Associations Between SNPs On 6q25.1 And In TOX3 With Risk Of Breast Cancer In A Fujian Population: Interaction Stratified Analysis

Object: Breast cancer(BC) is one of the most common malignancies worldwide and a great thereat to women’s health. It is a heterogeneous disease in which multiple genetic and environmental factors play critical roles. Related studies have indicated that differences in genetic background may influence breast cancer susceptibility in different individuals with the same environmental exposure factors. Until now, several high-penetrance inherited mutations, including BRCA1, BRCA2, TP53 and PTEN, were identified to contribute to increased susceptibility to breast cancer. However, only about 20-25% of the familial risk and 5% of breast cancer incidence can be explained by these high-penetrance mutations. SNP(Single nucleotide polymorphism) is one of the most common genetic variation and important forms of disease susceptibility caused by susceptibility genes. Recent genome-wide association studies(GWAS) have identified a series of new genetic susceptibility loci for breast cancer. However, the correlations between these variants and breast cancer are still not clear. In order to explore the role of breast cancer susceptibility variants in a Fujian population, we genotyped two common SNPs on chromosome 6q25(rs2046210) and in TOX3(rs4784227). In addition, we also evaluated the multiple interactions among genetic variants, risk factors, and tumor subtypes.Methods: The association between the selected SNPs and susceptibility to breast cancer was examined in a case-control study consisting of a total of 702 breast cancer cases and 794 healthy-controls derived from a Fujian population. Genomic DNA was extracted from the leukocyte of peripheral blood. Genotyping for the twoselected SNPs were performed by the SNP scanTM platform. Associations among genotypes, tumor subtypes and breast cancer risk were estimated by computing odds ratios(ORs) and 95% confidence intervals(CIs) from multivariate logistic regression.Results: In the single locus analyses, for rs2046210, the frequency distribution of allele G and A in the case group was 55.8% and 44.2%, the frequency distribution of allele G and A in the control group was 63.0% and 37.0%. For rs4784227, the frequency distribution of allele C and T in the case group was 68.8% and 31.2%, the frequency distribution of allele C and T in the control group was 73.1% and 26.9%. Both polymorphisms achieved significant differences in the genotype distribution between cases and controls(P<0.05). Multivariate logistic regression analyses also revealed that, for rs2046210, the GA or AA carriers were at higher risk of BC compared with the GG homozygote(OR=1.63, 95% CI=1.29-2.13 and OR=1.68, 95% CI=1.21-2.33, respectively), the A allele carrier(GA+AA genotype) achieved significant differences(OR=1.66, 95% CI=1.32-2.10) compared with the GG homozygote. Similarly for rs4784227, a significantly increased risk was observed in the CT+TT genotype, as compared to the CC genotype(OR=1.27, 95% CI=1.03-1.56). Furthermore, in subgroup stratified analyses, we observed that the T allele of rs4784227 was significantly associated with elevated OR among postmenopausal populations(OR=1.44, 95% CI=1.11-1.87) but not in premenopausal populations, with the heterogeneity P value of P=0.064, suggesting that rs4784227 potentially elevates a significant breast cancer risk in postmenopausal populations when compared with premenopausal populations.Conclusion: The genetic variants on chromosome 6q25 and in the TOX3 gene are associated with breast cancer risk in a Fujian population.