House John S, Li Huiling, DeGraff Laura M, Flake Gordon, Zeldin Darryl C, London Stephanie J
*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.
*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
FASEB J. 2015 Jan;29(1):323-35. doi: 10.1096/fj.14-253898. Epub 2014 Oct 23.
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.
人类全基因组关联研究（GWAS）已经确定了单核苷酸多态性（SNP）与肺功能之间的众多关联。然而，要证明GWAS所识别出的许多SNP（其中许多是非编码的且功能未知）与这些性状之间存在因果关系却并非易事。此外，GWAS所识别出的非编码SNP可能发挥反式调节作用，而非影响近端基因。5-羟色胺（血清素）受体4（HTR4）中的非编码变异与人类GWAS中的肺功能相关。为了深入了解这种关联是否具有因果性，我们测试了Htr4基因敲除小鼠的肺功能是否发生改变。我们发现，HTR4缺陷型小鼠的基线肺阻力高出12%，并且通过肺阻力（27%）、组织阻力（48%）和组织弹性（30%）测量发现，其对乙酰甲胆碱诱导的气道高反应性（AHR）也有所增加。此外，Htr4基因敲除小鼠对血清素诱导的AHR更为敏感。在暴露于细菌脂多糖、博来霉素以及由屋尘螨诱导的过敏性气道炎症的模型中，Htr4基因敲除小鼠的肺功能和细胞因子谱与其野生型对照相比差异不大。Htr4基因敲除小鼠基线肺功能改变和AHR增加的研究结果支持了人类GWAS中所确定的HTR4基因变异与肺功能之间的因果关系。
