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• Powerful evidence links specific SNPs (rs124936, rs4784227, rs2046210) to breast cancer susceptibility in large Chinese cohort. • Allele T of rs12493607 significantly increased the risks of invasive carcinoma. • SNP rs4784227 and rs3803662 were associated with invasive carcinoma and ER-positive breast cancer. • Allele A of rs2046210 significantly raises ductal carcinoma in situ risk. • SNPs (rs10484919, rs1038304) linked to HER2-positive breast cancers. Breast cancer is a complex disease influenced by both external and internal factors, among which genetic factors play a critical role. Single-nucleotide polymorphisms (SNPs) are major contributors to the heritability of breast cancer, and their frequencies vary across ethnic groups. In this study, we aimed to investigate the association between 34 SNPs identified in previous genome-wide association studies (GWAS) and overall breast cancer risk, as well as breast cancer subtypes, in the Chinese female population. To accomplish this, we conducted an extensive association analysis using the high-throughput Sequenom MassARRAY® platform in a case-control study comprising 1848 breast cancer patients and 709 healthy controls. Our analysis, which utilized the SNPassoc package in R based on chi-squared (χ2) test and genetic model analysis, identified significant associations between breast cancer risk and SNP rs12493607 (TGFBR2 , risk allele C, OR = 1.28 [1.11–1.47], P = 0.0005), as well as a less conservatively significant association with rs4784227 (CASC16 , risk allele T, OR = 1.24 [1.08–1.42], P = 0.0017) and rs2046210 (ESR1 , risk allele A, OR = 1.50 [1.16–1.95], P = 0.0016). Furthermore, our stratified analyses revealed that rs12493607 was significantly associated with invasive carcinoma, estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, HER2-negative, and young (aged younger than 45) breast cancer. SNP rs4784227 and rs3803662 (CASC16) were associated with invasive carcinoma and ER-positive breast cancer, while rs2046210 was linked to ductal carcinoma in situ , ER-negative, PR-negative, HER2-positive, and elder (aged more than 45) breast cancers. SNPs rs10484919 (ESR1) and rs1038304 (CCDC170) showed links to HER2-positive breast cancer, and rs616488 (PEX14) with premenopausal breast cancer. In summary, our study shed light on the relationship between SNPs and breast cancer susceptibility within a vast Chinese cohort, supporting the development of polygenetic risk scores for the Chinese population. These findings provide valuable insights into the genetic basis of breast cancer and have important implications for risk prediction, early detection, and personalized treatment of this disease. [ABSTRACT FROM AUTHOR]

Objectives Albeit single nucleotide polymorphisms related to ESR1 gene have been studied, only a number of them have been reported to be associated with breast cancer risk. rs1062577 is one of the most recent microRNA-related ESR1 SNPs; however, no study has been conducted to investigate the significance this polymorphism in Iranian population. In this study, we aimed to investigate the frequency and also the association between rs1062577 and breast cancer. Materials and methods rs1062577 position was genotyped by Tetra-primer ARMS-PCR in totally 182 blood specimens obtained from breast cancer patients ( n = 86), and healthy blood donors ( n = 96). The distribution of different genotypes was statistically analyzed in terms of the potential association between rs1062577 different alleles, breast cancer risk and clinicopathological criteria of breast cancer patients. Results The statistical analyses confidently indicated that rs1062577 A allele is associated with the increased breast cancer risk in both univariate and multivariate regression models (Odds Ratio = 8.403 and 32.602 respectively). rs1062577 T allele was statistically associated with stage I of breast cancer patients ( p -value = 0.025). In silico studies implied that rs1062577 A allele can alter the binding capacity of ESR1 mRNA and miRNAs via either breakage or formation of hydrogen bonds. Conclusion rs1062577 A allele is significantly and dramatically associated with the elevated risk and greater stages of breast cancer. [ABSTRACT FROM AUTHOR]

