Synergistic association of six well-characterized polymorphisms in three genes of the renin-angiotensin system with breast cancer among Han Chinese women

Objective: Breast cancer is the most common malignancy that is believed to be largely under genetic control. We therefore investigated both individual and interactive associations of six well-characterized polymorphisms in three genes of the renin-angiotensin system with breast cancer among Han Chinese women. Methods and results: This was a hospital-based study involving 606 patients diagnosed with sporadic breast cancer and 633 age- and ethnicity-matched controls. There were significant differences in genotype and allele distributions of ACE gene rs4343 (p(gentoype) = 0.002 and p(allele) < 0.001) and AGTR1 gene rs5186 polymorphisms (p(gentoype) < 0.001 and p(allele) < 0.001), even with a Bonferroni-corrected alpha of 0.0042 (0.05/12). Allele combinations of T-T-T-G-C-A (alleles in order of rs5050, rs699, rs4291, rs4343, rs188018 and rs5186), G-C-T-G-C-A and T-C-T-G-C-C, respectively, had the age-adjusted odds of 2.21 (p = 0.021), 3.01 (p = 0.021) and 5.24 (p = 0.015) for breast cancer, whereas allele combination T-C-T-A-T-A was associated with a 76% (p = 0.008) reduced risk. Interaction analysis revealed an overall best two-locus model including rs4343 and rs4291 polymorphisms, and this model had the maximal testing accuracy of 0.6259 with a cross-validation consistency of 10 (p = 0.0015). Conclusion: Our findings support a contributory role of the ACE gene, with its genetic polymorphisms acting synergistically, in predisposition to breast cancer among Han Chinese women.