BMC Cancer 2009, 9:438 http://www.biomedcentral.com/1471-2407/9/438 Table 5: Associations of SRC-3 haplotypes Haplotypesa CGA CCA CGG TGA CCG TCG TGG Cases (%) 1847 (77.0) 227 (9.5) 205 (8.5) 119 (4.9) 0 (0.0) 2 (0.1) 0 (0.0) Controls (%) 2199 (75.0) 298 (10.1) 267 (9.1) 162 (5.5) 8 (0.3) 1 (0.0) 1 (0.0) OR 1 0.91 0.91 0.87 0.07 2.38 0.39 95% CI 0.75-1.09 0.75-1.11 0.68-1.12 0.004-1.21 0.22-26.28 0.02-9.74 P 0.2963 0.3597 0.2824 0.0096 0.4651 0.3659 a haplotypes representing the alleles of C218R, Q586H and T960T compared with wildtype. Haplotype frequencies of SRC-3 polymorphisms C218R, Q586H and T960T in the German study population compared with the, odds ratios (OR) with 95% confidence intervals (95% CI) and P- values. of ethnic backgrounds. A number of recent studies suggest that a SNP association could be specific to the genetic background of a certain ethnic group [22,23]. It is possi- ble that the Q586H effect is only seen in European popu- lations, and/or that the lower number of unselected European cases within the Haiman study had insufficient power to detect this effect. The selection of high risk BRCA1/BRCA2 mutation negative cases in our study is expected to act as a multiplier to further increase our power to detect associations. Lastly, since only nonsynon- ymous SNPs were genotyped in the Haiman study, the stronger effect seen in the two-SNP SRC-3 haplotype could not be observed. We did not genotype the two SNPs (SMRT H52R and CALCOCO1 R12H) identified in the Haiman study to be associated with breast cancer risk since they were found either exclusively or predominantly in African Americans (European population MAF: SMRT H52R = 0%, CALCOCO1 R12H = 0.6%). Since our study exclusively contains Europeans, it was unlikely that we would obtain sufficient power to detect an association. Conclusions In summary, these results illustrate the dramatic differ- ences in polymorphism frequency that can be seen amongst closely related genes. Further, the fact that so many novel SNPs were identified through our sequencing effort, even common SNPs with MAF>5%, illustrates the huge amount of genetic diversity that has yet to be discov- ered. Finally, the strengthening of the association between the SRC-3 Q586H SNP and decreased breast cancer risk, and the identification of a rare haplotype within SRC-3 associated with decreased risk, suggest that this informa- tion could be used to help identify a subgroup of high-risk women at a more modest risk. However, this remains to be verified prospectively. Competing interests The authors declare that they have no competing interests. Authors' contributions RJH helped to draft the manuscript, analyzed the re- sequencing data, and participated in the study design and coordination. ST performed genotyping assays and was involved in the statistical analysis and manuscript revi- sions. ASR, JW, SEM, TCS, JMR, SO were involved in the acquisition of the Coriell samples and their sequencing. KH, CS, ND, PB, BHFW, DN, NA, RVM, BW, RKS, AM, CRB, BB were involved in the generation and analysis of the breast cancer case-control study. BB and SO contrib- uted equally to the study by conceiving it, participating in its design, and helping to draft the manuscript. All authors read and approved the manuscript. Additional material Additional file 1 SNP Discovery Table. All variants in SMRT, NCoR, SRC-1, and SRC-3 identified from the sequencing effort are presented in this additional excel file. Variant information includes: genomic position, coding domain posi- tion, rs# (if applicable), nucleotide exchange, amino acid position and exchange (if applicable), and frequency in each of the populations. Click here for file [http://www.biomedcentral.com/content/supplementary/1471- 2407-9-438-S1.XLSX] Acknowledgements This work was supported in part by a DoD Predoctoral fellowship W81XWH-07-BCRP-PREDOC (RJH) and by the Howard Hughes Medical Institute Med into Grad Initiative for the Translational Biology and Molec- ular Medicine Graduate Program (RJH, SO), by the Pharmacogenetics Research Network Grant # U-01 GM61373 which supports the Consor- tium on Breast Cancer Pharmacogenomics (COBRA) (SO, TCS, JMR), a SPORE Pilot Project (SO) from SPORE (CA58183), and the Fetzer Family Memorial Fund. We would like to thank all participants who joined this study. The German breast cancer samples were collected within a project funded by the Deutsche Krebshilfe (Grant number: 107054). This study was supported by the Helmholtz society, the German Cancer Research Center (DKFZ) and the Dietmar Hopp Foundation. Page 8 of 9 (page number not for citation purposes)