Introduction Reproductive factors pose a risk for sporadic breast cancer (BC) development owing to the lifetime exposure to estrogen, a hormone responsible for cell proliferation in the breast. Because variants of the estrogen receptor (ER) alpha and beta genes have been associated with BC risk in numerous populations, the objective of the study was to determine whether the risk and severity of sporadic BC was associated with the rs2228480 ( ESR1 ) and rs4986938 ( ESR2 ) variants in a Brazilian population. Methods A total of 253 DNA samples from sporadic BC patients and 257 DNA samples from healthy controls were studied. The samples were genotyped by PCR-RFLP. Epidemiological, clinical, and reproductive factors were analyzed. Statistical tests conducted included the χ 2 test, Fisher's exact test, and Mann-Whitney and Kruskal-Wallis tests or their parametric equivalents. Results There was a high frequency of the rs2228480*GG genotype among the ER-positive tumors (OR = 2.13; 95% CI = 1.189–3.816) and it showed minor association with clinical stage 0 (OR = 0.324; 95% CI = 0.116–0.904). The rs2228480*GA genotype was associated with minor ER expression, whereas rs2228480*GG was associated with high expression of the progesterone receptor (PR). The frequency of rs4986938*GA was high among women who breastfed (OR = 2.11; 95% CI = 1.203–3.702), and it showed high association with clinical stage 0 (OR = 4.383; 95% CI = 1.606–11.96) whereas it had minor association with systemic arterial hypertension (OR = 0.53; 95% CI = 0.319–0.880). The rs2228480*GG/rs4986938*GG haplotype occurred at a low frequency among women who breastfed (OR = 0.525; 95% CI = 0.298–0.924) but it was associated with a high expression of PR. Conclusion The rs2228480 and rs4986938 variants did not alter sporadic BC risk, but they did modulate the BC severity. [ABSTRACT FROM AUTHOR]

• Low expression of ESR1 is associated with ascending aortic dilation and AAAD. • Peripheral blood ESR1 expression may be a novel diagnostic biomarker of TAA. • ESR1 expression is positively correlated with ration of naive CD8 + T cells in AAAD. The common genetic signatures of ascending aortic dilation and acute type A aortic dissection (AAAD) remained unclear. This study aims to investigate the role of ESR1 in ascending aortic dilation and AAAD via a multi-omics approach combining transcriptome-wide association study (TWAS) and mRNA expression profiles. The TWAS analysis was performed by integrating expression quantitative trait loci (eQTL) data of aorta and the GWAS dataset of ascending aortic diameter using the FUSION software. Joint/Conditional Analysis was used to screen conditionally independent genes from TWAS significant regions. mRNA expression profiles were used to confirm the differential expression of ESR1 in ascending aortic dilation and AAAD. An independent mRNA expression profile dataset was used to validate the diagnostic efficiency of ESR1 expression on thoracic aortic aneurysm (TAA). Gene set enrichment analysis (GSEA) was utilized to explore the potential molecular function of ESR1 in mouse aorta. Immune infiltration analysis was performed to evaluate the association between ESR1 and immune infiltration in AAAD. ESR1 was among the top 10 most significant genes identified by TWAS of ascending aortic diameter (Z score = -7.3, P TWAS = 3.30 × 10-13). mRNA expression profiles confirmed the low expression of ESR1 both in ascending aortic dilation (P mRNA = 0.0361) and AAAD (P mRNA = 0.0142). The diagnostic efficiency of peripheral blood ESR1 expression on TAA was further validated by an independent mRNA expression profile dataset. GSEA showed that GO terms and KEGG pathways mainly involved in metabolism and oxidoreductase activity were enriched in aortic tissue of ERα knockout mice. The immune infiltration ration of naive CD8 + T cells was significantly lower in AAAD compared with normal aorta, and was positively correlated with ESR1 expression. Low expression of ESR1 is associated with ascending aortic dilation and AAAD. Peripheral blood ESR1 expression may be a novel diagnostic biomarker of TAA. ESR1 expression is positively correlated with immune infiltration ration of naive CD8 + T cells in AAAD. [ABSTRACT FROM AUTHOR]

