Mammographic breast density and breast cancer: evidence of a shared genetic basis.
Mammographic breast density and breast cancer: evidence of a shared genetic basis.
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DOI：
10.1158/0008-5472.can-11-3295
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发表时间：
2012-03-15
期刊：
影响因子：
11.2
通讯作者：
Easton DF
中科院分区：
文献类型：
--
作者：
Varghese JS;Thompson DJ;Michailidou K;Lindström S;Turnbull C;Brown J;Leyland J;Warren RM;Luben RN;Loos RJ;Wareham NJ;Rommens J;Paterson AD;Martin LJ;Vachon CM;Scott CG;Atkinson EJ;Couch FJ;Apicella C;Southey MC;Stone J;Li J;Eriksson L;Czene K;Boyd NF;Hall P;Hopper JL;Tamimi RM;MODE Consortium;Rahman N;Easton DF
乳房x光检查的乳腺密度百分比（PMD）是乳腺癌的一个很强的遗传风险因素。然而，这种风险介导的途径仍不清楚。为了探讨PMD和乳腺癌是否具有共同的遗传基础，我们在一项已发表的对五项全基因组关联研究（GWAS）的荟萃分析中发现了与PMD最密切相关的遗传变异，并利用这些变异构建了来自UK2乳腺癌GWAS的3628例乳腺癌病例和5190例对照的风险评分。snp的每等位基因效应估计与个体中相应的等位基因计数相乘，并对所有snp求和，得出个体的风险评分。这些分数被纳入以乳腺癌病例对照状态为结果的逻辑回归模型中作为暴露变量。使用10个不同的截断点重复该分析，以获得最显著的密度snp（1-10%代表5,222-50,899个snp）。还对所有10个截止点进行了排列分析。风险评分与乳腺癌之间的关联在最高密度snp的3-10%的所有截断点上都是显著的，在6%（双侧P=0.002）到10% （P=0.001）的截断点（总排列P=0.003）上最为显著。风险评分分布中前10%的女性患乳腺癌的风险比后10%的女性高31% [OR= 1.31 (95%CI 1.08-1.59)]。总之，我们的研究结果表明，PMD和乳腺癌具有共同的遗传基础，这是通过大量常见变异介导的。
Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3628 breast cancer cases and 5190 controls from the UK2 GWAS of breast cancer. The signed per-allele effect estimates of SNPs were multiplied with the respective allele counts in the individual and summed over all SNPs to derive the risk score for an individual. These scores were included as the exposure variable in a logistic regression model with breast cancer case-control status as the outcome. This analysis was repeated using ten different cut-offs for the most significant density SNPs (1-10% representing 5,222-50,899 SNPs). Permutation analysis was also performed across all 10 cut-offs. The association between risk score and breast cancer was significant for all cut-offs from 3-10% of top density SNPs, being most significant for the 6% (2-sided P=0.002) to 10% (P=0.001) cut-offs (overall permutation P=0.003). Women in the top 10% of the risk score distribution had a 31% increased risk of breast cancer [OR= 1.31 (95%CI 1.08-1.59)] compared to women in the bottom 10%. Together, our results demonstrate that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants.