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‣ Expressão do gene da aromatase (CYP19A1) nas células da granulosa murais luteinizadas de mulheres com endometriose submetidas a técnicas de reprodução assistida; Aromatase gene expression (CYP19A1) in mural lutein-granulosa cells of women with endometriosis undergoing assisted reproduction techniques

Abreu, Lauriane Giselle de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 26/03/2009 Português
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Introdução:Até 60% das mulheres com endometriose apresentam como sintoma a infertilidade. Entretanto, os mecanismos envolvidos ainda permanecem não totalmente esclarecidos, especialmente quando não há distorção da anatomia pélvica. A etiologia multifatorial e comprometimento poligênico nesta doença têm sido amplamente aceitos. A aromatase é uma molécula das mais estudadas e há evidências de aumento da expressão do seu gene no endométrio eutópico e ectópico na endometriose. Esta enzima, codificada pelo gene CYP19A1, converte andrógenos a estrógenos e está presente normalmente nas células da granulosa, onde é fundamental para a produção esteroidogênica intrafolicular. Estudos in vitropor cultivo de células da granulosa, mostraram redução da atividade da aromatase em mulheres com endometriose. Devido à escassez de estudos que analisem a expressão do seu gene (CYP19A1) nessas células foi o que estimulou a proposta deste estudo. Este trabalho tem porobjetivo medir a expressão do gene da aromatase por PCR em tempo real nas células da granulosa luteinizadas murais de mulheres com endometriose submetidas a técnicas de reprodução assistida. Pacientes e Métodos: Estudo caso-controle...

‣ Interaction of soy food and tea consumption with CYP19A1 genetic polymorphisms in the development of endometrial cancer 1

Xu, Wang Hong; Dai, Qi; Xiang, Yong Bing; Long, Ji Rong; Ruan, Zhi Xian; Cheng, Jia Rong; Zheng, Wei; Shu, Xiao Ou
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Certain polyphenols inhibit the activity of aromatase, a critical enzyme in estrogen synthesis that is coded by the CYP19A1 gene. Consumption of polyphenol-rich foods and beverages, thus, may interact with CYP19A1 genetic polymorphisms in the development of endometrial cancer. We tested this hypothesis in a population-based case-control study of 1,204 endometrial cancer cases and 1,212 controls. Dietary information was obtained using a validated food frequency questionnaire. Genotypes of CYP19A1 at rs28566535, rs1065779, rs752760, rs700519 and rs1870050 were available for 1,042 cases and 1,035 controls. Unconditional logistic regression models were used to calculate odds ratios (ORs) and their 95% confidence intervals (95% CI) after adjusting for potential confounding factors. Higher intake of soy foods and tea consumption were both inversely associated with the risk of endometrial cancer with ORs of 0.8 (95% CI: 0.6,1.0) for the highest versus the lowest tertiles intake of soy and 0.8 (95% CI: 06,0.9) for ever tea consumption. The association of SNPs rs1065779, rs752760, and rs1870050 with endometrial cancer was modified by tea consumption (P for interaction < 0.05) but not by soy isoflavone intake. Our findings suggest that tea polyphenols may modify the effect of CYP19A1 genetic polymorphisms on the development of endometrial cancer.

‣ Association Study of Aromatase Gene (CYP19A1) in Essential Hypertension

Shimodaira, Masanori; Nakayama, Tomohiro; Sato, Naoyuki; Saito, Kosuke; Morita, Akihiko; Sato, Ichiro; Takahashi, Teruyuki; Soma, Masayoshi; Izumi, Yoichi
Fonte: Ivyspring International Publisher Publicador: Ivyspring International Publisher
Tipo: Artigo de Revista Científica
Publicado em 07/02/2008 Português
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Background: As aromatase-deficient mice, which are deficient in estrogens, reportedly have reduced blood pressure, the aromatase gene (CYP19A1) is thought to be a susceptibility gene for essential hypertension (EH). The aim of the present study was to investigate the relationship between CYP19A1 and EH by examining single nucleotide polymorphisms (SNPs).

‣ Local expression of CYP19A1 and CYP19A2 in developing and adult killifish (Fundulus heteroclitus)

Dong, Wu; Willett, Kristine L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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P450 aromatase (CYP19) is the terminal enzyme in the steroidogenic pathway and catalyzes the conversion of androgens to estrogens. Fundulus heteroclitus like other teleosts, express two CYP19 genes, CYP19A1 and CYP19A2. The expression of CYP19s in Fundulus was measured by in situ hybridization throughout development. In 90 dpf (day post-fertilization) fish and adult fish, CYP19A1 was expressed in the ooplasm of early stage I oocytes (primary growth stage). Expression of CYP19A1 was localized in the follicle cell layer of late stage I (previtellogenic stage) and stage II (vitellogenic stage) follicles, but by stage III (early maturational follicles) CYP19A1 expression was localized in the vitelline envelope. Overall, CYP19A1 oocyte membrane expression gradually declined from highest expression at late stage I to nondetectable levels by stage IV. Highest expression of CYP19A2 was detected in the brain including the hypothalamus from 4, 6, 8, 10, 14 dpf embryos, 90 dpf fry fish and adult fish brain. In females compared to males, there was higher CYP19A2 expression in olfactory bulb. In addition to the brain, there was strong CYP19A2 signal in adrenal/kidney cells in 6-14 dpf embryos. This work establishes the localization and constitutive expression of CYP19s in Fundulus which can then be compared with potential disruption of CYP19A1 and CYP19A2 expression and physiological consequences caused by environmental contaminants.

‣ Association of two common single-nucleotide polymorphisms in the CYP19A1 locus and ovarian cancer risk

Goodman, Marc T; Lurie, Galina; Thompson, Pamela J; McDuffie, Katharine E; Carney, Michael E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Although the role of estrogen in the etiology of ovarian cancer is uncertain, there is increasing evidence that hormone replacement therapy is a risk factor for ovarian malignancy. The production of estrogen involves the conversion of androgens via P450 aromatase, encoded by the CYP19A1 gene. Genetic variation in two CYP19A1 single-nucleotide polymorphisms (SNPs), rs749292 and rs727479, has been found to produce 10–20% increases in estrogen levels among postmenopausal women. We tested the hypothesis that these SNPs were associated with the risk of ovarian cancer in a population-based case–control study in Hawaii, including 367 histologically confirmed epithelial ovarian cancer cases and 602 age- and ethnicity-matched controls. The A allele of rs749292 was positively associated with ovarian cancer risk in a codominant model for all races combined (AG versus AA genotype: odds ratio (OR), 1.48 and 95% confidence interval (CI, 1.07–2.04); GG versus AA: OR, 1.87 (CI, 1.24–2.82); Ptrend=0.002). Similar significant associations of the rs749292 A allele on the risk of ovarian cancer were found among Caucasian and Japanese women. No relation of the rs727479 SNP to ovarian cancer risk was observed overall, although Caucasian women carrying the variant A allele compared with women with an CC genotype had an OR of 2.91 (CI...

‣ Two Estrogen-Related Variants in CYP19A1 and Endometrial Cancer Risk: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium

