Genetic variation in HTR4 and lung function: GWAS follow‐up in mouse

Abstract

Human genome-wide association studies (GWASs) have identified numerous associations between single nucleotide polymorphisms (SNPs) and pulmonary function. Proving that there is a causal relationship between GWAS SNPs, many of which are noncoding and without known functional impact, and these traits has been elusive. Furthermore, noncoding GWAS-identified SNPs may exert trans-regulatory effects rather than impact the proximal gene. Noncoding variants in 5-hydroxytryptamine (serotonin) receptor 4 (HTR4) are associated with pulmonary function in human GWASs. To gain insight into whether this association is causal, we tested whether Htr4-null mice have altered pulmonary function. We found that HTR4-deficient mice have 12% higher baseline lung resistance and also increased methacholine-induced airway hyperresponsiveness (AHR) as measured by lung resistance (27%), tissue resistance (48%), and tissue elastance (30%). Furthermore, Htr4-null mice were more sensitive to serotonin-induced AHR. In models of exposure to bacterial lipopolysaccharide, bleomycin, and allergic airway inflammation induced by house dust mites, pulmonary function and cytokine profiles in Htr4-null mice differed little from their wild-type controls. The findings of altered baseline lung function and increased AHR in Htr4-null mice support a causal relationship between genetic variation in HTR4 and pulmonary function identified in human GWAS.-House, J. S., Li, H., DeGraff, L. M., Flake, G., Zeldin, D. C., London, S. J. Genetic variation in HTR4 and lung function: GWAS follow-up in mouse. FASEB J. 29, 323-335 (2015). www.fasebj.org

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…Interestingly, challenges with bacterial lipopolysaccharide (LPS), bleomycin, which promotes lung fibrosis, and house dust mite (HDM) to mimic an asthma phenotype were also performed. The pulmonary function and cytokine profiles of HTR4-deficient mice only modestly differed from their wild-type counterparts in these models, for example with a reduced IL1 responses in HTR4-/-following LPS instillation in the lungs (House et al, 2015).…”

“…For example, our research group prioritized genes at locus 4q24 previously associated with the lung function measure FEV1 and risk of COPD by identifying eQTL SNPs in a range of datasets generated in lymphoblastoid cell line, liver and brain tissue (Obeidat et al, 2013 (Hao et al, 2012;Obeidat et al, 2015), blood cells (Westra et al, 2013) and airway epithelial cells (X. Li et al, 2015;Luo et al, 2015). The diversity of human tissues and cells and cohort sizes with eQTL data available will continue to expand.…”

“…While we have focussed here on IMPC it is of course important to note that many transgenic strains of mice have been generated way in individual laboratories, including mice with gene deletions for lung function associated genes. For example, recent work has focused on gaining insight into whether candidate gene HTR4 plays a functional role in pulmonary function (House et al, 2015). Knockout of HTR4 resulted in no difference in the histology of lungs of HTR4-null mice and wildtype mice.…”

Response to Baur et al. (2017)

“…Even after controlling for confounders such as age, smoking history, job task etc, there may be a wide variety of lung function impairment. This is probably influenced by genetic factors as has been shown in numerous studies, including on twins, genetic polymorphisms, and pharmacokinetics …”

Progress in disease progression genetics: dissecting the genetic origins of lung function decline in COPD

“…Additional work is required to link these loci to pathophysiology. Functional studies on GWAS loci involving HHIP ,12 13 FAM13A ,14 HTR4 ,15 AGER 16 and IREB2 17 have already provided important insights into the biological mechanisms for genetic determinants of COPD and/or lung function.…”