The Role Of Vitamin D In Pulmonary Function And Lung Gene Expression
Decline in lung function is a risk factor for chronic obstructive pulmonary disease (COPD). Vitamin D may protect against loss of lung function by modulating inflammation and tissue remodeling. We investigated the association of serum 25-hydroxyvitamin D (25-OH-D) and genetic variants in vitamin D metabolic pathway genes with prognostic measures of obstructive lung disease including forced expiratory volume in the first second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) using data from the Health Aging and Body Composition cohort study of adults aged 70-79. We also obtained the first evidence of differential gene expression in lung epithelial cells associated with serum 25-hydroxyvitamin D in free-living humans. In regression models, there was a significant cross-sectional association of 25-OH-D with FEV1. We detected no association between 25OH-D and rate of FEV1 decline over 10 years. The longitudinal results suggest that vitamin D supplementation in non-deficient individuals is unlikely to prevent decline in lung function in this age range. However, results are also compatible with a beneficial effect of vitamin D earlier in life, which may explain the cross-sectional association of 25-OH-D with lung function. Single nucleotide polymorphisms (SNPs) in vitamin D metabolic pathway genes were tested in linear regression models stratified by race. In African-Americans, rs3886163 and 2 haplotypes in CYP24A1 were associated with FEV1, and rs11168293 in VDR was associated with FEV1/FVC, after correction for multiple testing. Two gene-environment interactions, between serum 25-OH-D and SNPs in RXRA, in European-Americans were significant with false discovery rate (FDR) < 0.2. Microarray analysis was used to investigate gene expression in small airway epithelial cells associated with serum 25 -OH-D in a separate study of 26 healthy, adult never-smokers. Analysis was restricted to 156 candidate genes with prior evidence of vitamin D-modulated gene expression in vitro and at least 1 predicted vitamin D response element. Thirteen genes had significant differences in expression, and 3 genes (KCNS3, FSTL1, and DAPK1) were significant with FDR < 0.2. Gene ontology and literature analysis of differentially expressed genes supported plausible mechanisms for functional roles in asthma, COPD, cancer, and respon se to infection in lung. The physiological range of 25-OH-D is associated with functional differences in molecular outcomes in lung, implying mechanisms that explain and strengthen the plausibility of population-level studies showing associations of vitamin D with lung health.
Vitamin D; Pulmonary Function; Gene Expression
Cassano, Patricia Ann
Haas, Jere Douglas; Clark, Andrew; Brannon, Patsy Marie
Ph.D. of Nutrition
Doctor of Philosophy
dissertation or thesis