Setiawan, Veronica Wendy; Doherty, Jennifer A.; Shu, Xiao-ou; Akbari, Mohammad R.; Chen, Chu; De Vivo, Immaculata; DeMichele, Angela; Garcia-Closas, Montserrat; Goodman, Marc T.; Haiman, Christopher A.; Hankinson, Susan E.; Henderson, Brian E.; Horn-Ross,
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/2009 Português
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Common variants in CYP19A1 (the A alleles of rs749292 and rs727479) have been associated with a 10% to 20% increase in circulating estrogen levels in postmenopausal women. We hypothesized that the presence of one or both A alleles in these single nucleotide polymorphisms (SNP) is associated with increased endometrial cancer risk. We tested this hypothesis in a large pooled analysis of 4,998 endometrial cancer cases and 8,285 controls from 10 studies in the Epidemiology of Endometrial Cancer Consortium. The majority of women (>66%) were whites, with smaller proportions of other races and ethnic groups (blacks, Asians, and Latinas) also included in this pooled analysis. Unconditional logistic regression was used to model the association between SNPs/haplotypes and endometrial cancer risk. Carrying the A allele of either of these SNPs was associated with an increased risk of endometrial cancer, with pooled odds ratios per allele of 1.14, 95% confidence interval of 1.09-1.21, and P =7.1 × 10-7 for rs749292, and odds ratio per allele of 1.08, 95% confidence interval of 1.02-1.14, and P = 0.009 for rs727479. For rs749292, these associations were generally stronger among women age ≥55 years. For both SNPs, risk increased with increasing body mass index...

‣ Genetic variation in CYP19A1 and risk of breast cancer and fibrocystic breast conditions among women in Shanghai, China

Chen, Chu; Sakoda, Lori C.; Doherty, Jennifer A.; Loomis, Melissa M.; Fish, Sherianne; Ray, Roberta M.; Lin, Ming Gang; Fan, Wenhong; Zhao, Lue Ping; Gao, Dao Li; Stalsberg, Helge; Feng, Ziding; Thomas, David B.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/2008 Português
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CYP19A1 encodes for aromatase, which irreversibly converts androgens to estrogens; therefore, variation in this gene may affect individual susceptibility to breast cancer and other sex hormone-dependent outcomes. In a case-control study nested within a breast self-examination trial conducted in Shanghai, China, we examined whether ten CYP19A1 polymorphisms (rs1870049, rs1004982, rs28566535, rs936306, rs11636639, rs767199, rs4775936, rs11575899, rs10046, rs4646) were associated with risk of breast cancer and fibrocystic breast conditions. Cases were diagnosed with breast cancer (n=614) or fibrocystic breast conditions (n=465) during 1989–2000. Controls were free of breast disease during the same time period (n=879). Proliferative changes within the extratumoral tissue of women with breast cancer and the lesions of women with fibrocystic conditions were assessed. None of the polymorphisms were associated with overall risk of breast cancer or fibrocystic breast conditions. Differences in breast cancer risk, however, were observed by proliferation status. The risk of breast cancer with (but not without) proliferative fibrocystic conditions was increased among women homozygous for the minor allele of rs1004982 (C), rs28566535 (C), rs936306 (T)...

‣ CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium

Travis, Ruth C.; Schumacher, Fredrick; Hirschhorn, Joel N.; Kraft, Peter; Allen, Naomi E.; Albanes, Demetrius; Berglund, Goran; Berndt, Sonja I.; Boeing, Heiner; Bueno-de-Mesquita, H. Bas; Calle, Eugenia E.; Chanock, Stephen; Dunning, Alison M.; Hayes, Ri
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Sex hormones, in particular the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiological evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterised variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However...

‣ Variation in the CYP19A1 gene and risk of colon and rectal cancer

Slattery, Martha L.; Lundgreen, Abbie; Herrick, Jennifer S.; Kadlubar, Susan; Caan, Bette J.; Potter, John D.; Wolff, Roger K.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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CYP19A1, or aromatase, influences estrogen-metabolizing enzymes and may influence cancer risk. We examine variation in the CYP19A1 gene and risk of colorectal cancer using data from population-based case–control studies (colon n = 1,574 cases, 1,970 controls; rectal n = 791 cases, 999 controls). Four SNPs were statistically significantly associated with colon cancer and four were associated with rectal cancer. After adjustment for multiple comparisons, the AA genotype of rs12591359 was associated with an increased risk of colon cancer (OR 1.44 95% CI 1.16–1.80) and the AA genotype of rs2470144 was associated with a reduced risk of rectal cancer (OR 0.65 95% CI 0.50–0.84). Variants of CYP19A1 were associated with CIMP+ and CIMP+/KRAS2-mutated tumors. CT/TT genotypes of rs1961177 were significantly associated with an increased likelihood of a MSI+ colon tumor (OR 1.77 95% CI 1.26–2.37). We observed statistically significant interactions between genetic variation in NFκB1 and CYP19A1 for both colon and rectal cancer. Our data suggest the importance of CYP19A1 in the development of colon and rectal cancer and that estrogen may influence risk through an inflammation-related mechanism.

