Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans
Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans
复制标题
DOI：
10.1093/hmg/ddr367
复制
发表时间：
2011-11-15
影响因子：
3.5
通讯作者：
Haiman, Christopher A.
中科院分区：
文献类型：
--
作者：
Chen, Fang;Chen, Gary K.;Haiman, Christopher A.
全基因组关联研究（GWAS）揭示了19种与乳腺癌风险相关的常见遗传变异。对通过GWAS发现的指数信号进行测试，并对不同人群中的每个基因座进行精细绘图，对于描述这些风险区域在遗传易感性方面的作用是必要的。在这项针对非裔美国女性乳腺癌的大型研究中（3016例和2745例对照），我们测试了19种已知的由GWAS识别的风险变异，并复制了只有4种变异的相关性（P < 0.05）。通过精细定位，我们确定了四个区域的标记，这些标记可以更好地捕捉非裔美国人乳腺癌风险的关联，这些标记由指数信号（2q35、5q11、10q26和19p13）定义。我们还发现了与四个独立区域（8q24、10q22、11q13和16q12）标记的统计学显著关联，这些区域独立于指数信号，可能代表假定的新风险变异。总的来说，研究中发现的更多信息标记增强了这些危险区域与非裔美国人乳腺癌的关联[每等位基因优势比（OR） 1.18, P = 2.8 3 10(-24) vs OR =1.04, P = 6.1 x 10(-5)]。在对已知乳腺癌风险位点的详细分析中，我们验证并改进了风险标记，更好地表征了非洲血统女性乳腺癌的相关性。
Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and replicated associations (P < 0.05) with only 4 variants. Through fine-mapping, we identified markers in four regions that better capture the association with breast cancer risk in African Americans as defined by the index signal (2q35, 5q11, 10q26 and 19p13). We also identified statistically significant associations with markers in four separate regions (8q24, 10q22, 11q13 and 16q12) that are independent of the index signals and may represent putative novel risk variants. In aggregate, the more informative markers found in the study enhance the association of these risk regions with breast cancer in African Americans [per allele odds ratio (OR) 5 1.18, P = 2.8 3 10(-24) versus OR =1.04, P = 6.1 x 10(-5)]. In this detailed analysis of the known breast cancer risk loci, we have validated and improved upon markers of risk that better characterize their association with breast cancer in women of African ancestry.