Vitamin D and Mammographic Density

描述（由申请人提供）：乳房x线摄影密度一直被证明是乳腺癌的最强危险因素之一。乳房密度在75%或以上的女性患乳腺癌的风险是无密度女性的4到6倍。尽管没有直接的数据支持这一假设，但乳房x线摄影密度是雌激素暴露累积的反映。我们的初步数据和积累的证据表明，乳房x线摄影密度影响乳腺癌的机制与循环雌激素水平无关。越来越多的生态学、流行病学和生物学数据表明，维生素D途径与乳腺癌的发生有关，这使其成为乳房x线摄影密度与乳腺癌关系的一个令人信服的潜在中介。在护士健康研究队列中，我们发现血浆中维生素D代谢物、25-羟基维生素D和1,25-二羟基维生素D水平与乳腺癌之间存在不显著的负相关，该研究有701例病例和724例对照。在同一组女性中，我们还发现维生素D受体中的Fokl多态性与乳腺癌之间存在关联。我们建议进行横断面分析，以检查上述巢式病例对照研究中对照组之间维生素d乳房x线摄影密度的关系。所有实验室分析、基因分型和乳房x线摄影密度测量都已作为先前研究的一部分进行。这是一个有效的研究设计，以检查维生素D和乳房x线摄影密度在现有数据中的作用。我们特别假设：1.)血浆25-羟基维生素D和1,25-二羟基维生素D水平与乳房x线摄影密度百分比呈负相关；维生素D受体基因的多态性与乳房x线摄影密度有关。此外，我们将探讨维生素D乳房x线摄影密度的关系是否被维生素D受体的多态性所改变。鉴于维生素D水平很容易改变，乳房x线摄影密度是乳腺癌的非侵入性中间标记，这一建议对乳腺癌预防具有重要意义。

DESCRIPTION (provided by applicant): Mammographic density has consistently been shown to be one of the strongest risk factors for breast cancer. Women with 75% or more breast density are at a 4 to 6-fold greater risk of breast cancer than women with no density. It has been hypothesized that mammographic density is the reflection of cumulative estrogen exposure, despite the fact that there are no direct data supporting this. Our preliminary data, and accumulating evidence suggest that the mechanism by which mammographic density influences breast cancer is independent of circulating estrogen levels. There is increasing ecologic, epidemiologic and biologic data implicating the vitamin D pathway in breast carcinogenesis, making it a compelling potential mediator of the mammographic density-breast cancer relation. In the Nurses' Health Study cohort, we found a non-significant inverse association between plasma levels of vitamin D metabolites, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and breast cancer in a nested case-control study with 701 cases and 724 controls. In the same group of women, we also found an association between the Fokl polymorphism in the vitamin D receptor and breast cancer. We propose to conduct a cross-sectional analysis to examine the vitamin D-mammographic density relationship among controls in the nested case-control study described above. All laboratory assays, genotyping and measurements of mammographic density have already been conducted as part of prior studies. This is an efficient study design to examine the role of vitamin D and mammographic density in existing data. We specifically hypothesize that: 1.) Plasma levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are inversely associated with percent mammographic density, and 2.) Polymorphisms in the vitamin D receptor gene are associated with mammographic density. In addition, we will explore if the vitamin D-mammographic density relationship is modified by polymorphisms in the vitamin D receptor. Given that vitamin D levels are readily modifiable and that mammographic density is a noninvasive intermediate marker of breast cancer this proposal has important implications for breast cancer prevention.