‣ The Aromatase Gene CYP19A1: Several Genetic and Functional Lines of Evidence Supporting a Role in Reading, Speech and Language

Anthoni, Heidi; Sucheston, Lara E.; Lewis, Barbara A.; Tapia-Páez, Isabel; Fan, Xiaotang; Zucchelli, Marco; Taipale, Mikko; Stein, Catherine M.; Hokkanen, Marie-Estelle; Castrén, Eero; Pennington, Bruce F.; Smith, Shelley D.; Olson, Richard K.; Tomblin,
Fonte: Springer US Publicador: Springer US
Tipo: Artigo de Revista Científica
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Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias...

‣ Plasma estrone sulfate concentrations and genetic variation at the CYP19A1 locus in postmenopausal women with early breast cancer treated with letrozole

Lunardi, G.; Piccioli, P.; Bruzzi, P.; Notaro, R.; Lastraioli, S.; Serra, M.; Marroni, P.; Bighin, C.; Mansutti, M.; Puglisi, F.; Porpiglia, M.; Ponzone, R.; Bisagni, G.; Garrone, O.; Cavazzini, G.; Clavarezza, M.; Del Mastro, L.
Fonte: Springer US Publicador: Springer US
Tipo: Artigo de Revista Científica
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Estrogen synthesis suppression induced by aromatase inhibitors in breast cancer (BC) patients may be affected by single nucleotide polymorphisms (SNPs) of the gene encoding aromatase enzyme, CYP19A1. We assessed the association between plasma estrone sulfate (ES), letrozole treatment, and four SNPs of CYP19A1 gene (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G) which seem to be related to circulating estrogen levels. Patients were enrolled into a prospective, Italian multi-center clinical trial (Gruppo Italiano Mammella, GIM-5) testing the association of CYP19A1 SNPs with the efficacy of letrozole adjuvant therapy, in postmenopausal early BC patients. SNPs were identified from peripheral blood cell DNA. Plasma ES concentrations were evaluated by Radio Immuno Assay. Blood samples were obtained immediately before letrozole therapy (N = 204), at 6-weeks (N = 178), 6 (N = 152) and 12-months (N = 136) during treatment. Medians (IQR) of ES were 160 pg/mL (85–274) at baseline, 35 pg/mL (12–64) at 6-weeks, 29 pg/mL (17–48) at 6 months and 25 pg/mL (8–46) after 12 months treatment. No statistically significant association was evident between polymorphisms and ES circulating levels during letrozole therapy. Letrozole suppression of the aromatase enzyme function is not affected by polymorphisms of CYP19A1 gene in postmenopausal BC patients.

‣ SIRT1 Positively Regulates Breast Cancer Associated Human Aromatase (CYP19A1) Expression

