title: 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.
authors.affiliation: *Division of Intramural Research, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA; and Division of the National Toxicology Program, U.S. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: House
authors.affiliation: *Division of Intramural Research, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA; and Division of the National Toxicology Program, U.S. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: Huiling
authors.initials: H
authors.lastname: Li
authors.affiliation: *Division of Intramural Research, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA; and Division of the National Toxicology Program, U.S. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.affiliation: *Division of Intramural Research, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA; and Division of the National Toxicology Program, U.S. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Flake
authors.affiliation: *Division of Intramural Research, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA; and Division of the National Toxicology Program, U.S. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: *Division of Intramural Research, National Institute of Environmental Health Sciences, U.S. National Institutes of Health, Research Triangle Park, North Carolina, USA; and Division of the National Toxicology Program, U.S. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA london2@niehs.nih.gov.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: London
mesh_terms: D000403:Airway Resistance / Q000235:genetics / Q000502:physiology; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage; D001761:Bleomycin / Q000633:toxicity; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D055106:Genome-Wide Association Study; D006801:Humans; D008168:Lung / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D044422:Receptors, Serotonin, 5-HT4 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D012129:Respiratory Function Tests; D013045:Species Specificity
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; D001761:Bleomycin; D044422:Receptors, Serotonin, 5-HT4
keywords: airway hyperresponsiveness; mouse models; pulmonary function