Novel KITLG regulatory variants are associated with lung function in African American children with asthma

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, {beta} = 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 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, {beta} = 0.316). This study identified a novel protective genetic association with FEV1, possibly mediated through KITLG, in African American children with asthma.