Department of Pathology and Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Melbourne 3053, Australia.
Cancer Res. 2010 Feb 15;70(4):1449-58. doi: 10.1158/0008-5472.CAN-09-3495. Epub 2010 Feb 9.
Mammographic density for age and body mass index (BMI) is a heritable risk factor for breast cancer. We aimed to determine if recently identified common variants associated with small gradients in breast cancer risk are associated with mammographic density. We genotyped 497 monozygotic and 330 dizygotic twin pairs and 634 of their sisters from 903 families for 12 independent variants. Mammographic dense area, percent dense area, and nondense area were measured by three observers using a computer-thresholding technique. Associations with mammographic density measures adjusted for age, BMI, and other determinants were estimated (a) cross-sectionally using a multivariate normal model for pedigree analysis (P(x)), (b) between sibships, and (c) within sibships using orthogonal transformations of outcomes and exposures. A combined test of association (P(c)) was derived using the independent estimates from b and c. We tested if the distributions of P values across variants differed from the uniform distribution (P(u)). For dense area and percent dense area, the distributions of P(c) values were not uniform (both P(u) <0.007). Consistent with their breast cancer associations, rs3817198 (LSP1) and rs13281615 (8q) were associated with dense area and percent dense area (all P(x) and P(c) <0.05), and rs889312 (MAP3K1), rs2107425 (H19), and rs17468277 (CASP8) were marginally associated with dense area (some P(x) or P(c) <0.05). All associations were independent of menopausal status. At least two common breast cancer susceptibility variants are associated with mammographic density measures that predict breast cancer. These findings could help elucidate how those variants and mammographic density measures are associated with breast cancer susceptibility.
乳腺密度与年龄和体重指数（BMI）相关，是乳腺癌的一个可遗传风险因素。我们旨在确定与乳腺癌风险小梯度相关的最近鉴定的常见变体是否与乳腺密度相关。我们对 903 个家庭中的 497 对同卵双胞胎和 330 对异卵双胞胎及其 634 位姐妹进行了 12 个独立变体的基因分型。通过三位观察者使用计算机阈值技术测量乳腺密度的致密区域、致密区域百分比和非致密区域。使用多元正态模型进行系谱分析（P(x)）、在同胞之间以及在同胞内使用结果和暴露的正交变换（b 和 c）来估计与乳腺密度测量值相关的关联（a）。使用 b 和 c 的独立估计值推导出联合关联检验（P(c)）。我们测试了变体之间的 P 值分布是否与均匀分布（P(u)）不同。对于致密区域和致密区域百分比，P(c)值的分布不均匀（均 P(u) <0.007）。与乳腺癌关联一致，rs3817198（LSP1）和 rs13281615（8q）与致密区域和致密区域百分比相关（均 P(x)和 P(c) <0.05），rs889312（MAP3K1）、rs2107425（H19）和 rs17468277（CASP8）与致密区域呈边缘相关（某些 P(x)或 P(c) <0.05）。所有关联均独立于绝经状态。至少有两个常见的乳腺癌易感性变体与预测乳腺癌的乳腺密度测量值相关。这些发现可以帮助阐明这些变体和乳腺密度测量值如何与乳腺癌易感性相关。
