Interaction of Vitamin D & Vitamin A with Lung Cancer Risk in Non-Smoking Females

描述(申请人提供)：项目概述维生素D是一种很有前途的营养性癌症预防药物，但大多数相关研究都是针对乳腺癌、结直肠癌和前列腺癌进行的。人们对维生素D与肺癌风险之间的联系知之甚少。肺癌预防研究的一个主要挑战是，吸烟仍然是最强的风险因素，并有可能在检查饮食和其他暴露的分析中残留混淆。妇女健康倡议(WHI)提供了一个很好的环境，可以在其中检查吸烟以外的肺癌风险因素，因为吸烟率很低，而且大量肺癌病例属于从不吸烟的人。因此，我们的主要目标是确定WHI中从不吸烟的绝经后妇女中维生素D状态与肺癌风险的关系。在一项针对300例肺癌病例和300名对照的嵌套病例对照研究中，我们将测试血清中高和低浓度的25-羟基维生素D[25(OH)D]，这是维生素D状态的生物标志物，是否与从不吸烟的女性中肺癌风险的降低有关。此外，我们假设维生素A可能会改变血清25(OH)D与肺癌风险的关系。在细胞核中，高浓度的9-顺式维甲酸阻碍了维生素D受体的正常功能。9-顺式维甲酸是维生素A的活性代谢物，也是维甲酸X受体的配体。因此，维生素A的高摄入量，如补充维生素A的使用，可能会导致循环和细胞中的9-顺式维甲酸浓度过高。以前的文献没有考虑到这种潜在的重要的营养-营养相互作用。根据我们的初步数据，在既往吸烟者和从不吸烟者中，血清25(OH)D浓度与肺癌死亡率呈负相关；这种关联可能会被过量循环中的维生素A或维生素A补充剂使用而减弱。因此，在第二个目标中，我们将测试在没有过量循环维生素A的女性中，与循环维生素A过剩的女性相比，与高血清25(OH)D浓度相关的肺癌风险的降低是否更强。循环中过量的维生素A被定义为血清视黄酸酯E7？g/mL和视黄酯与视黄醇的比率e0.08。我们将使用化学发光免疫分析法检测25(OH)D，并使用带有紫外检测器的高效液相色谱检测诊断前血清中的视黄酸酯和视黄醇。血清25(OH)D浓度将通过使用季节特定的四分位数、季节标准化的四分位数和临床相关的浓度来分类。物流 回归将被用来估计多变量调整的优势比和血清25(OH)与肺癌风险之间的95%可信区间。血清25(OH)D和过量维生素A对肺癌风险的交互作用也将在回归模型中进行评估。

DESCRIPTION (provided by applicant): Project Summary Vitamin D is a promising nutritional cancer prevention agent, but most of the relevant research has been conducted on breast, colorectal and prostate cancer. Less is known about the association of vitamin D with lung cancer risk. A major challenge of lung cancer prevention research is that smoking remains the strongest risk factor and has the potential for residual confounding in analyses that examine diet and other exposures. The Women's Health Initiative (WHI) provides an excellent environment in which to examine lung cancer risk factors other than smoking since smoking prevalence was low and a large number of the lung cancer cases are among never smokers. Therefore, our primary objective is to determine the association of vitamin D status with lung cancer risk in never-smoking, postmenopausal women in the WHI. In a nested case-control study of 300 incident lung cancer cases and 300 controls, we will test whether high vs. low serum concentrations of 25- hydroxyvitamin D [25(OH)D], a biomarker of vitamin D status, are associated with reduced lung cancer risk among never-smoking women. In addition, we hypothesize that vitamin A may modify the association of serum 25(OH)D with lung cancer risk. In nuclei, high concentrations of 9-cis-retinoic acid, an active metabolite of vitamin A and the ligand of retinoid X receptor, impedes the proper function of the vitamin D receptor. Thus, high intake of vitamin A, such as supplemental vitamin A use, likely leads to excessively high 9-cis-retinoic acid concentrations both in the circulation and in cells. Previous literature has not considered this potentially important nutrient-nutrient interaction. From our preliminary data, serum concentrations of 25(OH)D are inversely associated with lung cancer mortality among former and never smokers; the association may be attenuated by excess circulating vitamin A or vitamin A supplement use. Thus, in the secondary aim, we will test whether the reduced lung cancer risks associated with high serum concentrations of 25(OH)D are stronger among women without excess circulating vitamin A compared to those with excess circulating vitamin A. The excess circulating vitamin A is defined as serum retinyl esters e7 ¿g/mL and the ratio of retinyl esters to retinol e0.08. We will use a chemiluminescent immunoassay to measure 25(OH)D and high-performance liquid chromatography with UV detector to measure retinyl esters and retinol in pre-diagnostic sera. Serum 25(OH)D concentrations will be classified by using season-specific quartiles, season-standardized quartiles, and clinically relevant concentrations. Logistic regression will be used to estimate multivariate-adjusted odds ratios and 95% confidence intervals for the associations of serum 25(OH) and lung cancer risk. The interaction of serum 25(OH)D and excess vitamin A on lung cancer risk will also be evaluated in regression models.