Abstract: Background: Since osteoporosis is a complex disease characterized by low bone mineral density (BMD), which is determined by an interaction of genetics with metabolic and environmental factors, the aim of this study was to analyze the possible association among one polymorphism of VDR and two polymorphisms of ESR1; as well as their haplotypes with BMD in postmenopausal Mexican-mestizo women. Methods: We studied 742 postmenopausal Mexican-mestizo women. A structured questionnaire for risk factors was applied and BMD was measured in the lumbar spine and total hip by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. One polymorphism of VDR (rs11568820) and two of ESR1 (rs2234693 and rs9340799) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Hardy–Weinberg equilibrium was tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r 2; haplotype analysis was conducted. Results: Rs9340799 of ESR1 and one haplotype formed by the two polymorphisms of the ESR1 were significantly associated with FN-BMD variations. Moreover, analysis of the genotype of rs11568820 of VDR and the rs2234693 of ESR1 showed no significant differences with BMD variations. Conclusions: Our results showed that rs9340799 and one haplotype of ESR1 were significantly associated with BMD only at the femoral neck and this association remained after adjusting for covariates. [Copyright &y& Elsevier]

Abstract: Objectives: The association between passive smoking and breast cancer risk differs in pre- and post-menopausal women. We aimed to explore the modification effects of PARP1 rs1136410 and ESR1 rs2234693 on the association between passive smoking and breast cancer risk among pre- and post-menopausal women. Design and methods: A case–control study of 839 breast cancer cases and 863 controls was conducted. The gene–environment interactions were tested after adjusting for potential breast cancer risk factors with unconditional logistic regression models. Results: We found that the effect of passive smoking was modified by the genotypes in both pre- and post-menopausal women, but in opposite directions. The combination of the TC/CC genotypes of ESR1 rs2234693 and passive smoking significantly increased the risk of breast cancer [OR (95%CI): 2.06 (1.39–3.05)] in pre-menopausal women. A significant association was observed between TT genotype and passive smoking [OR (95%CI): 2.40 (1.27–4.53)] in postmenopausal women. For PARP1 rs1136410, similar differential associations were observed, but the interactions were not significant. Conclusions: These results imply that the risk of breast cancer from passive smoking may be influenced by genetic factors, and that the association may differ depending on menopausal status. [Copyright &y& Elsevier]

• SNVs in estrogen receptor genes are markers for cancer but poorly studied in PCOS. • Several SNVs in ESR1/2 genes were found associated with PCOS in Tunisian population. • Haplotype analysis of ESR1 indicated correlation with metabolic features of PCOS. SNV (single nucleotide variation) in estrogen receptor (ESR1 and ESR2) genes are susceptibility markers for complex diseases, such as cancer, metabolic disorders and women infertility. We explored six widely used SNVs in ESR1 (rs2234693, rs9340799, rs3798577, rs3020314) and ESR2 (rs1256049, rs4986938) in polycystic ovary syndrome (PCOS) in women from Tunisia (n = 254) compared to controls (n = 170). Genotyping was performed by RFLP-PCR or real-time PCR and analyzed in GoldenHelix statistical package. Logistic regression revealed association of rs2234693, rs3798577 and rs3020314 (ESR1) and rs1256049 (ESR2), the association of rs2234693 (C/T) being the strongest with P < 4.81 × 10-6, 2.88 × 10-5 after Bonferroni correction, OR 0.31, 95%CI (0.18–0.53)). Correlations were found with LH, LH/FSH or hyperandrogenism and even more significant with metabolic syndrome (rs9340799) and hyperglycemia (rs3798577). Among 14 haplotypes reconstructed in ESR1 gene, four haplotypes (H1 to H4) were associated with PCOS the strongest being that of H1 (P < 0.002) supported by Bonferroni (P < 0.033) and permutation tests (P < 4 x10-4). In haplotype trend regression, concordant correlations were found with insulin resistance (P < 0.033) for H2 and with high blood pressure for H3 (P < 0.048). While these data revealed influential role on metabolic rather and hormonal features of PCOS, the association of rs2234693 was the strongest among all ethnic populations studied thus far giving a new insight on estrogen receptor gene variation in distant North African populations and their role in metabolic alteration of PCOS. [ABSTRACT FROM AUTHOR]

