Fine-mapping CASP8 risk variants in breast cancer.
Fine-mapping CASP8 risk variants in breast cancer.
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DOI：
10.1158/1055-9965.epi-11-0845
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发表时间：
2012-01
期刊：
影响因子：
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通讯作者：
Cox A
中科院分区：
文献类型：
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作者：
Camp NJ;Parry M;Knight S;Abo R;Elliott G;Rigas SH;Balasubramanian SP;Reed MW;McBurney H;Latif A;Newman WG;Cannon-Albright LA;Evans DG;Cox A
为了寻找乳腺癌的常见风险变异，已经进行了多个全基因组和候选基因关联研究。最近的大型荟萃分析巩固了这些研究的证据，一致强调了caspase-8(CASP8)基因在这方面的重要性。为了确定一个风险单倍型并定位CASP8基因区域与潜在的易感变异/S，我们在2q33-q34的CASP8区域筛查了四个乳腺癌风险基因。来自英国和美国的两个独立的数据集，包括3888例乳腺癌病例和对照，对扩展的CASP8区域的45个标签单核苷酸多态(TSNP)进行了基因分型。使用基于蒙特卡罗的方法进行SNP和单倍型关联检验。我们在rs3834129、rs6723097和rs3817578上发现了一个与乳腺癌显著相关的三个SNP单倍型(p<；5×10−6)，其显性风险比和95%可信区间为1.28(1.21-1.35)，频率为0.29。在两个研究地点，这种风险单倍型的证据非常一致，也与之前的数据一致。这三个SNP风险单倍型代表了迄今为止易感变异所在的染色体的最佳特征。风险单倍型的特征为重新测序以识别潜在的风险变量提供了坚实的基础，这可能被证明对个体水平的风险预测有用，并为乳腺癌的发生提供了新的见解。
Multiple genome-wide and candidate gene association studies have been performed in search of common risk variants for breast cancer. Recent large meta analyses, consolidating evidence from these studies, have been consistent in highlighting the caspase-8 (CASP8) gene as important in this regard. In order to define a risk haplotype and map the CASP8 gene region with respect to underlying susceptibility variant/s, we screened four genes in the CASP8 region on 2q33-q34 for breast cancer risk. Two independent data sets from the United Kingdom and the United States, including 3,888 breast cancer cases and controls, were genotyped for 45 tagging single nucleotide polymorphisms (tSNP) in the expanded CASP8 region. SNP and haplotype association tests were carried out using Monte Carlo based methods. We identified a three-SNP haplotype across rs3834129, rs6723097 and rs3817578 that was significantly associated with breast cancer (p<5×10−6), with a dominant risk ratio and 95% confidence interval of 1.28 (1.21–1.35) and frequency of 0.29 in controls. Evidence for this risk haplotype was extremely consistent across the two study sites and also consistent with previous data. This three-SNP risk haplotype represents the best characterization so far of the chromosome upon which the susceptibility variant resides. Characterization of the risk haplotype provides a strong foundation for re-sequencing efforts to identify the underlying risk variant, which may prove useful for individual-level risk prediction, and provide novel insights into breast carcinogenesis.