ESR1 PvuII Research Articles

The genetic background of osteoporosis in cystic fibrosis: Association analysis with polymorphic markers in four candidate genes

Background Reduced Bone Mass Density (BMD) is frequent in Cystic Fibrosis (CF). Potentially, other genes than the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene may contribute to the bone phenotype variability in CF patients. Methods Four candidate genes likely associated with BMD variability were studied: the vitamin D receptor (VDR) gene, the estrogen receptor alpha (ESR1), the calcitonin receptor (CALCR) and the type I alpha 1 collagen (COL1A1) gene. A complete bone and CF evaluation was obtained for 82 subjects (39 m, 43 f): 15 had normal BMD (group 1), 46 were osteopenic (group 2), and 21 were osteoporotic (group 3). Results No statistical difference was found among the three groups for age, sex, pancreatic status, and vertebral fractures, nor for any of the biochemical markers. Weight, Body Mass Index (BMI), and FEV1, scored significantly worse in the two groups with the lowest T score. The CFTR mutations R1162X and F508del were more frequent in patients with lower BMD ( p = 0.044 and p = 0.071). There was no significant difference in the distribution of the five marker genotypes among the 3 groups defined according to the unadjusted or adjusted (BMI and FEV1) BMD T score. No significant correlation was found between the VDR, CALCR, or COL1A1 gene polymorphisms and reduced BMD values. The individual ESR1 PvuII- XbaI haplotype C–A is associated to elevated u-calcium levels whereas the haplotype T–A is associated to lower values ( p = 0.00251). Conclusions There was no evidence that the genes under study, with the possible exception of ESR1 gene variants, may modulate bone phenotype in CF.

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

Influence of Estrogen Receptor α and Progesterone Receptor Polymorphisms on the Effects of Hormone Therapy on Mammographic Density

Postmenopausal hormone therapy increases mammographic density, a strong breast cancer risk factor, but effects vary across women. We investigated whether the effect of hormone therapy use is modified by polymorphisms in the estrogen receptor (ESR1) and progesterone receptor (PGR) genes in the Dutch Prospect-EPIC and the English EPIC-Norfolk cohorts. Information on hormone therapy use was obtained through questionnaires at recruitment and after 5 years. Blood samples were collected and consecutive mammograms were available through breast cancer screening programs. For 795 hormone therapy users, one mammogram before and a second mammogram during hormone therapy use was included. For 781 never hormone therapy users, mammograms with similar time intervals were included. Mammographic density was assessed using a computer-assisted method. Changes in density were analyzed using linear regression. A statistically significant difference in percentage density change between hormone therapy users and never users was seen in women with the ESR1 PvuII Pp or pp genotype (2.24%; P < 0.01), but not in those with the PP genotype (0.90%; P = 0.47). Similarly, effects of hormone therapy on percentage density were observed in women with the ESR1 XbaI Xx or xx genotype (2.20%; P < 0.01), but not in those with the XX genotype (-0.65%; P = 0.70). Also, effects were seen in women with the PGR +331 GG genotype (2.04%; P < 0.01), but not in those with the GA or AA genotype (0.98%; P = 0.53). The PGR PROGINS polymorphism did not seem to make women more susceptible to the effects of hormone therapy use. In conclusion, our results suggest that specific polymorphisms in the ESR1 and PGR genes may make women more susceptible to the effects of hormone therapy use on mammographic density.

Phytoestrogen Exposure Correlation with Plasma Estradiol in Postmenopausal Women in European Prospective Investigation of Cancer and Nutrition-Norfolk May Involve Diet-Gene Interactions

Abstract Cross-sectional studies investigating the relationship between phytoestrogens in diet, urine, or blood with plasma estradiol and sex hormone binding globulin (SHBG) have been inconclusive. We investigated the relationship among phytoestrogen exposure, polymorphisms in the ESR1, COMT, CYP19, and SHBG genes, and plasma estradiol and SHBG levels in 125 free-living postmenopausal women taking part in a cohort study (European Prospective Investigation of Cancer and Nutrition-Norfolk) using three different markers: dietary, urinary, and serum phytoestrogens. Phytoestrogen levels (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) in spot urine and serum were analyzed by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, respectively. Plasma estradiol and SHBG were measured by immunoassays. Adjusting for age and body mass index, urinary daidzein, genistein, glycitein, and serum daidzein and glycitein were negatively correlated with plasma estradiol (R = −0.199 to −0.277, P &amp;lt;0.03), with particularly strong associations found in the 18 women with CC genotype for ESR1 PvuII polymorphism (R = −0.597 to −0.834, P &amp;lt; 0.03). The negative correlations observed between isoflavones and estradiol in women as a whole became no longer significant when we excluded women with ESR1 PvuII CC genotype, indicating that the correlations observed were due mainly to this group of women. There was no relationship between dietary isoflavones and plasma estradiol and no association was found between any of the dietary, urinary, and serum phytoestrogen and plasma SHBG or between these factors and polymorphisms in CYP19, SHBG, and COMT. We conclude that higher isoflavone exposure is associated with lower plasma estradiol in postmenopausal women and that this preliminary study is suggestive of the involvement of diet-gene interactions.