Vitiligo is an acquired epidermal pigment loss of the skin. Oxidative stress is one of the major theories in the pathophysiology of vitiligo. FOXO3A is the forkhead members of the class O (FOXO) transcription factors, and plays an important role in cell cycle regulation, apoptosis, oxidative stress, and DNA repair. The aim of our study was to investigate FOXO3A gene polymorphisms and FOXO3A protein levels, activities of superoxide dismutase (SOD) and catalase antioxidant enzymes in vitiligo patients and healthy controls. Moreover, the level of plasma advanced oxidation protein products (AOPP) in subjects was evaluated to understand the possible role of protein oxidation in disease etiology. Study groups included 82 vitiligo patients and 81 unrelated healthy controls. FOXO3A polymorphisms were determined using polymerase chain reaction-restriction fragment length polymorphism method. FOXO3A levels and catalase activity were measured by ELISA whereas AOPP levels and SOD activity was measured by spectrophotometric analysis. We found a significant relationship between rs4946936 polymorphism of FOXO3A gene and vitiligo/active vitiligo patients (p=0.017; p=0.019 respectively), but not for rs2253310 (p>0.05). SOD activity and AOPP levels of vitiligo patient were increased compared with control group, whereas FOXO3A levels and catalase enzyme activity of vitiligo patient were decreased compared with control group (p<0.05). Our study indicates that rs4946936 of FOXO3A gene may associate susceptibility of vitiligo, especially active vitiligo. Moreover, our results confirm that oxidative stress may play a role in the pathophysiology of vitiligo. Further studies with larger samples are required to elucidate the role of FOXO3A in vitiligo., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In mammals, genomic imprinting has evolved as a dosage-controlling mechanism for a subset of genes that play critical roles in their unusual reproduction scheme involving viviparity and placentation. As such, many imprinted genes are highly expressed in sex-specific reproductive organs. In the current study, we sought to test whether imprinted genes are differentially expressed between the two sexes. According to the results, the expression levels of the following genes differ between the two sexes of mice: Peg3, Zim1, Igf2, H19 and Zac1. The expression levels of these imprinted genes are usually greater in males than in females. This bias is most obvious in the developing brains of 14.5-dpc embryos, but also detected in the brains of postnatal-stage mice. However, this sexual bias is not obvious in 10.5-dpc embryos, a developmental stage before the sexual differentiation. Thus, the sexual bias observed in the imprinted genes is most likely attributable by gonadal hormones rather than by sex chromosome complement. Overall, the results indicate that several imprinted genes are sexually different in terms of their expression levels, and further suggest that the transcriptional regulation of these imprinted genes may be influenced by unknown mechanisms associated with sexual differentiation., (© 2013 Elsevier B.V. All rights reserved.)

Background: Since obesity and osteoporosis present a high genetic predisposition and polymorphisms of IL-6, IL6R, LRP5, ESR1 and SP7 may influence the risk of both diseases, the aim of this study was to analyze the possible association of polymorphisms in these genes, as well as their haplotypes, with BMD variations in postmenopausal Mexican-Mestizo women with grade 2 or grade 3 obesity., Methods: One hundred eighty unrelated postmenopausal women with grade 2 or grade 3 obesity were included. BMD was measured in total hip and lumbar spine by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Rs1800795 of IL-6, rs2228145 of IL6R, rs3736228 of LRP5, rs9340799 (XbaI) and rs2234693 (PvuII), of ESR1, rs10876432 and rs2016266, of SP7 (and their haplotypes), were studied by real-time PCR allelic discrimination. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r(2), and haplotype analysis was conducted., Results: Using WHO criteria, 54.5% had grade 2 obesity, and 45.5% had grade 3 obesity. Regarding DXA results, 11.1% women had osteoporosis, 41.7% had osteopenia, and 47.2% had normal BMD. Genotype and haplotype analysis showed no significant differences with BMD variations at the lumbar spine, total hip or femoral neck., Conclusions: We did not find a significant association between the polymorphisms analyzed or their haplotypes and BMD variations in postmenopausal women with obesity. The higher BMD observed in women with obesity could be the result of an adaptive response to the higher loading of the skeleton., (© 2013 Elsevier B.V. All rights reserved.)