In the present study, of the 14 independent variants identified in GWAS conducted among women of European ancestry (excluding rs2981582 in 10q26.13/FGFR2 and rs2046210 (6q25.1/unknown), which were initially identified in a Chinese population), 8 SNPs showed an association consistent with that observed in women of European ancestry, and the per allele ORs were either statistically significant [rs4973768 (3p24/SLC4A7), rs889312 (5q11.2/MAP3K1), rs1219648 (10q26.13/FGFR2), rs3817198 (11p15.5/LSP1), rs8051542 (16q12.1/TOX3), rs3803662 (16q12.1/ TOX3)], or marginally significant [rs10941679 (5p12/MRPS30), and rs13281615(8q24.21)]. Analyses by ER status showed that the association of breast cancer for some SNPs may differ by ER status. Our fine-mapping analyses revealed several promising candidates that could be further evaluated. Overall, the results from this study provide further evidence for the association of GWAS identified SNPs in relation to breast cancer risk in non-European populations.
SNPs rs11249433 (1p11.2/NOTCH2) and rs999737 (14q24.1/RAD51L1) have a very low MAF in Chinese (3.0% and 0.2%, respectively). Intriguingly, the MAFs for these SNPs are quite high in European populations, 42.5% for rs11249433 (1p11.2/NOTCH2) and 26.1% for rs999737 (14q24.1/RAD51L1). Therefore, the genetic architectures in these two loci between Chinese and Europeans are quite different. For the other 4 SNPs, we found either a null or very weak association, rs13387042 (2q35/unknown), rs12443621 (16q12.1/TOX3), rs6504950 (17q23.2/COX11) or an association that was the opposite of that observed previously [rs2180341 (6q22.33/ECHDC1)]. With the sample size of the current study we have 80% of statistical power to detect an OR as small as 1.13, 1.08, 1.14, and 1.09 for SNPs rs13387042 (2q35/unknown), rs12443621 (16q12.1/TOX9), rs6504950 (17q23.2/COX11), and rs2180341 (6q22.33/ECHDC1). Therefore, we could reasonably conclude that these 4 SNPs are not strongly associated with breast cancer risk in Chinese. Stratification analyses by ER status for these 4 SNPs did not show any association consistent with that observed in women of European ancestry.
Previous studies among women of European origins showed that the association of breast cancer with rs1219648 (10q26.13/FGFR2
), rs10941679 (5p12/MRPS30
), and rs889312 (5q11.2/MAP3K1
) was stronger in ER-positive than ER-negative tumor (8
). Results from this study were in general consistent with previous findings for these SNPs, although the test for heterogeneity was statistically significant for rs1219648 (10q26.13/FGFR2
) with P=0.001. We found that rs13281615 (8q24.21/unknown) was more related to ER-negative than ER positive cancer, a finding that was inconsistent with that from a previous study among women of European ancestry (14
). The reason for this inconsistency is unknown. As reported previously (5
), rs2046210 (6q25.1/unknown) was found to be more closely related to ER-negative than ER-positive breast cancer. This association in non-Chinese women remains to be evaluated.
SNP rs13387042 at 2q35 was originally associated with breast cancer, especially estrogen-receptor-positive cancer, in a study conducted among Europeans (3
). This SNP lies in a 90-kb high LD region that contains neither known genes nor non-coding RNAs (3
). Recently, this SNP was investigated in approximately 30,000 cases and 30,000 controls from 25 studies in the Breast Cancer Association Consortium (BCAC) (16
). A significant association was observed in Europeans with an OR (95% CI) of 1.12 (1.09 - 1.15), which is much smaller than that originally observed of 1.20 (1.14 - 1.26). A significant association with this SNP was also observed in our previous study of African-American women, which included 810 cases and 1,784 controls (17
). However, no significant association has been observed in Asian populations (3
SNP rs12443621 is located in 16q12.1, a region where two additional genetic risk variants for breast cancer (rs8051542 and rs3803662) were reported previously in a study conducted among women of European ancestry (1
). Recently, we identified a functional genetic variant (rs4784227) at this chromosome region for breast cancer risk (18
). In the present study, the other two reported SNPs, rs3803662 and rs8051542, showed significant associations consistent with that observed in women of European ancestry. The LD pattern of this region in Asians is very different from the pattern found in European descendents. For example, there is no LD between rs12443621 and rs3803662 (r2
=0.04) in Chinese, but there is moderate LD (r2
=0.3) in Europeans.