Holloway, Kimberly R.; Barbieri, Andreia; Malyarchuk, Svitlana; Saxena, Madhurima; Nedeljkovic-Kurepa, Ana; Cameron Mehl, Mathieu; Wang, Allison; Gu, Xin; Pruitt, Kevin
Fonte: Endocrine Society Publicador: Endocrine Society
Tipo: Artigo de Revista Científica
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Breast cancer remains one of the leading causes of death in women diagnosed with cancer. In breast cancer, aberrant expression of the CYP19A1 gene, which encodes the aromatase enzyme, contributes to increased intratumoral levels of estradiol. Regardless of whether this estrogen is produced by peripheral tissues or within specific subpopulations of cells within the breast tumor, it is clear that the aromatase enzymatic activity is critical for the growth of estrogen-dependent tumors. Currently, aromatase inhibitors have proven to be highly effective in blocking the growth of estrogen-dependent forms of breast cancer. CYP19A1 transcription is tightly controlled by 10 tissue-specific promoters. In breast cancer, however, aromatase transcription is driven by multiple promoters that somehow override the tissue-specific regulation of normal tissue. Here, we explore the role that the deacetylase, sirtuin-1 (SIRT1), plays in positively regulating aromatase in breast cancer. We demonstrate that the use of cambinol and the SIRT1/2 inhibitor VII, 2 small molecule inhibitors of SIRT1 and SIRT2, as well as small molecule inhibitors and small interfering RNA specific to SIRT1, all reduce the levels of aromatase mRNA. We further demonstrate that pharmacologic inhibition causes a marked reduction in aromatase protein levels. Additionally...

‣ Cyp19a1 (Aromatase) Expression in the Xenopus Brain at Different Developmental Stages

Coumailleau, P; Kah, O
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
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Cytochrome P450 aromatase (P450arom; aromatase) is a microsomal enzyme involved in the production of endogeneous sex steroids by converting testosterone into oestradiol. Aromatase is the product of the cyp19a1 gene and plays a crucial role in the sexual differentiation of the brain and in the regulation of reproductive functions. In the brain of mammals and birds, expression of cyp19a1 has been demonstrated in neuronal populations of the telencephalon and diencephalon. By contrast, a wealth of evidence established that, in teleost fishes, aromatase expression in the brain is restricted to radial glial cells. The present study investigated the precise neuroanatomical distribution of cyp19a1 mRNA during brain development in Xenopus laevis (late embryonic to juvenile stages). For this purpose, we used in situ hybridisation alone or combined with the detection of a proliferative (proliferating cell nuclear antigen), glial (brain lipid binding protein, Vimentin) or neuronal (acetylated tubulin; HuC/D; NeuroβTubulin) markers. We provide evidence that cyp19a1 expression in the brain is initiated from the very early larval stage and remains strongly detected until the juvenile and adult stages. At all stages analysed, we found the highest expression of cyp19a1 in the preoptic area and the hypothalamus compared to the rest of the brain. In these two brain regions...

‣ Genotypic and Allelic Variability in CYP19A1 among Populations of African and European Ancestry

Starlard-Davenport, Athena; Orloff, Mohammed S.; Dhakal, Ishwori; Penney, Rosalind B.; Kadlubar, Susan A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 03/02/2015 Português
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CYP19A1 facilitates the bioconversion of estrogens from androgens. CYP19A1 intron single nucleotide polymorphisms (SNPs) may alter mRNA splicing, resulting in altered CYP19A1 activity, and potentially influencing disease susceptibility. Genetic studies of CYP19A1 SNPs have been well documented in populations of European ancestry; however, studies in populations of African ancestry are limited. In the present study, ten ‘candidate’ intronic SNPs in CYP19A1 from 125 African Americans (AA) and 277 European Americans (EA) were genotyped and their frequencies compared. Allele frequencies were also compared with HapMap and ASW 1000 Genomes populations. We observed significant differences in the minor allele frequencies between AA and EA in six of the ten SNPs including rs10459592 (p<0.0001), rs12908960 (p<0.0001), rs1902584 (p = 0.016), rs2470144 (p<0.0001), rs1961177 (p<0.0001), and rs6493497 (p = 0.003). While there were no significant differences in allele frequencies between EA and CEU in the HapMap population, a 1.2- to 19-fold difference in allele frequency for rs10459592 (p = 0.004), rs12908960 (p = 0.0006), rs1902584 (p<0.0001), rs2470144 (p = 0.0006), rs1961177 (p<0.0001), and rs6493497 (p = 0.0092) was observed between AA and the Yoruba (YRI) population. Linkage disequilibrium (LD) blocks and haplotype clusters that is unique to the EA population but not AA was also observed. In summary...

