Early Life Exposures and Breast Density in Young Women

背景：青年肥胖与乳腺癌风险呈负相关，但潜在的 机制不被理解。乳腺密度是最强的乳腺癌危险因素之一。在我们正在进行的 研究表明，青年肥胖与成年乳腺密度呈显著负相关 这是因为体重较重的女孩乳房纤维腺体组织密度较低。我们也发现了青春 饱和脂肪的摄入量与成年人正相关，不饱和脂肪的摄入量与成年人负相关。 乳腺密度目的：本研究的目的是确定可能介导的生理机制， 青年肥胖症和膳食脂肪摄入与乳腺密度的关系，因此可以采取有针对性的干预措施， 开发具体目的：主要目的是1）确定青年血清中的代谢组学特征 与青年肥胖和青年乳腺密度相关; 2）确定血清中的代谢组学特征 在与青年脂肪亚型（饱和、多不饱和和单不饱和脂肪）相关的青年中收集 第二个目标将正式评估协会的中介作用 青年肥胖症和膳食脂肪摄入量与乳腺密度表型的关系， 目标1和目标2中确定的青年。研究设计：我们将使用先前在膳食中收集的资源， 儿童干预研究（DISC）和DISC 06随访研究。DISC评估了以下药物的安全性和有效性： 通过饮食干预降低儿童的低密度脂蛋白胆固醇。301名7-10岁健康女童参加DISC 并继续研究，直到他们平均17岁。每年测量人体测量值， 每半年进行一次召回和血液采集。DISC 06在参与者年龄为25-29岁时进行， 评估干预对乳腺癌相关生物标志物的长期影响，包括 血液采集和人体测量、饮食和乳房密度评估。约300名与会者将 纳入青年肥胖症和饮食与血清中代谢物的相关性分析， DISC中的年轻人，而182名参与者将被纳入与乳腺密度相关性的分析中 表型将在DISC青春期采集的储存血清中测量代谢组学特征。 混合效应线性回归将用于确定与青少年肥胖相关的单个代谢物 和膳食脂肪摄入量和成人乳房密度，而富集和途径分析将用于确定 相关代谢途径。重要性：我们处于独特的地位，能够解决一个重要而及时的问题。 这是一个极具创新性的问题。因为这是一个乳腺快速增生的时期， 青春期可能是与乳腺癌有关的接触的特别脆弱的时期。研究结果将 增加对决定乳房密度的青少年因素的了解，并确定生理机制 青少年肥胖和膳食脂肪摄入与成年乳腺密度之间的潜在联系， 乳腺癌风险。确定的代谢物可能作为新的预防策略的一部分。

Background: Adiposity in youth is inversely related to breast cancer risk throughout life, but the underlying mechanism is not understood. Breast density is one of the strongest breast cancer risk factors. In our ongoing research, adiposity in youth is strongly and significantly inversely associated with adult percent breast density as a consequence of heavier girls having less dense breast fibroglandular tissue. We also found youth saturated fat intake to be positively associated and unsaturated fat intake inversely associated with adult breast density. Objectives: The goal of this study is to identify physiological mechanisms that could mediate the associations of youth adiposity and dietary fat intake with breast density so targeted interventions can be developed. Specific Aims: Primary aims are to 1) identify metabolomic profiles in serum collected in youth associated with youth adiposity and young adult breast density; and 2) identify metabolomic profiles in serum collected in youth associated with youth fat subtype (saturated, polyunsaturated and monounsaturated fat) consumption and young adult breast density A secondary aim will formally evaluate mediation of associations of youth adiposity and dietary fat intake with breast density phenotypes by metabolites in serum collected in youth identified in aims 1 and 2. Study Design: We will use resources previously collected in the Dietary Intervention Study in Children (DISC) and DISC06 Follow-Up Study. DISC evaluated the safety and efficacy of a diet intervention to reduce LDL-cholesterol in children. 301 healthy girls 7-10 years old were enrolled in DISC and continued on study until they averaged 17 years old. Anthropometry was measured annually and dietary recalls and blood were collected biannually. DISC06 was conducted when participants were 25-29 years old to evaluate the longer-term effects of the intervention on biomarkers associated with breast cancer and included blood collection and assessment of anthropometry, diet and breast density. Approximately 300 participants will be included in analyses of associations of youth adiposity and diet with metabolites in serum collected during youth in DISC, while 182 participants will be included in analysis of associations with breast density phenotypes. Metabolomics profiles will be measured in stored serum collected during adolescence in DISC. Mixed effects linear regression will be used to identify individual metabolites associated with youth adiposity and dietary fat intake and adult breast density, while enrichment and pathway analysis will be used to identify relevant metabolic pathways. Significance: We are uniquely positioned to address an important and timely question that is highly innovative. Because it is a time of rapid proliferation of the mammary glands, adolescence may be a particularly vulnerable time for exposures related to breast cancer. Study results will increase understanding of adolescent determinants of breast density and identify physiological mechanisms underlying the association of adiposity and dietary fat intake in youth with adult breast density and possibly breast cancer risk. Metabolites identified could potentially be targeted as part of a novel preventive strategy.