Polycyclic Aromatic Hydrocarbons, Vitamin D and Breast Cancer

项目摘要 申请人。这个博士前奖学金（F31）应用程序旨在促进乔伊斯罗登的培训， 他是北卡罗来纳州大学流行病学系的博士预科生。她的目标是 成为一个独立的研究人员谁进行创新，转化健康研究。在F31 培训申请人将指导她的赞助商博士。玛丽Gammon和凯瑟琳Hoyo。 意义乳腺癌是美国女性中最常见的癌症。 多环芳烃（PAHs）是不完全燃烧的产物，普遍存在。许多但不是 总之，研究表明多环芳烃和乳腺癌风险之间存在正相关。维生素D能显著保护 抗乳腺上皮细胞的氧化应激，并与降低乳腺癌风险有关。维生素D 预防暴露于PAH致癌物后乳腺外植体中的癌前病变7，12- 二甲基苯并（a）-蒽（DMBA）。然而，还没有流行病学研究调查， 多环芳烃和乳腺癌的发病率与血浆维生素D或维生素D多态性有关。研究 一种假设是，与多环芳烃相关的乳腺癌发病率升高的风险仅在以下情况下明显： 维生素D水平低的女性，或可能降低维生素D水平的基因型。目标1.确定PAH是否 措施（PAH-DNA加合物和PAH来源（主动和被动吸烟，烧烤/烟熏食品，室内 壁炉使用、车辆交通））与血浆25-羟基维生素D（25-OHD）浓度相互作用， 乳腺癌风险。目标2.确定PAH指标是否与25种维生素D相关的遗传单基因相互作用， 核苷酸多态性（SNPs）影响乳腺癌发病率。目标3：确定是否遗传 预测的维生素D水平影响乳腺癌风险，并评估遗传预测的维生素D水平是否 水平改变PAH-乳腺癌的关联。Approach.本论文将利用现有的信息 来自1508名乳腺癌患者和1556名非乳腺癌患者。PAH和维生素D的测量 在诊断后不久进行了评估。对于目标1-3，将进行逻辑回归以估计比值 比率和95%置信区间，以检查乘法和加法量表上的相互作用。对于目标3， 调整后的两阶段最小二乘回归方法将用于估计加权遗传预测 分数，然后可以在逻辑模型中使用。创新本文的主要内容如下：（1）将是第一篇 流行病学研究，检查多环芳烃和维生素D之间的相互作用与乳腺癌风险; (2)包括多水平PAH和维生素D测量;（3）探索生物学上合理的SNP;（4）将估计 遗传预测的维生素D水平;和（5）使用充分表征的基于人群的样本。冲击 拟议的论文可以确定一个潜在的低成本降低乳腺癌风险的策略。

PROJECT SUMMARY Applicant. This pre-doctoral fellowship (F31) application is designed to promote the training of Joyce Rhoden, a pre-doctoral student in the Department of Epidemiology at the University of North Carolina. Her goal is to become an independent researcher who conducts innovative, translational health research. During the F31 training the applicant will be mentored by her sponsors Drs. Marilie Gammon and Cathrine Hoyo. Significance. Breast cancer is the most commonly diagnosed cancer among women in the United States. Polycyclic aromatic hydrocarbons (PAHs) result from incomplete combustion and are ubiquitous. Many, but not all, studies show positive associations between PAHs and breast cancer risk. Vitamin D significantly protects against oxidative stress in breast epithelial cells and is associated with lower breast cancer risk. Vitamin D prevents pre-neoplastic lesions in mammary gland explants after exposure to the PAH carcinogen 7,12- dimethylbenz(a)-anthracene (DMBA). However, no epidemiologic study has examined if associations between PAHs and breast cancer incidence vary with plasma vitamin D or vitamin D polymorphisms. The study hypothesis is that elevated risks for breast cancer incidence associated with PAHs will be evident only in women with low vitamin D levels, or with genotypes that may lower vitamin D levels. Aim 1. Determine if PAH measures (PAH-DNA adducts and PAH sources (active and passive smoking, grilled/smoked foods, indoor fireplace use, vehicular traffic)) interact with plasma 25-hydroxyvitaminD (25-OHD) concentrations to influence breast cancer risk. Aim 2. Determine if PAH measures interact with any of 25 vitamin D-related genetic single- nucleotide polymorphisms (SNPs) to influence breast cancer incidence. Aim 3. Determine if genetically predicted vitamin D levels influences breast cancer risk and assess whether the genetically predicted vitamin D levels modify the PAH-breast cancer associations. Approach. The dissertation will use existing information from 1508 women with breast cancer and 1556 women without breast cancer. Measures of PAH and vitamin D were assessed shortly after diagnosis. For Aims 1-3, logistic regression will be conducted to estimate odds ratios and 95% confidence intervals to examine interaction on the multiplicative and additive scales. For Aim 3, an adjusted two-stage least squares regression method will be used to estimate a weighted genetic predictive score, which can then be used in logistic models. Innovation. This dissertation: (1) will be the first epidemiologic study to examine interaction between PAHs and vitamin D in association with breast cancer risk; (2) includes multi-level PAH and vitamin D measures; (3) explores biologically plausible SNPs; (4) will estimate genetically predicted vitamin D levels; and (5) uses a well-characterized population-based sample. Impact. The proposed dissertation may identify a potential low-cost risk reduction strategy for breast cancer.