Vitamin D, Interaction with Vitamin A and Lung Cancer

Abstract

Vitamin D inhibits several pathways of lung cancer carcinogenesis and cells in the respiratory tract produce and utilize vitamin D. Vitamin D's functions rely on vitamin D receptor together with retinoid X receptor, which ligands with 9-cis-retinoic acid, a vitamin A (retinol) metabolite. The objectives of this dissertation are to investigate 1) whether high versus low vitamin D intake is associated with lower lung cancer incidence, 2) whether high/excess vitamin A intake attenuates the inverse association of vitamin D intake with lung cancer, and 3) whether vitamin D intake is associated with vitamin D status, represented by serum 25-hydroxyvitamin D concentrations. Data sources were the Women's Health Initiative Clinical Trials and Observational Study (WHI-CT and OS), recruiting postmenopausal women mostly former/never smokers, and the Carotene and Retinol Efficacy Trial (CARET), recruiting male and female current/former heavy smokers and workers with occupational exposure to asbestos. Vitamin D exposure included total vitamin D intake from food and dietary supplements and 1 g calcium+400 IU vitamin D3 daily supplementation from the WHI Calcium/Vitamin D Trial. Vitamin A exposure included total vitamin A intake from food and dietary supplements and CARET's intervention--30 mg beta-carotene+25,000 IU retinyl palmitate daily supplementation (22,500 µg/day Retinal Activity Equivalent [RAE]). Results from the WHI-OS showed that total vitamin D intake was strongly associated with serum 25-hydroxyvitamin D concentrations after adjusting for available covariates and sun exposure variables. The vitamin D intake-lung cancer associations were examined separately in the WHI CT+OS and CARET. High (≥400 IU/day in WHI and ≥600 IU/day in CARET) versus low total vitamin D intake was associated with a lower risk of lung cancer, particularly for non-small cell lung cancer and adenocarcinoma, among never smokers in WHI and former smokers in CARET. The patterns of effect modification of vitamin A intake were heterogeneous according to participants' smoking status. Among current smokers (and CARET former smokers, who generally were heavy smokers before quitting), an inverse association of total vitamin D intake with lung cancer was only observed among those with high total vitamin A intake (≥3,000 µg/day RAE in WHI [P-interaction=0.26] and ≥1,500 µg/day RAE in CARET [P-interaction=0.08]) or receiving the CARET intervention (P-interaction=0.24). However, among WHI participants as a whole, high vitamin A intake (≥1,000 µg/day RAE) may attenuate a protective association of 1 g calcium+400 IU vitamin D3 supplementation with lung cancer (P-interaction=0.09). The difference in smoking between WHI and CARET may contribute to the discrepant findings on vitamin A effect modification. The findings need further confirmation by biomarkers of vitamin A that reflects internal dose and have less measurement error compared to dietary data. This work demonstrates that vitamin D is an important determinant for postmenopausal women and provides important fundamentals for vitamin D and vitamin A in lung cancer prevention.