Fine-mapping of the 6q25 locus identifies a novel SNP associated with breast cancer risk in African-American women

Slone Epidemiology Center at Boston University, Boston, MA.
Carcinogenesis (Impact Factor: 5.33). 10/2012; 34(2). DOI: 10.1093/carcin/bgs334
Source: PubMed


The rs2046210 single nucleotide polymorphism (SNP) in the 6q25.1 region was identified in a breast cancer genome-wide association study of Chinese women. The SNP has been replicated in European ancestry populations but replication efforts have failed in African ancestry populations. We evaluated a total of 13 tagging SNPs in the linkage disequilibrium block around rs2046210 in a case-control study of breast cancer nested within the Black Women's Health Study (BWHS), which included 1,191 cases and 1,941 controls. Replication of initial significant findings was carried out in 665 cases and 821 controls of African ancestry from the Women's Circle of Health Study (WCHS). No significant association was found for rs2046210 in univariate analysis. A new SNP, rs2046211, was significantly associated with reduced risk of breast cancer and was replicated in data from WCHS. In joint analyses that included both SNPs, the rs2046210-A allele was associated with increased risk of breast cancer (odds ratio = 1.14; 95% confidence interval = 1.02-1.28), and the rs2046211-G allele was associated with reduced risk (odds ratio = 0.80; 95% confidence interval = 0.67-0.95). Haplotype analysis confirmed these results and showed that the rs2046210-A allele is present in high-risk (rs2046211-C/rs2046210-A) and low-risk (rs2046211-G/rs2046210-A) haplotypes. Our results confirm the importance of 6q25.1 as a breast cancer susceptibility region. We replicated the rs2046210 association, after accounting for the haplotype background that included rs2046211 in African American women, and we report the presence of a novel signal that is tagged by rs2046211.

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    ABSTRACT: Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium (LD) is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI]: 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI: 1.09-1.36; P = 0.00053), and 10p15.1 (OR = 1.22, 95% CI: 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13, and 16q12.1-q12.2) previously confirmed by fine-mapping in women of African ancestry. In addition, polygenic model indicated that 8 best markers in this study, compared to 22 GWAS-identified SNPs, could better predict breast cancer risk in Black women (per allele OR = 1.21, 95% CI: 1.16-1.27; P = 9.7×10-16). Our results demonstrate that fine-mapping is a powerful approach to better characterizing breast cancer risk alleles in diverse populations. Future studies in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African Diaspora.
    Preview · Article · Mar 2013 · Carcinogenesis
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    ABSTRACT: The novel single nucleotide polymorphism (SNP), rs2046210, was identified in a breast cancer genome-wide association study of Chinese women. The SNP is located on 6q25.1 in proximity to the C6orf97 and estrogen receptor 1 (ESR1) genes. To replicate this susceptibility, a number of case–control studies have been conducted in various populations. However, some results were inconclusive due to the restriction of sample size or ethnic diversity. To derive a more precise estimation of the relationship between rs2046210 and genetic risk of breast cancer, we performed the first comprehensive meta-analysis which included 121,494 cases and 119,295 controls from 14 published studies. Overall, significant increased risk between the A allele of rs2046210 and breast cancer was found in the total population (allelic model: OR = 1.16, 95 %CI = 1.11–1.21, P heterogeneity < 0.0001; dominant model: OR = 1.22, 95 %CI = 1.14–1.29, P heterogeneity < 0.0001; recessive model: OR = 1.21, 95 %CI = 1.13–1.29, P heterogeneity < 0.0001). When stratified by ethnicity, significant elevated risk was found among Europeans and Asians. However, no significant association was detected in African descent population. In the subgroup analyses according to estrogen receptor (ER) positive/negative status, our results suggested that this polymorphism tended to increase breast cancer risk in ER negative tumors by a greater magnitude compared to ER positive tumors. In addition, our subgroup analysis also indicated that this SNP was significantly associated with the risk of breast cancer for BRCA1 mutation carriers and exhibited weaker association with the risk for BRCA2 mutation carriers. Substantial heterogeneity was present in the overall analysis, but largely disappeared after stratification by ethnicity. Despite some limitations, this meta-analysis demonstrates that the rs2046210 polymorphism may be a risk factor associated with increased breast cancer risk. However, the association varies in different ethnicities.
    No preview · Article · Apr 2013 · Breast Cancer Research and Treatment
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    ABSTRACT: Genome-wide association studies (GWAS) have identified several genetic susceptibility loci for breast cancer (BC). One of them, conducted among Chinese women, found an association of rs2046210 at 6q25.1 with the risk of BC recently. Since then, numerous association studies have been carried out to investigate the relationship between this polymorphism and BC risk in various populations. However, these have yielded contradictory results. We therefore performed a meta-analysis to clarify this inconsistency. Overall, a total of 235003 subjects based on 13 studies were included in our study. Significantly increased BC risk was detected in the pooled analysis [allele contrast: OR = 1.13, 95%CI = 1.10-1.17, P(Z) <10(-5), P(Q) <10(-4); dominant model: OR = 1.21, 95%CI = 1.14-1.27, P(Z) <10(-5), P(Q) <10(-4); recessive model: OR = 1.18, 95%CI = 1.12-1.24, P(Z) <10(-5), P(Q) = 0.04]. In addition, our data revealed that rs2046210 conferred greater risk in estrogen receptor (ER)-negative tumors [OR = 1.27, 95%CI = 1.15-1.40, P(Z) <10(-5), P(Q) <10(-4)] than in ER-positive ones [OR = 1.18, 95%CI = 1.09-1.28, P(Z) <10(-4), P(Q) = 0.0003]. When stratified by ethnicity, significant associations were found in Caucasian and Asian populations, but not detected among Africans. There was evidence of heterogeneity (P<0.05), however, the heterogeneity largely disappeared after stratification by ethnicity. The present meta-analysis demonstrated that the rs2046210 polymorphism may be associated with increased BC susceptibility, but this association varies in different ethnicities.
    Full-text · Article · Jun 2013 · PLoS ONE
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