Vitamin D-responsive SGPP2 variants associated with lung cell expression and lung function

Brian J Reardon,Jemma B Wilk,Jason Mezey,Yongmei Liu,Kurt Lohman,Ronald G Crystal,Joyanna G Hansen,Stephen B Kritchevsky,Denise K Houston,Tamara Harris,George T O’Connor,Chuan Gao,Patricia A Cassano

doi:10.1186/1471-2350-14-122

Abstract

BackgroundVitamin D is associated with lung health in epidemiologic 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.MethodsMicroarray analysis investigated the association of gene expression in small airway epithelial cells with serum 25(OH)D in adult non-smokers. 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 the Health, Aging, and Body Composition (Health ABC) study, stratified by race, with replication in the Framingham Heart Study (FHS).Results13 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.ConclusionsSGPP2, a sphingosine-1-phosphate phosphatase, is a novel vitamin D-responsive gene associated with lung function. The identified associations will need to be followed up in further studies.

Highlights

Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood
A highly statistically significant cis expression quantitative trait loci (eQTL) reaching genome-wide significance thresholds was identified for Sphingosine-1phosphate phosphatase 2 (SGPP2); a cluster of SNPs in the 3’ region of SGPP2 was associated with SGPP2 gene expression in lung tissue
A SNP in SGPP2 is associated with Forced expiratory volume in the first second (FEV1) in Health ABC European-Americans and SGPP2 variants were associated with FEV1 in the Framingham Heart Study, confirming effects across racial groups and in two cohort

Summary

Introduction

Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood. The active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], when bound to the vitamin D receptor (VDR), regulates the expression of genes in many molecular pathways, including inflammation, cell proliferation, cell death, and tissue-remodeling pathways [1]. A cross-sectional study in the National Health and Nutrition Examination Survey (NHANES) III reported a strong positive association between serum 25(OH)D and lung function, with clinically relevant effect sizes for forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) [7]. A subsequent cross-sectional study in the U.K. reported no association between serum 25 (OH)D and FEV1 [8]. Causal inferences are limited in the cross-sectional design, effect estimates may be biased by uncontrolled confounders such as physical activity, and, comparisons are limited by differences in the range in serum 25(OH)D between studies. Vitamin D supplementation led to a statistically significant reduction in COPD exacerbations in the subgroup with severe vitamin D deficiency at the study baseline (serum 25(OH)D < 10 ng/mL) [9], underscoring the importance of considering the potential to benefit in studies of nutritional supplementation

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