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Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development

Miller, Suzanne; Mel�n, Erik; Merid, S. K.; Hall, Ian P.; Sayers, Ian

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Authors

Dr SUZANNE MILLER suzanne.miller@nottingham.ac.uk
Senior Clinical Studies and Project Manager

Erik Mel�n

S. K. Merid

Ian P. Hall



Abstract

Background
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. 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 (eQTL) approaches.
Methods
The 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.
Results
29 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.
Conclusions
We 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.

Citation

Miller, S., Melén, E., Merid, S. K., Hall, I. P., & Sayers, I. (in press). Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development. Respiratory Research, 17(95), https://doi.org/10.1186/s12931-016-0410-z

Journal Article Type Article
Acceptance Date Jul 19, 2016
Online Publication Date Jul 29, 2016
Deposit Date Aug 1, 2016
Publicly Available Date Aug 1, 2016
Journal Respiratory Research
Print ISSN 1465-9921
Electronic ISSN 1465-993X
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 17
Issue 95
DOI https://doi.org/10.1186/s12931-016-0410-z
Keywords Lung function; development; expression; genetics; TMEM163; CDC123
Public URL https://nottingham-repository.worktribe.com/output/798514
Publisher URL https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-016-0410-z
Contract Date Aug 1, 2016

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