Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium.
Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium.
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DOI：
10.1371/journal.pgen.1001002
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发表时间：
2010-06-24
期刊：
影响因子：
4.5
通讯作者：
Zheng W
中科院分区：
文献类型：
--
作者：
Long J;Cai Q;Shu XO;Qu S;Li C;Zheng Y;Gu K;Wang W;Xiang YB;Cheng J;Chen K;Zhang L;Zheng H;Shen CY;Huang CS;Hou MF;Shen H;Hu Z;Wang F;Deming SL;Kelley MC;Shrubsole MJ;Khoo US;Chan KY;Chan SY;Haiman CA;Henderson BE;Le Marchand L;Iwasaki M;Kasuga Y;Tsugane S;Matsuo K;Tajima K;Iwata H;Huang B;Shi J;Li G;Wen W;Gao YT;Lu W;Zheng W
遗传因素在乳腺癌的病因中起着重要作用。我们在28,000多个病例和对照中进行了一项多阶段全基因组关联(GWA)研究，这些病例和对照来自12个在亚洲和欧洲美国女性中进行的研究，以确定乳腺癌的遗传易感基因。在分析了2,073例中国女性和2,084名对照中的684,457个SNPs后，我们在一组独立的4,425例病例和1,915名中国对照中评估了53个SNPs的快速复制。在一组独立的6,173例病例和6,340名对照中，对4个重复的SNPs进行了进一步研究，这些病例和对照来自于在亚洲女性中进行的其他7项研究。在所有研究中，SNP rs4784227与乳腺癌风险一致，在所有亚洲样本的合并分析中，调整后的优势比(95%可信区间)为每等位基因1.25(1.20−1.31)(P = 3.2x10−25)。该单核苷酸多态与欧洲裔美国人患乳腺癌的风险相关(每等位基因OR = 1.19，95%CI = 1.09−1.31，P = 1.3×10−4，2,797例和2,662例对照)。SNP rs4784227位于16q12.1，这是以前在欧洲人中发现的乳腺癌风险区域。在亚洲人中，这种SNP与乳腺癌风险的相关性在调整了该地区以前报告的SNP后，在统计学上仍然具有高度统计学意义。在体外实验中，使用荧光素酶报告和电泳迁移率改变分析证明了该SNP的功能意义。这些结果提供了强有力的证据，暗示rs4784227是16q12.1基因座乳腺癌的功能性原因变异，并证明了在具有不同遗传结构的人群中进行遗传关联研究的有效性。乳腺癌是全世界女性中最常见的恶性肿瘤之一。遗传因素在乳腺癌的病因中起着重要作用。为了确定乳腺癌的遗传易感基因，我们对15,468例乳腺癌患者和13,001名对照进行了全基因组关联研究。位于染色体16q12.1上的单核苷酸多态(SNP)rs4784227被发现与乳腺癌风险相关。在调整了该地区以前报道的所有SNP后，这种SNP与乳腺癌风险的关联在亚洲人中仍然非常显著。使用荧光素酶报告和凝胶迁移率改变分析的体外生化实验证实了该SNP的功能重要性。我们的结果证明了在具有不同遗传背景的人群中进行遗传关联研究以识别功能变异的重要性。
Genetic factors play an important role in the etiology of breast cancer. We carried out a multi-stage genome-wide association (GWA) study in over 28,000 cases and controls recruited from 12 studies conducted in Asian and European American women to identify genetic susceptibility loci for breast cancer. After analyzing 684,457 SNPs in 2,073 cases and 2,084 controls in Chinese women, we evaluated 53 SNPs for fast-track replication in an independent set of 4,425 cases and 1,915 controls of Chinese origin. Four replicated SNPs were further investigated in an independent set of 6,173 cases and 6,340 controls from seven other studies conducted in Asian women. SNP rs4784227 was consistently associated with breast cancer risk across all studies with adjusted odds ratios (95% confidence intervals) of 1.25 (1.20−1.31) per allele (P = 3.2×10−25) in the pooled analysis of samples from all Asian samples. This SNP was also associated with breast cancer risk among European Americans (per allele OR = 1.19, 95% CI = 1.09−1.31, P = 1.3×10−4, 2,797 cases and 2,662 controls). SNP rs4784227 is located at 16q12.1, a region identified previously for breast cancer risk among Europeans. The association of this SNP with breast cancer risk remained highly statistically significant in Asians after adjusting for previously-reported SNPs in this region. In vitro experiments using both luciferase reporter and electrophoretic mobility shift assays demonstrated functional significance of this SNP. These results provide strong evidence implicating rs4784227 as a functional causal variant for breast cancer in the locus 16q12.1 and demonstrate the utility of conducting genetic association studies in populations with different genetic architectures. Breast cancer is one of the most common malignancies among women worldwide. Genetic factors play an important role in the etiology of breast cancer. To identify genetic susceptibility loci for breast cancer, we performed a genome-wide association study in 15,468 breast cancer cases and 13,001 controls. A single nucleotide polymorphism (SNP) rs4784227 located on chromosome 16q12.1, a previously-reported region for breast cancer risk, was found to be associated with breast cancer risk. The association of this SNP with breast cancer risk remained highly significant in Asians after adjusting all previously-reported SNPs in this region. In vitro biochemical experiments using both luciferase reporter and electrophoretic mobility shift assays confirmed the functional importance of this SNP. Our results demonstrate the importance of conducting genetic association studies in populations with different genetic backgrounds to identify functional variants.
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影响因子：
30.8
作者：
Zheng, Wei;Long, Jirong;Gao, Yu-Tang;Li, Chun;Zheng, Ying;Xiang, Yong-Bin;Wen, Wanqing;Levy, Shawn;Deming, Sandra L.;Haines, Jonathan L.;Gu, Kai;Fair, Alecia Malin;Cai, Qiuyin;Lu, Wei;Shu, Xiao-Ou
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Shu, Xiao-Ou
影响因子：
30.8
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通讯作者：
Stefansson, Kari
影响因子：
4.7
作者：
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通讯作者：
Shen, Hongbing
影响因子：
30.8
作者：
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通讯作者：
Hunter, David J.
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4.7
作者：
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通讯作者：
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