| 1. |
- Byrnes, Andrea, et al.
(författare)
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Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue : no evidence of a biomarker
- 2009
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:6, s. e5805-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chronic fatiguing illness remains a poorly understood syndrome of unknown pathogenesis. We attempted to identify biomarkers for chronic fatiguing illness using microarrays to query the transcriptome in peripheral blood leukocytes. METHODS: Cases were 44 individuals who were clinically evaluated and found to meet standard international criteria for chronic fatigue syndrome or idiopathic chronic fatigue, and controls were their monozygotic co-twins who were clinically evaluated and never had even one month of impairing fatigue. Biological sampling conditions were standardized and RNA stabilizing media were used. These methodological features provide rigorous control for bias resulting from case-control mismatched ancestry and experimental error. Individual gene expression profiles were assessed using Affymetrix Human Genome U133 Plus 2.0 arrays. FINDINGS: There were no significant differences in gene expression for any transcript. CONCLUSIONS: Contrary to our expectations, we were unable to identify a biomarker for chronic fatiguing illness in the transcriptome of peripheral blood leukocytes suggesting that positive findings in prior studies may have resulted from experimental bias.
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| 2. |
- Jiao, Hong, et al.
(författare)
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Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene for Human Obesity
- 2011
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 96:6, s. E962-E966
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Tidskriftsartikel (refereegranskat)abstract
- Context: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Objective: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. Design: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. Setting: General community and referral centers for specialized care was the setting for the study. Participants: We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. Main Outcome Measures: We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. Results: FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 x 10(-6), which was P = 7.0 x 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). Conclusions: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.
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| 3. |
- Jiao, Hong, et al.
(författare)
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Genome wide association study identifies KCNMA1 contributing to human obesity
- 2011
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 4, s. 51-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. Methods: We performed a GWA analysis in 164 morbidly obese subjects (BMI: body mass index > 40 kg/m(2)) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for 14 adults. Results: Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P = 2.82 x 10(-10) and an odds ratio (OR) based on cases vs controls of 1.26 [95% C. I. 1.12-1.41] and for BDNF rs988712*G with P = 5.2 x 10(-17) and an OR of 1.36 [95% C. I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity. Conclusions: We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.
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| 4. |
- Brundin, Peik, et al.
(författare)
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Gene Expression of Estrogen Receptors in Pbmc From Patients With Puumala-Virus Infection
- 2012
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Ingår i: Shock. - Philadelphia : Lippincott Williams & Wilkins. - 1073-2322 .- 1540-0514. ; 37:4, s. 355-359
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Tidskriftsartikel (refereegranskat)abstract
- The influence of estrogen signaling on infectious diseases is not fully known. Males seem to be more susceptible to infections than females. This has also been noted for the Scandinavian form of hemorrhagic fever with renal syndrome caused by Puumala hantavirus (PUUV). To investigate the differences in estrogen receptors in relation to sex and clinical severity, 20 patients (10 males, 10 females) with confirmed PUUV infection were studied. Real-time polymerase chain reaction was performed for analyzing mRNA expression of estrogen receptor-alpha (ERV), ER beta, and ER beta 2 (ER beta cx) in peripheral blood mononuclear cells from patients and healthy age-and sex-matched blood donors. Blood chemistry and peripheral blood mononuclear cells sampling were performed during the acute and convalescent phases. None or very small amounts of ER beta were detected, and ER alpha and ER beta 2 mRNA were elevated in the patient group. The samples from the males were correlated with ER beta 2; the female samples, with ER alpha. Furthermore, the female and male samples are partly separated using multivariate statistic analysis (principal component analysis), supporting findings that clinical symptoms differ depending on sex.
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| 5. |
- Dahlman-Wright, Karin, et al.
(författare)
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Interplay between AP-1 and estrogen receptor α in regulating gene expression and proliferation networks in breast cancer cells
- 2012
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 33:9, s. 1684-91
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor α (ERα) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERα can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that c-Fos is a fundamental factor for ERα-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent proproliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERα can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross talk between AP-1 and estrogen signaling, we identify a novel ERα/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-β), which is overexpressed in ERα-positive breast cancer tissues. Knockdown of PKIB results in robust growth suppression of breast cancer cells. Collectively, our findings support c-Fos as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs.
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| 6. |
- González-Bengtsson, Amanda, et al.
