br The ESR intron SNP rs C T
The ESR1 intron SNP rs3020314 (+2464 C/T) was reported to be associated with altered mRNA splicing (Dunning et al., 2009). This SNP has been found to be related with several diseases. It was associated with an increased risk of endometrial cancer mainly among Caucasian populations (Zhou et al., 2013), and hip fractures (Velasco et al., 2010; Wang et al., 2008); but with decreased risk of follicular lymphoma (Skibola et al., 2008). The contribution of the polymorphic variant of ESR1 rs3020314 to breast cancer susceptibility has been extensively investigated in Caucasian and Asian populations. It was found to be associated with the susceptibility to breast cancer in European women (Dunning et al., 2009; Lipphardt et al., 2013). In our current study, the association of the genotypes of rs3020314 with breast cancer
SNP Risk factor Genotype Cases Controls OR (95%CI) Cases Controls OR (95%CI)
Age at menarche
Age at menarche
Association tests of ESR1 Haplotypes.
Haplotype Cases frequency Controls frequency OR (95%CI) p value
a The (ref) indicates which haplotype has been selected to be the baseline, reference category; in phase Olivetolic Acid are TC/CT; Likelihood ratio test: chi-square = 0.93, df = 3, p = 0.82; Order of SNPs: rs1643821 rs3020314; The reference allele is underlined with a single line, and the risk allele with a double line.
susceptibility, risk factors, pathological and clinical characteristics were assessed in a series of Sudanese women. The frequency of the hetero-zygous genotype was significantly higher in breast cancer patients compared to control groups. Similarly, the heterozygous genotype was significantly more frequent in the subgroup of breast cancer patients with BMI ≥25 kg/m2, and in postmenopausal patient. However, no significant associations were detected between the distribution of genotypes and age at menarche, parity, tumor histology, tumor stage, lymph node involvement, metastasis, ER and PR expression. Our find-ings are in agreement with many published studies; a comprehensive SNP-tagging association study suggested that ESR1 rs3020314 had an independent statistically significant association with slightly increased breast cancer susceptibility in European populations, nonetheless no association was detected in Asian populations (Dunning et al., 2009). In line with our data, Lipphardt et al., (2013) reported an association between the heterozygous genotype and breast cancer risk, however testing the relation between the genotypes and the estrogen receptor status, histology and tumor grade, none reached the significance level. It was shown that no conclusive evidence was obtained that age at menarche, parity, age at first birth or BMI modify the established as-sociations of breast cancer risk with ESR1 rs3020314 (Milne et al., 2010). The SNP rs3020314 proved to be in a highly significant asso-ciation with breast cancer, however on subgrouping breast cancer by
morphology type or hormone receptor status, this relation was not observed (Mavaddat et al., 2009). Furthermore, in meta-analyses this SNP showed a significant association with breast cancer risk in Cau-casians (Zhang et al., 2011). Recently, it was reported that SNP rs3020314 is significantly associated with increased risk of breast cancer in women of European ancestry, but not in those of African ancestry. Additionally, when stratified by ER status, this SNP showed stronger associations in ER-positive than in ER-negative breast cancer only in European women (Quan et al., 2014).
The second SNP that was included in the present study was rs1514348 (−4576 A/C). This SNP was shown to be associated with other diseases, including type 2 diabetes in an African-American po-pulation (Billings et al., 2012; Gallagher et al., 2007; Keene et al., 2008) and Alzheimer's disease in Chinese population (Ma et al., 2009). So far, only a single study has investigated for possible link of ESR1 intron SNP rs1514348 (−4576 A/C) to breast cancer susceptibility, this recently published data reported that SNP-rs1514348 was associated with in-creased risk of breast cancer among Caucasian European women (Lipphardt et al., 2013). In contrast, our findings indicate that the genotype distribution of rs1514348 was likely to be associated with reduced risk of breast cancer in Sudanese women, especially the het-erozygous genotypes. Besides, in this study, the heterozygous genotypes also associated with decreased risk of breast cancer in postmenopausal women, and in women with body mass index ≥25 kg/m2. However, the ESR1 polymorphism rs1514348 was not associated with established risk factors of breast cancer, such as BMI, menopausal status, age at me-narche, and clinicopathlogical variables, such as lymph node involve-ment, distant metastasis, tumor grade, histopathologic type, ER and PR expression of tumors.