‣ Genetic Variant in the CYP19A1 Gene Associated with Coronary Artery Disease

Bampali, Konstantina; Grassos, Charalampos; Mouzarou, Angeliki; Liakos, Charalampos; Mertzanos, Georgios; Lamnissou, Klea; Babalis, Dimitrios
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
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The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the biosynthesis of estrogens. The rs10046 polymorphism of CYP19A1 gene has been investigated in two studies on the occurrence of hypertension, but there are no studies on its correlation with coronary artery disease (CAD). We investigated 189 subjects who were hospitalized at “KAT” General Hospital of Athens and underwent coronary angiography. Of these, 123 were found with CAD with an average age of 60 years and constituted the patients group and 66 subjects with an average age of 58 years without damage in the coronary vessels and constituted the control group (healthy). The frequencies of genotypes CC, CT, and TT of rs10046 polymorphism are significantly different between the group of CAD patients and the control group (0.34, 0.48, and 0.18 versus 0.20, 0.48, and 0.32, resp., P = 0.034) as the frequency of C allele (0.58 versus 0.44, resp., OR = 1.771 and P = 0.010). We found similar results for men, but not for women (small sample). The results of this study show that the rs10046 (C/T) polymorphism of CYP19A1 gene exhibits correlation with CAD and that patients with C allele have an increased probability of manifesting the disease.

‣ S4646 polymorphism in CYP19A1 gene is associated with the efficacy of hormone therapy in early breast cancer

Shao, Xiying; Cai, Jinwei; Zheng, Yabing; Wang, Jiwen; Feng, Jianguo; Huang, Yuan; Shi, Lei; Chen, Zhanhong; Guo, Yong; Wang, Xiaojia
Fonte: e-Century Publishing Corporation Publicador: e-Century Publishing Corporation
Tipo: Artigo de Revista Científica
Publicado em 01/05/2015 Português
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Purpose: The aim was to verify the potential association between CYP19A1 genetic polymorphisms and clinical outcome of hormone therapy in hormone receptor (HR)-positive early breast cancer. Methods: Genotyping for CYP19A1 rs4646 (C/A) polymorphism was performed on 287 women with HR-positive early breast cancer. Associations were evaluated between CYP19A1 rs4646 genotypes and disease-free survival (DFS). Results: Totally, women with the minor allele (AA or AC) had an improved DFS when compared with those carrying the homozygous common allele (CC) (AA or AC vs. CC: 62.7 months versus 55.6 months; Hazard ratio (HR), 0.745; 95% CI, 0.562-0.988; P = 0.04). The difference was further demonstrated by multivariate analyses (HR, 0.681; 95% CI, 0.506-0.917; P = 0.011). In premenopausal women, AA genotype was associated with a prolonged DFS (AA versus CC or AC: 98.2 months versus 56.2 months; HR, 0.425; 95% CI, 0.198-0.914; P = 0.024). In addition, women with the A allele had an improved DFS when compared with those carrying the homozygous C allele (AA or AC vs. CC: 62.7 months versus 55.6 months; HR, 0.709; 95% CI, 0.516-0.975; P = 0.033). These findings were further confirmed by the Cox regression model (HR, 0.336, 0.670; 95% CI, 0.160-0.836...

‣ Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women

Flote, Vidar G; Furberg, Anne-Sofie; McTiernan, Anne; Frydenberg, Hanne; Ursin, Giske; Iversen, Anita; Lofteroed, Trygve; Ellison, Peter T; Wist, Erik A; Egeland, Thore; Wilsgaard, Tom; Makar, Karen W; Chang-Claude, Jenny; Thune, Inger
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
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Introduction: High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women. Methods: Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17β-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17β-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models. Results: The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17β-estradiol. We observed an 87% lower level of daily 17β-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m2) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore...

