Vitamin-D Responsive SGPP2 Variants Associated with Lung Cell Expression and Lung Function

Background: Vitamin D is associated with lung health in epidemiologi studies, but mechanisms mediating observed associations are poorly understood. This study explores mechanisms for an effect of vitamin D in lung through an in vivo gene expression study, an expression quantitative trait loci (eQTL) analysis in lung tissue, and a population-based cohort study of sequence variants. Methods: Microarray analysis investigated the association of gene expression in small airway epithelial cell with serum 25[OH]D in adult nonsmokers. Sequence variants in candidate genes identified by the microarray were investigated in a lung tissue eQTL database, and also in relation to cross-sectional pulmonary function in Health, Aging, and Body Composition [Health ABC] study, stratified by race, with replication in the Framingham Heart Study [FHS]. Results: 13 candidate genes had significant differences in expression by serum 25[OH]D (nominal p<0.05), and a genome-wide significant eQTL association was detected for SGPP2. In Health ABC, SGPP2 SNPs were associated with FEV1 in both European and African-Americans, and the gene-level association was replicated in European-American FHS participants. SNPs in 5 additional candidate genes (DAPK1, FSTL1, KAL1, KCNS3 and RSAD2) were associated with FEV1 in Health ABC participants. Conclusions: SGPP2, a sphingosine-1-phosphate, is a novel vitamin D-responsive gene associated with lunh function. The identified associations will need to be followed up in further studies. Bronchial brushing used to collect airway epithelial cells from 26 healthy nonsmokers. Microarray analysis investigated the association of gene expression in small-airway epithelial cells and genotypes from blood DNA from 116 individuals with serum 25(OH)D for 156 genes regulated by vitamin D