Vitamin D related genes in lung development and asthma pathogenesis

Alvin T Kho,Barbara Klanderman,Chris Anderson,James S Leeder,Sunita Sharma,Simin Niu,Kelan G Tantisira,Roger Gaedigk,Weiliang Qiu,Scott T Weiss

doi:10.1186/1755-8794-6-47

Abstract

BackgroundPoor maternal vitamin D intake is a risk factor for subsequent childhood asthma, suggesting that in utero changes related to vitamin D responsive genes might play a crucial role in later disease susceptibility. We hypothesized that vitamin D pathway genes are developmentally active in the fetal lung and that these developmental genes would be associated with asthma susceptibility and regulation in asthma.MethodsVitamin D pathway genes were derived from PubMed and Gene Ontology surveys. Principal component analysis was used to identify characteristic lung development genes.ResultsVitamin D regulated genes were markedly over-represented in normal human (odds ratio OR 2.15, 95% confidence interval CI: 1.69-2.74) and mouse (OR 2.68, 95% CI: 2.12-3.39) developing lung transcriptomes. 38 vitamin D pathway genes were in both developing lung transcriptomes with >63% of genes more highly expressed in the later than earlier stages of development. In immortalized B-cells derived from 95 asthmatics and their unaffected siblings, 12 of the 38 (31.6%) vitamin D pathway lung development genes were significantly differentially expressed (OR 3.00, 95% CI: 1.43-6.21), whereas 11 (29%) genes were significantly differentially expressed in 43 control versus vitamin D treated immortalized B-cells from Childhood Asthma Management Program subjects (OR 2.62, 95% CI: 1.22-5.50). 4 genes, LAMP3, PIP5K1B, SCARB2 and TXNIP were identified in both groups; each displays significant biologic plausibility for a role in asthma.ConclusionsOur findings demonstrate a significant association between early lung development and asthma–related phenotypes for vitamin D pathway genes, supporting a genomic mechanistic basis for the epidemiologic observations relating maternal vitamin D intake and childhood asthma susceptibility.

Highlights

Poor maternal vitamin D intake is a risk factor for subsequent childhood asthma, suggesting that in utero changes related to vitamin D responsive genes might play a crucial role in later disease susceptibility
In each case we observed that the sample configuration along the first three principal components (PC1-3) correlated with age, time-tobirth or a transition between histo-morphological stages of lung development
We have performed a multi-staged analysis that demonstrates the prominence of vitamin D within the developing lung transcriptome and that supports the role of these developmental genes in asthma pathogenesis

Summary

Introduction

Poor maternal vitamin D intake is a risk factor for subsequent childhood asthma, suggesting that in utero changes related to vitamin D responsive genes might play a crucial role in later disease susceptibility. The increase in asthma has been greatest in industrialized countries and in those countries undergoing rapid urbanization [2,3] This has led to the so-called Western lifestyles hypothesis, which states that factors accompanying the transition from a predominantly rural to a predominantly urban lifestyle may increase susceptibility to asthma and other auto-immune diseases [2,3,4,5]. In an analysis of 1,194 mother-child pairs from Boston, MA, 3-year-old children born to mothers with vitamin D intake in the highest quartile during pregnancy had a 62% reduction in risk of recurrent wheeze (adjusted odds ratio OR 0.38, 95% confidence interval CI: 0.22-0.65) [7]. High maternal dietary vitamin D intake during pregnancy appears to be protective for the development of wheezing outcomes (OR 0.56, 95% CI: 0.42-0.73) [10]

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