Department of Medicine, Division of General Internal Medicine, Institute for Human Genetics and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
Hum Mol Genet. 2012 Apr 15;21(8):1907-17. doi: 10.1093/hmg/ddr617. Epub 2012 Jan 6.
Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (P(corrected)). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65-0.85, P= 1.1 × 10(-5), P(corrected)= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68-0.87, P= 4.3 × 10(-5), P(corrected)= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5' region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association.
在美国拉丁裔和墨西哥裔女性中，具有较高欧洲血统的人患乳腺癌的风险增加。我们结合混合映射和全基因组关联映射方法，寻找可能解释这一观察结果的基因组区域。使用 Affymetrix 和 Illumina 阵列对患有乳腺癌的拉丁裔女性（n=1497）和拉丁裔对照（n=1272）进行基因分型。我们推断了每个基因座的遗传祖先，并比较了病例和对照之间的祖先。我们还在感兴趣的区域进行了单核苷酸多态性（SNP）关联分析。使用置换（P(corrected)）对多假设检验进行了校正。我们确定了一个区域，其中遗传祖先是与乳腺癌风险显著相关的：6q25 [每个美洲原住民染色体的优势比（OR）为 0.75，95%置信区间（CI）为 0.65-0.85，P=1.1×10(-5)，P(corrected)=0.02]。11p15 上的第二个区域显示出与关联的趋势（每个美洲原住民染色体的 OR 为 0.77，95% CI：0.68-0.87，P=4.3×10(-5)，P(corrected)=0.08）。在这两个区域中，乳腺癌风险随着美洲原住民遗传祖先的增加而降低，与全球祖先观察结果一致。6q25 信号的峰值包括雌激素受体 1（ESR1）基因和 5'区域，该区域先前与乳腺癌有关。全基因组关联分析发现，多 SNP 模型解释了两个区域的混合信号。我们的结果证实，美国拉丁裔人群中遗传祖先是与乳腺癌风险相关的部分原因是欧洲和美洲原住民人群之间的遗传差异。在 6q25 和可能的 11p15 基因座内进行精细映射将导致发现该关联背后的生物学功能变体。