‣ La régulation du gène CYP19A1 dans les cellules de granulosa bovine in vitro

Sahmi, Fatiha
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
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L’oestradiol joue un rôle important dans la reproduction en général, particulièrement dans la croissance folliculaire chez la vache. La production de l’œstradiol nécessite l’expression du gène CYP19A1 suite à la stimulation des cellules de granulosa par l’hormone folliculostimulante (FSH) ou le facteur de croissance insulinique de type 1 (IGF-1). Chez la vache, il existe six promoteurs (1.1 ; 1.2 ; 1.3 ; 1.4 ; 1.5 et 2) qui dirigent la transcription du gène CYP19A1 dans les cellules de la granulosa. Le principal promoteur qui dirige la transcription au niveau de l’ovaire (cellules de granulosa) est le promoteur 2 (P2). Cependant, l’effet de la FSH et de l’IGF-1 sur l’activation de ces promoteurs d’aromatase demeure mal connu. De plus, la demi-vie du transcrit CYP19A1 est très courte avec une région 3’UTR relativement longue. L’analyse de la séquence 3’UTR montre la présence des motifs ARE (séquence riche en AU), des études antérieur montrent que ces séquences impliquent dans la régulation de la stabilité ou la dégradation de l’ARNm, ce qui est fort probable que la courte demi-vie de l’ARNm CYP19A1 est sous le contrôle post-transcriptionel. L’objectif de la thèse visait à étudier la régulation de l’expression du gène CYP19A1 chez la vache. Il y a deux thèmes soit étude de la régulation transcriptionnelle ciblant le promoteur et soit étude de la régulation post-transcriptionnelle impliquant la région 3’non traduite (3’UTR). Le premier objectif vise à étudier la régulation transcriptionnelle du gène CYP19A1. Nous avons étudié l'activité du promoteur ovarien bovin dans deux modèles de cellules de la granulosa...

‣ The Aromatase Gene (CYP19A1) Variants and Circulating Hepatocyte Growth Factor in Postmenopausal Women

Gunter, Marc J.; Cochrane, Barbara B.; Chlebowski, Rowan T.; Lin, Jennifer H.; Manson, JoAnn Elisabeth; Rexrode, Kathryn Marian; Cook, Nancy Romanowicz; Kraft, Peter; Ho, Gloria Y. F.; Zhang, Shumin
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
27.743247%
Background: Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations. Design We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who later developed colorectal cancer from the Women's Health Initiative Observational Cohort. As the distribution of HGF levels was highly skewed, we transformed HGF concentrations for all women into a log-, ranked-, or normal score-scale value. Multiple linear regression with adjustment for age was used to evaluate the associations. Results: We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and HGF levels in ranked and normal score scales (corrected p values ≤0.02), although the association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.16). The associations remained unchanged after additional adjustment for hormone therapy use and estradiol levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D′≥97%...

‣ CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer.

Thompson, Deborah J.; O?Mara, Tracy A.; Glubb, Dylan M.; Painter, Jodie N.; Cheng, Timothy; Folkerd, Elizabeth; Doody, Deborah; Dennis, Joe; Webb, Penelope M.; Australian National Endometrial Cancer Study Group (ANECS); Gorman, Maggie; Martin, Lynn; Hodgs
Fonte: Bioscientifica Publicador: Bioscientifica
Tipo: Article; published version
Português
Relevância na Pesquisa
37.743247%
This is the author accepted manuscript. The final version is available from Bioscientifica via http://dx.doi.org/10.1530/ERC-15-0386; Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol concentrations. We analysed 2,937 SNPs in 6,608 endometrial cancer cases and 37,925 controls and report the first genome wide significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8x10-11). SNP rs727479 was also among those most strongly associated with circulating estradiol concentrations in 2,767 post-menopausal controls (P=7.4x10- 8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11- 1.21) is compatible with that predicted by the observed effect on estradiol concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by estradiol. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.; Fine-mapping analysis was supported by NHMRC project grant [ID#1031333] to ABS...