Gender-specific effects of estrogen receptor α gene haplotype on high-density lipoprotein cholesterol response to atorvastatin: interaction with apolipoprotein AI gene polymorphism

Statins can modestly raise the levels of HDL cholesterol and apolipoprotein A-I ( APOA1). Recently, associations between polymorphisms in the estrogen receptor α ( ESR1) and the HDL cholesterol response to hormone replacement therapy were reported. To test the hypothesis that common polymorphisms in ESR1 and APOA1 genes are associated with the response to statin therapy, two ESR1 (PvuII and XbaI) and two APOA1 (G–75A and +83) polymorphisms were examined in 338 hypercholesterolemic patients treated with atorvastatin 10 mg. The ESR1 PvuII(−)XbaI(+) haplotype was significantly, and independently, associated with a greater response of HDL raising in women (+13% versus +7%, p = 0.010) but not in men (+9% versus +7%, p = 0.248). Effects of the APOA1 +83 variant allele on HDL cholesterol response also differed significantly by gender ( p = 0.012). The APOA1 +83 variant allele was associasted with higher basal LDL cholesterol levels in men as well, but not in women. Finally, significant interactions were observed between the ESR1 PvuII(−)XbaI(+) haplotype and the APOA1 +83 variant allele regarding both HDL ( p = 0.042) and LDL ( p = 0.031) cholesterol responses. In conclusion, the ESR1 haplotype was associated with a greater HDL-raising to atorvastatin in a gender-specific manner, and the interactions between ESR1 and APOA1 genotypes regarding HDL and LDL cholesterol response were also gender specific.

The effect of hormone replacement therapy on atherosclerotic severity in relation to ESR1 genotype in postmenopausal women

Objective: The atheroprotective action of estrogen is mediated by estrogen receptors ( ESR) 1 and 2, expressed in atherosclerotic lesions. The effects of hormone replacement therapy (HRT) and ESR1 PvuII genotypes on atherosclerosis have not previously been studied prospectively in postmenopausal women. Methods: We investigated the effect of HRT on the progression of atherosclerosis in a 5-year follow-up study of 88 postmenopausal women aged 45–71 years at baseline allocated into three groups based on the use of HRT. The HRT-EVP group ( n=26) used sequential estradiol valerate (EV) plus progestin (P), the HRT-EV group EV alone ( n=32), and a control group ( n=30) was without HRT. The atherosclerosis severity score (AS) of the abdominal aorta and carotid arteries were determined by sonography and the ESR1 PvuII genotypes (P/P, P/p and p/p) by PCR. Results: HRT, time and ESR1 PvuII genotype had a statistically significant or borderline significant main effect on AS during 5-year follow-up ( P=0.004, P<0.001 and P=0.090, respectively), when analyzed by repeated measures analysis of variance. There was a significant genotype-by-treatment (HRT-EVP and control groups) interaction for AS ( P=0.034). In response to HRT-EVP, subjects with P/P, compared with those with P/p and p/p genotypes, had a less increase in AS (1.61±1.14 vs. 1.71±1.27 vs. 2.43±1.27). Baseline AS as covariate in similar model does not change the significant interaction effect between HRT-EVP and control groups ( P=0.036). But this effect was not found between HRT-EV and control groups. Conclusions: Our results suggest that the effect of HRT-EVP in postmenopausal women on progression of AS may be determined in part by the genotype of ESR1 PvuII.

Oestrogen receptor gene variation is a determinant of coronary reactivity in healthy young men.

Oxidised low-density lipoprotein (ox-LDL) is a determinant of impaired coronary function and oestrogens inhibit its formation probably throughout genetically-variable oestrogen receptor 1 (ESR1) in artery wall. We hypothesized that the ESR1 polymorphism might influence coronary function and reactivity as measured by positron emission tomography (PET), which allows the detection of coronary dysfunction before appearance of angiographic lesions. Fifty-one healthy young men (aged 35 +/- 4 years), with normal or slightly-elevated serum cholesterol, underwent PET with intravenous adenosine. ESR1 PvuII genotypes P/P, P/p, and p/p in addition to the plasma autoantibody titre against ox-LDL, a marker of in vivo oxidation, were determined. The ESR1 genotype persisted as the only significant predictor of adenosine stimulated coronary flow (P = 0.035) after adjustment for other coronary risk factors. Subjects with P/P genotype had 33.4 and 41.8% lower adenosine-stimulated flow values than subjects with P/p and p/p genotypes (P = 0.030). Furthermore, plasma levels of ox-LDL titre were on average 59 and 77% higher in subjects with P/P genotype than in subjects with P/p or p/p genotypes (P = 0.049). These tentative findings from our pilot study provide evidence that genetic variation in ESR1 may modify coronary reactivity and LDL oxidation and reflect differences in the early pathogenesis of coronary dysfunction in these healthy young men.

Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study.

Estrogen receptors (ESR) 1 and 2 are expressed in the normal and atherosclerotic arteries mediating the atheroprotective action of estrogen to artery wall cells. Whether variants of these receptor genes associate with autopsy-verified coronary artery wall atherosclerosis is not known. This study investigated whether variants of the ESR1 gene are associated with autopsy-verified coronary artery wall atherosclerosis and thrombosis. Coronary arteries were taken from 300 white Finnish male autopsy cases aged 33-69 years included in the Helsinki Sudden Death Study. Areas of coronary wall covered with fatty streaks, fibrotic, calcified, and complicated lesions were measured using computer-assisted planimetry and related to ESR1 PvuII genotypes (P/P, P/p, and p/p) determined by PCR. The mean area of complicated lesions of three major coronaries and the presence of coronary thrombosis were significantly associated with the ESR1 genotype in men aged 53 years or older (median age as a cut off point). No such association was found in men aged under 53 years. After adjusting for age and body mass index the men aged 53 years or over with P/p and P/P genotype had areas of complicated lesions on average two- and fivefold larger than subjects with the p/p genotype. The age and body mass index adjusted odds ratios for coronary thrombosis were 6.2 for P/p and 10.6 for P/P compared to men with the p/p genotype. After additional adjustment for diabetes and hypertension the ESR1 genotype persisted as an independent predictor of complicated lesions ( P=0.007) and coronary thrombosis. In conclusion, the ESR1 gene is a potential candidate behind the pathogenesis of acute coronary events.