SNP rs6504950 at 17q23.2 did not show a significant association in the present study; this finding was consistent with the results in Asians in the original GWAS (7
) that discovered this SNP. No statistically significant association was observed in Asian women, although the per-allele OR was very similar: 0.96 (0.82–1.12) for Asians and 0.95 (0.93–0.98) for Europeans(7
). The genetic architecture in this locus differs considerably across populations, for example, the MAF is 8% in Chinese and 30% in Europeans.
SNP rs2180341 was originally discovered in the Ashkenazi Jewish population (19
). Later, it was replicated in an additional 487 Ashkenazi Jewish breast cancer cases and in a European American population of 1,466 breast cancer cases and 1,467 controls (20
). There was no data available for Asians. In the present study, we observed a borderline significant association with ER positive tumors; however, the association was opposite to the original finding in the Ashkenazi Jewish population.
There are some potential explanations for the failure of direct replication of the loci identified in Europeans or European Americans. One possibility is that, in the Chinese populations, no common SNPs exist in the regions that are associated with breast cancer. It is possible that other common SNPs in these regions have not been reported and thus were not included in the current study. It is also possible that some other types of variants located in these regions, such as copy number variation (CNV), small insertion-deletion (indel) polymorphisms, or rare variants, are associated with breast cancer. Additionally, Asian women might have different lifestyles or environmental exposures that may mask the effect of these SNPs in breast cancer risk. Genetic interactions with other SNPs that differ in frequency between populations could also manifest as effect heterogeneity.
In an attempt to identify risk variants for breast cancer in regions where the original GWAS-identified SNP showed no apparent association with breast cancer risk, we performed fine-mapping for 4 breast cancer susceptibility loci, 2q35, 5p12, 8q24.21, and 17q23.2. We investigated the associations for all 868 SNPs on HapMap, covering at least a 200 kb region for each locus in a total sample size of over 10,000 subjects. All SNPs were either imputed with high quality or directly genotyped. A total of 5 SNPs, including rs10169372 (2q35/unknown), rs283720 (8q24.21/unknown), rs10515083 (17q23.2/COX11), rs16955329 (17q23.2/COX11), and rs2787487 (17q23.2/COX11), showed a consistent association with breast cancer risk in both stages. Although the associations with these SNPs in the combined analyses all reach a nominal significance level, they were not significant after adjusting for multiple comparisons. Nevertheless, these SNPs are good candidates for future studies. One limitation for this finemapping work is that SNPs not included in HapMap were not investigated. It would be helpful to sequence the targeted region for future studies to discover variants not included in the HapMap database.
In summary, we have now evaluated 14 independent SNPs that were initially reported in Europeans or European Americans. Eight of these SNPs showed strong evidence of association with breast cancer risk (statistically significant or marginally significant with an association consistent with those seen in previous GWAS), which brings the total number of GWAS-identified SNPs in Chinese populations to nine. We searched for additional independent genetic risk variants in four GWAS-mapped loci, in which the reported SNPs showed no apparent associations in Chinese. Several SNPs in these regions showed a statistically significant association with breast cancer risk. Although these associations were not statistically significant after adjusting for multiple comparisons, they may be good candidates for future studies. Additional in-depth, fine-mapping studies with large sample sizes may be needed to fully evaluate these regions and to identify potential risk variants for breast cancer in Asian women.