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

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