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

维生素D是一种很有前途的营养性癌症预防剂，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。关于维生素D与肺癌风险之间的关系知之甚少。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，并且在检查饮食和其他暴露的分析中有可能残留混杂。妇女健康倡议为研究吸烟以外的肺癌风险因素提供了一个良好的环境，因为吸烟率很低，而且大量肺癌病例是从不吸烟者。因此，我们的主要目的是确定维生素D状态与WHI中从不吸烟的绝经后妇女肺癌风险的关系。在300例肺癌病例和300例对照的巢式病例对照研究中，我们将测试25-羟基维生素D [25（OH）D]（维生素D状态的生物标志物）的高血清浓度与低血清浓度是否与从不吸烟女性肺癌风险降低相关。此外，我们假设维生素A可能改变血清25（OH）D与肺癌风险的相关性。在细胞核中，高浓度的9-顺式-视黄酸（维生素A的活性代谢物和类维生素A X受体的配体）阻碍维生素D受体的正常功能。因此，高摄入量的维生素A，如补充维生素A的使用，可能会导致过高的9-顺式-视黄酸浓度在循环和细胞。以前的文献没有考虑到这种潜在的重要的营养素-营养素相互作用。从我们的初步数据来看，血清25（OH）D浓度与既往吸烟者和从不吸烟者的肺癌死亡率呈负相关;过量使用循环维生素A或维生素A补充剂可能会减弱这种相关性。因此，在第二个目标中，我们将测试与高血清25（OH）D浓度相关的肺癌风险降低是否在没有过量循环维生素A的女性中比那些过量循环维生素A的女性更强。过量的循环维生素A定义为血清视黄酯e7 μ g/mL，视黄酯与视黄醇之比e0.08。我们将使用荧光免疫分析法来测量25（OH）D和高效液相色谱法与紫外检测器来测量诊断前血清中的视黄酯和视黄醇。血清25（OH）D浓度将使用季节特异性四分位数、季节标准化四分位数和临床相关浓度进行分类。Logistic 回归将用于估计血清25（OH）和肺癌风险相关性的多变量调整优势比和95%置信区间。还将在回归模型中评估血清25（OH）D和过量维生素A对肺癌风险的相互作用。

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.