(författare)
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Estrogen Enhances the Expression of the Polyunsaturated Fatty Acid Elongase Elovl2 via ERa in Breast Cancer Cells
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- Endocrine therapy is the first-line targeted adjuvant therapy for hormone-sensitive breast cancer. In view of the potential anticancer property of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) together with chemotherapy in estrogen receptor alpha (ER alpha) positive mammary tumors, we have explored the regulation by estradiol of the fatty acid desaturation and elongation enzymes involved in DHA synthesis in the human breast cancer cell line MCF7, which expresses ER alpha but not ER beta. We demonstrate a robust up-regulation in the expression of the fatty acid elongases Elovl2 and Elovl5 upon estradiol stimulation in MCF7 cells, which was sustained for more than 24 hours. Exposure with the ER inhibitor tamoxifen abolished specifically the Elovl2 but not the Elovl5 expression. Similarly, knockdown of ER alpha eliminated almost fully the Elovl2 but not the Elovl5 expression. Furthermore, ER alpha binds to one specific ERE within the Elovl2 enhancer in a ligand dependent manner. The involvement of ER alpha in the control of especially Elovl2, which plays a crucial role in DHA synthesis, may have potential implications in the treatment of breast cancer.
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| 7. |
- Goumidi, Louisa, et al.
(författare)
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Study of estrogen receptor-α and receptor-β gene polymorphisms on Alzheimer's disease.
- 2011
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 26:3, s. 431-9
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer's disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor α 1 (ESR1) and estrogen receptor α 2 (ESR2) genes on late onset AD risk. We analyzed 39 SNPs in ESR1 and 5 SNPs in ESR2 in a French case-control study of sporadic AD (1007 cases/647 controls). Individuals carrying the minor allele of rs7450824 had a lower risk of AD than homozygous subjects for the major allele (age, gender, and APOE ε4 allele adjusted odds ratio = 0.71 [0.57-0.89], p = 0.003). However, this association did not resist Bonferroni correction for multiple testing (p-threshold < 0.001). Consistently, no significant association could be detected when considering age of onset. We also tested for possible interactions between the ESR SNPs and APOE status (ε4 allele) or gender but no significant interaction could be observed. Even after stratifying the sample on APOE status or gender, no significant association with AD risk could be detected. Finally, we searched for potential gene-gene interactions between ESR1 and ESR2 SNPs but no significant interaction could be detected. Our results reinforce the notion that SNPs in the ESR1 or ESR2 genes do not seem to play a major role in the genetic susceptibility of AD.
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| 8. |
- Gräns, Hanna, et al.
(författare)
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Reduced levels of oestrogen receptor beta mRNA in Swedish patients with chronic fatigue syndrome.
- 2007
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 60:2, s. 195-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chronic fatigue syndrome (CFS) is an illness with unknown aetiology and pathophysiology. The difference in incidence by sex observed for CFS indicates a role for oestrogen and oestrogen receptors in disease development. Furthermore, an immunomediated pathogenesis has been suggested for CFS, providing an additional connection to oestrogen, which displays immunomodular functions. AIMS: To investigate a possible association of oestrogen receptor (ER) mRNAs and two ERbeta single-nucleotide polymorphisms (SNPs) with CFS. METHODS: Messenger RNA levels of ERalpha, ERbeta wt and ERbeta cx were investigated in peripheral blood mononuclear cells from 30 patients with CFS and 36 healthy controls by quantitative real-time polymerase chain reaction. Two ERbeta SNPs were scored in the same material. RESULTS: The CFS group showed significantly lower mRNA expression levels of ERbeta wt compared with the healthy control group. No differences were observed for ERalpha or ERbeta cx between patients and controls. There were no significant differences in frequency for the investigated ERbeta SNPs between cases and controls. CONCLUSIONS: The reduced ERbeta wt expression level observed in this study is consistent with an immune-mediated pathogenesis of CFS. Additionally, the observation that ERbeta wt expression is decreased in CFS could provide an entry point to identify interesting, potentially disease-causing, candidate molecules for further study. A possible connection between oestrogen, oestrogen receptors and CFS should be evaluated further.
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| 9. |
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| 10. |
- Jia, Min, et al.
(författare)
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Estrogen Receptor a Promotes Breast Cancer by Reprogramming Choline Metabolism
- 2016
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 76:19, s. 5634-5646
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor alpha (ER alpha) is a key regulator of breast growth and breast cancer development. Here, we report how ER alpha impacts these processes by reprogramming metabolism in malignant breast cells. We employed an integrated approach, combining genome-wide mapping of chromatin-bound ER alpha with estrogeninduced transcript and metabolic profiling, to demonstrate that ER alpha reprograms metabolism upon estrogen stimulation, including changes in aerobic glycolysis, nucleotide and amino acid synthesis, and choline (Cho) metabolism. Cho phosphotransfse CHPT1, identified as a direct era-regulated gene, was required for estrogen- induced effects on Cho metabolism, including increased phosphatidylcholine synthesis. CHPT1 silencing inhibited anchorage- independent growth and cell proliferation, also suppressing early-stage metastasis of tamoxifen-resistant breast cancer cells in a zebrafish xenograft model. Our results showed that era promotes metabolic alterations in breast cancer cells mediated by its target CHPT1, which this study implicates as a candidate therapeutic target. (C) 2016 AACR.
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