​[This site contains pages, such as this, to describe your study.  In addition, pre-created "Document Libraries" (much like file folders on a PC) are set up for the storage of raw and analytical datasets, data dictionaries, data preparation documents, and other relevant study documentation.  For help in using the features of this site, along with guidelines for data submission, please consult the Data Submission Guidelines and Help Topics]

AS327 - Serum 25-hydroxyvitamin D and Lung Cancer Risk in Never-smoking, Postmenopausal Women

 

Investigator Names and Contact Information

Marian Neuhouser, Ph.D. [mneuhous@fredhutch.org]

David Cheng [Ting-Yuan.Cheng@RoswellPark.org]

Introduction/Intent

Vitamin D is a promising nutritional cancer prevention agent, but most of the 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 lung cancer cases were never smokers. Therefore, the main purpose of this project is to determine the association of vitamin D status with lung cancer risk in never-smoking, postmenopausal women. In a nested case-control study of 300 incident lung cancer cases and 300 controls in the WHI, we will test whether high 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 is an effect modifier of the serum 25(OH)D-lung cancer association. In nuclei, high concentrations of 9-cis-retinoic acid, an active metabolite of vitamin A and the ligand of retinoid X receptor, will impede the function of the vitamin D​​ receptor. High intake of vitamin A, such as supplemental vitamin A use, is likely lead to excessively high 9-cis-retinoic acid concentrations in circulation and in cells. Thus, as a secondary aim, we test whether the reduced lung cancer risks associated with high serum 25(OH)D concentrations 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 ≥7µg/mL and the ratio of retinyl esters to retinol ≥0.08. 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 baseline sera. Logistic regressions will be used to estimate multivariate-adjusted odds ratios and 95% confidence intervals for the associations of serum 25(OH) and lung cancer risk. This evidence is important for lung cancer prevention in U.S. women, as they have high prevalence of vitamin D insufficiency and consume high-dose vitamin A in dietary supplements.
 
Specific Aims
 
The overall goal of this proposal is to test whether serum 25-hydroxyvitamin D [25(OH)D], a biomarker of vitamin D status, is associated with lung cancer incidence in women. Vitamin D is involved in many key carcinogenesis processes and lung epithelial tissues have a high density of vitamin D receptors. Evidence for an association of serum 25(OH)D in relation to lung cancer is limited by strong residual confounding from cigarette smoking and small sample sizes in previous studies. Additionally, a potentially important, yet under-appreciated effect modifier of the association is vitamin A (retinol). In nuclei, excessive 9-cis-retinoic acid, an active form of retinol and the ligand of retinoid X receptor, can change the structure of vitamin D receptor–retinoid X receptor heterodimer and thus impede vitamin D-signaled transcriptions.1 From our preliminary data, excess circulating vitamin A, measured as fasting serum retinyl esters, may attenuate the beneficial association of serum 25(OH)D with lung cancer.2 To our knowledge, no other previous studies have examined this important effect modification of excess circulating vitamin A, which likely leads to excessively high 9-cis-retinoic acid concentrations in nuclei, with 25(OH)D in relation to lung cancer risk. Therefore, to further investigate this issue, we propose a nested case-control study in the Women’s Health Initiative (WHI). This study population has a low prevalence of smoking and a large number of lung cancer cases from never smokers. We will test the following Specific Aims:
 
Primary Specific Aim: To test whether high vs. low serum 25(OH)D concentrations are associated with reduced lung cancer risks among never-smoking, postmenopausal women.
 
Secondary Specific Aim: To test whether the reduced lung cancer risks associated with high serum 25(OH)D concentrations are stronger among women without excess circulating vitamin A compared to those with excess circulating vitamin A .
 
            Worldwide, the number of lung cancer deaths among never smokers is more than deaths from cervix, pancreas, or prostate cancers.3 Half of lung cancer cases in women are not attributable to smoking and etiological explanations are needed in order to develop the most appropriate programs for prevention and control. Since more than one-third of U.S. adults have insufficient vitamin D status,4 even a modest association of vitamin D with lung cancer would have substantial impact on the prevention of lung cancer. Additionally, multivitamin supplements containing high-dose of vitamin A are widely consumed in the U.S. If we find that high vitamin D status has a beneficial association with lung cancer and excessively high circulating vitamin A could counteract the association, this information will be very important for developing dietary guidelines related to cancer prevention.  
 
Results/ Findings
A complete list of WHI papers is available in the Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.