Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV1), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole genome sequencing data from the National Heart, Lung, and Blood Institute TOPMed project, we identified a novel genetic association with FEV1 on chromosome 12 in 867 African American children with asthma (p = 1.26 x 10-8, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded 9 variants as the most likely candidates responsible for the association with FEV1. Hi-C data and eQTL analysis demonstrated that these variants physically interacted with KITLG (aka SCF) and their minor alleles were associated with increased expression of KITLG gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year SO2 exposure (p = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV1, possibly mediated through KITLG, in African American children with asthma.

中文翻译：

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新型KITLG / SCF调节变异体与非洲裔美国哮喘儿童的肺功能相关

基线肺功能（在呼气的第一秒（FEV1）中被量化为强制呼气量）是临床医生用于识别和分类肺部疾病的标准诊断标准。使用美国国家心脏，肺和血液研究所TOPMed项目的全基因组测序数据，我们在867名非洲裔美国哮喘儿童中发现了与12号染色体上FEV1的新型遗传关联（p = 1.26 x 10-8，β= 0.302）。在标记信号（rs73429450）的1 Mb之内进行条件分析，在该峰内产生了一个主要信号和另外两个较弱的独立信号。我们探索了具有三个独立信号的连锁不平衡中所有变体的统计和功能证据，并产生了9个变体，作为最有可能与FEV1关联的候选基因。Hi-C数据和eQTL分析表明，这些变异体与KITLG（aka SCF）发生了物理相互作用，其次要等位基因与KITLG基因在鼻上皮细胞中的表达增加有关。基因对空气污染的相互作用分析发现，候选变体rs58475486与去年的SO2暴露有相互作用（p = 0.003，β= 0.32）。这项研究确定了可能通过KITLG介导的非裔美国哮喘儿童与FEV1的新型保护性遗传关联。