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Estrogen receptor ? (ESR1) IVS1-397T>C polymorphism lowers risk of fracture.

ABSTRACT: BACKGROUND:Genetic factors are reported to affect fracture incidence. Many groups have explored the correlation of fracture risk with ESR1 IVS1-397T>C. The observed associations, however, are largely inconsistent. This meta-analysis of data from early-released studies was performed in an effort to determine the role of IVS1-397T>C in fracture. METHODS:Relevant studies were searched through Pubmed, Embase, ScienceDirect, and Wiley Online Library databases. 16 studies meeting all selection criteria were finally identified. We calculated ORs with 95% CIs to assess risk of fracture. Subgroup analyses were performed by subtype, ethnicity and gender. RESULTS:Data on 2916 cases and 19170 controls were analyzed in the meta-analysis. Overall, we found moderately decreased risk in association with IVS1-397 CC genotype (OR = 0.82, 95% CI = 0.73-0.92; OR = 0.84, 95% CI = 0.76-0.94). The decrease persisted in both hip fracture (OR = 0.82, 95% CI = 0.71-0.94; OR = 0.83, 95% CI = 0.73-0.94) and vertebral fracture (OR = 0.67, 95% CI = 0.50-0.91; OR = 0.78, 95% CI = 0.64-0.97; OR = 0.82, 95% CI = 0.68-0.98) when data were stratified by subtype. We also found a significant trend of decreasing risk in relation to the CC genotype in Caucasian, male and female. All fixed-effects meta-analysis results were homogeneous. CONCLUSION:The meta-analysis demonstrates that risk of fracture seems likely to be decreased due to IVS1-397 CC or CT genotype.

SUBMITTER: Wang J

PROVIDER: S-EPMC4612868 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Estrogen receptor α (ESR1) IVS1-397T>C polymorphism lowers risk of fracture.

Wang Jian J Feng Gang G Li Hang H Li Weixu W Pan Zhijun Z Wang Jianwei J

International journal of clinical and experimental medicine 20150815 8

<h4>Background</h4>Genetic factors are reported to affect fracture incidence. Many groups have explored the correlation of fracture risk with ESR1 IVS1-397T>C. The observed associations, however, are largely inconsistent. This meta-analysis of data from early-released studies was performed in an effort to determine the role of IVS1-397T>C in fracture.<h4>Methods</h4>Relevant studies were searched through Pubmed, Embase, ScienceDirect, and Wiley Online Library databases. 16 studies meeting all se ...[more]

PMID: 26550183

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Project description:Single nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown.We assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol.We observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002-0.026), these associations were strongest in lean women (BMI, ?23.6 kg/m2.). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3-6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025-0.079) that the level of 17?-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (<28.5 %) percent mammographic density and higher in women with high (>28.5 %) percent mammographic density, when compared to women with the major genotype.Our results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies.

Project description:Estrogen receptor-? (ESR1) is an important transcriptional regulator in the mammalian oviduct, however ESR1-dependent regulation of the transcriptome of this organ is not well defined, especially at the genomic level. The objective of this study was therefore to investigate estradiol- and ESR1-dependent regulation of the transcriptome of the oviduct using transgenic mice, both with (ESR1KO) and without (wild-type, WT) a global deletion of ESR1. Oviducts were collected from ESR1KO and WT littermates at 23 days of age, or ESR1KO and WT mice were treated with 5 IU PMSG to stimulate follicular development and the production of ovarian estradiol, and the oviducts collected 48 h later. RNA extracted from whole oviducts was hybridized to Affymetrix Genechip Mouse Genome 430-2.0 arrays (n = 3 arrays per genotype and treatment) or reverse transcribed to cDNA for analysis of the expression of selected mRNAs by real-time PCR. Following microarray analysis, a statistical two-way ANOVA and pairwise comparison (LSD test) revealed 2428 differentially expressed transcripts (DEG's, P < 0.01). Genotype affected the expression of 2215 genes, treatment (PMSG) affected the expression of 465 genes, and genotype x treatment affected the expression of 438 genes. With the goal of determining estradiol/ESR1-regulated function, gene ontology (GO) and bioinformatic pathway analyses were performed on DEG's in the oviducts of PMSG-treated ESR1KO versus PMSG-treated WT mice. Significantly enriched GO molecular function categories included binding and catalytic activity. Significantly enriched GO cellular component categories indicated the extracellular region. Significantly enriched GO biological process categories involved a single organism, modulation of a measurable attribute and developmental processes. Bioinformatic analysis revealed ESR1-regulation of the immune response within the oviduct as the primary canonical pathway. In summary, a transcriptomal profile of estradiol- and ESR1-regulated gene expression and related bioinformatic analysis is presented to increase our understanding of how estradiol/ESR1 affects function of the oviduct, and to identify genes that may be proven as important regulators of fertility in the future.

Dataset Information

Estrogen receptor ? (ESR1) IVS1-397T>C polymorphism lowers risk of fracture.

Publications

Estrogen receptor α (ESR1) IVS1-397T>C polymorphism lowers risk of fracture.

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