion

The present study shows that the polymorphism of matrix metalloproteinase-9 rs17576 may be associated with pelvic organ prolapse.     

Polymorphisms of the vitamin D receptor gene predict the onset of surgical menopause in Caucasian females.

We tested association of four single nucleotide polymorphisms (SNPs) of the vitamin D receptor gene (VDR) with age at surgical and natural menopause in a sample of Caucasians composed of 153 women with surgical and 260 with natural menopause. A significant association was observed between age at surgical menopause and two SNPs, rs1544410 (BsmI) and rs731236 (TaqI) (p < 0.05). For rs1544410, homozygotes of the minor allele, AA, had about two-fold higher risk of surgical menopause than homozygotes of the major allele, GG (95% confidence ratio (CI) 1.09-3.82). For rs731236, the CC subjects had a greater chance of surgical menopause than the TT subjects (odds ratio = 2.01, 95% CI 1.07-3.78). Since rs1544410 and rs731236 are in strong linkage disequilibrium, the haplotypes based on these two loci were also tested. The haplotype AC was highly significantly associated with age at surgical menopause (p = 0.008). Women with this haplotype had surgical menopause on average 2.8 years earlier than non-carriers. These results reveal the potential effect of the VDR gene on ovaries and uterus, and suggest that its SNPs can be used as predictors of genetic susceptibility for early surgical menopause and respective causal health problems.     

Analysis of vitamin D receptor gene (VDR) polymorphisms in Turner syndrome patients

Individuals with Turner syndrome (TS) have increased risk for autoimmune diseases, especially thyroid abnormalities. The function of the vitamin D receptor (VDR) gene is influenced by several genetic polymorphisms which are associated with a susceptibility to a range of autoimmune diseases. Thus, we have hypothesized a possible relationship between thyroid abnormalities and VDR polymorphisms (ApaI/G1025-49T, TaqI/T1056C, FokI/T2C and BsmI G1024?+?283A) in TS patients. A case-control study was performed comprising 101 Brazilian women with TS and a control group consisting of 133 healthy fertile women without a history of autoimmune diseases. In TS group, 21.8% had Hashimoto's thyroiditis. Detection of VDR polymorphisms was performed using TaqMan system by real-time PCR. The χ(2) was used to compare allele and genotype frequencies between groups. Combined genotypes of VDR gene polymorphisms were assessed by the haplotype analysis. A p value <0.05 was considered statistically significant. Relatively similar VDR polymorphisms genotype and allelic frequencies in cases and controls were found, even when only considering the patients with thyroid abnormalities. Haplotype analysis showed that none of the VDR haplotypes were associated to thyroid diseases in TS patients. In conclusion, the results showed no association between VDR gene polymorphisms and thyroid abnormalities in Brazilian TS patients tested.     

Association of estrogen receptor alpha and beta3-adrenergic receptor polymorphisms with endometrial cancer

OBJECTIVE: To investigate the association of estrogen receptor alpha and beta3-adrenergic receptor polymorphisms with endometrial cancer risk in Kagoshima, Japan. METHODS: Ninety-two patients with endometrial cancer and 65 healthy women were enrolled in this study. Blood samples were collected, and deoxyribonucleic acid (DNA) was extracted. Estrogen receptor alpha and beta3-adrenergic receptor gene variants were analyzed by restriction fragment length polymorphisms using the restriction enzymes, Pvu II, Xba I for estrogen receptor alpha, and Mva I for beta3-adrenergic receptor. Multivariable logistic regression analysis was performed, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: The Pvu II PP genotype was associated with a decreased risk of endometrial cancer (multivariable OR 0.23; 95% CI 0.07, 0.82) compared with the pp genotype. The Xba I XX genotype was associated with a decreased risk for endometrial cancer (multivariable OR 0.26; 95% CI 0.09, 0.79) compared with the xx genotype. The Mva I variants were not associated with endometrial cancer risk (multivariable OR 0.55; 95% CI 0.20, 1.51). CONCLUSION: Estrogen receptor alpha polymorphisms, but not beta3-adrenergic receptor gene, may be associated with a risk of endometrial cancer.     

Associations between two single nucleotide polymorphisms in the adiponectin gene and polycystic ovary syndrome.

In the present study we determined whether genetic variability in the gene encoding adiponectin is associated with polycystic ovary syndrome (PCOS). Altogether 143 Caucasian women with PCOS and 245 healthy controls were genotyped for two single nucleotide polymorphisms (SNPs) in exon 2 and intron 2 in the adiponectin gene. Single-point analysis was expanded to pair-of-loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, in the PCOS and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization algorithm. A significantly different allele distribution in intron 2 SNP was observed between the groups, with the T allele being significantly reduced in the PCOS group (25.9%) compared with the control group (32.7%) ( p = 0.047), at an odds ratio of 0.72 (95% confidence interval 0.52-0.99). Otherwise, the allele and genotype distributions in either SNP were not statistically different between the groups. In haplotype estimation analysis, there was a lower frequency of the haplotype T-T in the PCOS group (25.9%) than in the control group (32.7%) ( p = 0.058). We conclude that polymorphisms of the adiponectin gene may be implicated in individual susceptibility to PCOS.