Abstract
BackgroundRecent meta-analyses of genome-wide association studies have identified single nucleotide polymorphisms (SNPs) within/near 54 genes associated with lung function measures. Current understanding of the contribution of these genes to human lung development is limited. We set out to further define i) the expression profile of these genes during human lung development using a unique set of resources to examine both mRNA and protein expression and ii) the link between key polymorphisms and genes using expression quantitative trait loci (eQTL) approaches.MethodsThe mRNA expression profile of lung function associated genes across pseudoglandular and canalicular stages of lung development were determined using expression array data of 38 human fetal lungs. eQTLs were investigated for selected genes using blood cell and lung tissue data. Immunohistochemistry of the top 5 candidates was performed in a panel of 24 fetal lung samples.ResultsTwenty-nine lung function associated genes were differentially expressed during lung development at the mRNA level. The greatest magnitude of effect was observed for 5 genes; TMEM163, FAM13A and HHIP which had increasing expression and CDC123 and PTCH1 with decreased expression across developmental stages. Focussed eQTL analyses investigating SNPs in these five loci identified several cis-eQTL’s. Protein expression of TMEM163 increased and CDC123 decreased with fetal lung age in agreement with mRNA data. Protein expression in FAM13A, HHIP and PTCH1 remained relatively constant throughout lung development.ConclusionsWe have identified that > 50 % of lung function associated genes show evidence of differential expression during lung development and we show that in particular TMEM163 and CDC123 are differentially expressed at both the mRNA and protein levels. Our data provides a systematic evaluation of lung function associated genes in this context and offers some insight into the potential role of several of these genes in contributing to human lung development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0410-z) contains supplementary material, which is available to authorized users.
Highlights
Recent meta-analyses of genome-wide association studies have identified single nucleotide polymorphisms (SNPs) within/near 54 genes associated with lung function measures
Lung function genes are expressed in human fetal lung and show differential expression To identify whether the 54 lung function genes (Additional file 1: Table S1) were expressed during normal human lung development, we utilised the gene expression array data of 38 lung samples across the Pseudoglandular and Canalicular (17–26 weeks) stages
Identification of genes with greatest magnitude of differential expression Significant probes in lung function associated genes from the expression profiles of 38 fetal lung samples were ordered by Beta coefficient to highlight the greatest magnitude of difference in expression across the developmental stages (Tables 1 and 2)
Summary
Recent meta-analyses of genome-wide association studies have identified single nucleotide polymorphisms (SNPs) within/near 54 genes associated with lung function measures. Current understanding of the contribution of these genes to human lung development is limited. Current knowledge of human lung development is based on evidence provided by anatomical dissections and histological staging. Previous work by Kho et al sought to further our understanding of human lung development and consider differences in expression at the molecular level [5]. The authors investigated the hypothesis that the temporal changes in gene expression regulated the morphological transformation of early cells to a fully functional differentiated organ. Profiling the gene expression signatures in a panel of human fetal lungs identified differential gene expression during organ development and revealed the presence of several molecular stages. The late pseudoglandular stage was enriched for genes related to surfactant function-gas exchange and immunologicalMHC class II attributes providing evidence of at least a second distinct molecular phase of development [5]
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