Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
PLoS Genet. 2012;8(2):e1002532. doi: 10.1371/journal.pgen.1002532. Epub 2012 Feb 23.
Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively.
遗传因素在散发型和家族性乳腺癌的病因学中都起着重要作用。我们旨在发现乳腺癌的新的遗传易感性位点。我们对东亚裔的 19091 例病例和 20606 例对照（包括中国、韩国和日本女性）进行了四阶段全基因组关联研究（GWAS）。在对 2918 例病例和 2324 例对照中的 690947 个 SNP 进行分析后，我们评估了 5365 个 SNP 在 3972 例病例和 3852 例对照中的复制情况。有 94 个 SNP 在 5203 例病例和 5138 例对照中进一步进行了评估，最后在多达 17423 例额外的受试者（7489 例病例和 9934 例对照）中对前 22 个 SNP 进行了调查。位于染色体 6q25.1 附近的 TGF-β激活激酶（TAB2）基因附近的 SNP rs9485372 在所有四个阶段都与乳腺癌风险一致相关，在所有样本的合并分析中 P 值为 3.8×10(-12)。调整后的比值比（95%置信区间）分别为 A/G 和 A/A 基因型与 G/G 基因型相比为 0.89（0.85-0.94）和 0.80（0.75-0.86）。位于 ESR1 基因内含子 5 中的 SNP rs9383951（来自所有样本的合并分析的 P 值为 1.9×10(-6)）和位于 11q24.3 的 SNP rs7107217（P 值为 4.6×10(-7)）在四个阶段中的每一个阶段也都显示出一致的相关性。这项研究为代表 TAB2 基因（6q25.1）附近的 rs9485372 的新乳腺癌易感性位点提供了强有力的证据，并分别确定了位于 ESR1 基因和 11q24.3 的两个可能的易感性位点。
