BMC Cancer 2009, 9:438 http://www.biomedcentral.com/1471-2407/9/438 other coregulator SNPs we rationalized may have func- tional consequences based on the severity of the amino acid change and proximity to functional domains [rs1804645 (SRC-1), rs6094752 (SRC-3), and rs2229840 & rs7978237 (SMRT)] (positions are highlighted in Figure 1). For example, rs1804645 (SRC-1 P1272S) was chosen since it is the only non-synonymous SNP in SRC-1, is located in the second activation domain, and is predicted to be 'probably damaging' by a polymorphism phenotype prediction tool (PolyPhen, http://genetics.bwh.har vard.edu/pph/). Rs6094752 (SRC-3 R218C) was chosen because of the loss of charge and size as a result of the amino acid substitution, and is one of the most common non-synonymous SNPs in SRC-3. The SNPs in SMRT, rs2229840 (A1706T) and rs7978237 (G781E) were cho- sen for genotyping due to high frequency, severity of amino acid change, and location in a functional domain. Several approaches to design TaqMan assays for rs7978237 failed. We were therefore unable to obtain gen- otyping information for this SNP. The genotyping results were in Hardy-Weinberg equilib- rium in controls for all SNPs investigated (p = 0.309 for rs1804645; p = 0.112 for rs6094752; p = 0.058 for rs2230782; p = 0.067 for rs2076546; p = 0.140 for rs2229840). The three SNPs that we rationalized may have functional consequences that we were able to geno- type, namely SRC-1 P1272S (rs1804645), SRC-3 R218C (rs6094752), and SMRT A1706T (rs2229840), did not significantly associate with breast cancer risk (Table 2). Also, stratification for age (> = 50 year and <50 years of Table 4: Associations with stratification by bilateral cases age) in order to investigate a possible risk influence in pre- or postmenopausal women revealed no significant associ- ations except for rs6094752 where a significant effect could be detected for heterozygous carriers only (Table 3). However, this is most likely a chance effect due to multi- ple testing. Stratification by bilateral cases revealed no sig- nificant associations (Table 4). We observed a protective effect of the homozygous c-allele carrier of SRC-3 Q586H rs2230782 (GG+GC versus CC: OR = 0.45, 95%CI = 0.041, Table 2), similar to the findings that have been reported before (GG+GC versus CC: OR = 0.39, 95%CI = 0.14-1.05 p = 0.061) [15]. As our study included a portion of the samples of the previous reported study it is note- worthy to mention that the results of the current study excluding the previously analyzed samples show the same protective effect and borderline significance (GG+GC ver- sus CC: OR = 0.37, 95%CI = 0.13-1.08, p = 0.059). How- ever, we failed to replicate previous associations between SRC-3 rs2076546 (T960T) SNP and breast cancer risk. The haplotype analysis of the variants analysed in SRC-3 revealed a protective haplotype including the C-C-G-alle- les of R218C, Q586H and T960T, respectively (Table 5). As the haplotype is very rare occurring with a frequency of 0.03 in controls this result has to be verified in further multi-center collaboration studies. The discordant findings between our studies and the Haiman study [16] with respect to SRC-3 Q586H may be due to the inherent differences in the populations exam- ined. For example, our studies exclusively examined Euro- peans while the study by Haiman et al. examined a range SNP Genotypes Cases Controls SRC-1 Rs1804645 P1272S SRC-3 rs6094752 C218R SRC-3 Rs2230782 Q586H SRC-3 rs2076546 T960T SMRT rs2229840 A1706T CC (%) CT (%) TT (%) CC (%) CT (%) TT (%) GG (%) GC (%) CC (%) AA (%) AG (%) GG (%) GG (%) AG (%) AA (%) Cases bilateral 106 (93.8) 1432 (94.9) 6 (5.3) 77 (5.1) 1 (0.9) 0 (0.0) [CT + TT]<-> [CC] 95 (86.4) 1330 (89.3) 14 (12.7) 152 (10.2) 1 (0.9) 8 (0.5) [CT + TT]<-> [CC] 88 (80.0) 1207 (80.3) 22 (20.0) 272 (18.1) 0 (0.7) 24 (1.6) [CC]<-> [GG + CT] 89 (80.2) 1240 (82.2) 21 (18.9) 249 (16.5) 1 (0.9) 20 (1.3) [AG + GG]<-> [AA] 79 (72.5) 1004 (67.6) 27 (24.8) 423 (28.5) 3 (2.7) 57 (3.9) [AG + GG]<-> [AA] Odds ratios (OR) with 95% confidence intervals (95% CI) and P-values. OR 1 1.05 - 1.22 1 1.29 1.75 1.31 1 1.11 0.28 1.02 1 1.17 0.69 1.14 1 0.81 0.67 0.79 95% CI 0.44-2.47 - 0.55-2.73 0.72-2.32 0.22-14.14 0.74-2.32 0.68-1.80 0.017-4.62 0.63-1.65 0.72-1.93 0.09-5.25 0.70-1.85 0.52-1.27 0.20-2.18 0.51-1.23 P 0.906 - 0.613 0.393 0.595 0.347 0.675 0.186 0.938 0.522 0.724 0.597 0.363 0.502 0.298 Page 7 of 9 (page number not for citation purposes)