Lung function in African American Children with asthma is associated with novel regulatory variants of the KIT ligand KITLG/SCF and gene-by-air-pollution interaction

Angel C.Y. Mak, Satria Sajuthi, Jaehyun Joo, Shujie Xiao, Patrick M. Sleiman, Marquitta J. White, Eunice Y. Lee, Benjamin Saef, Donglei Hu, Hongsheng Gui, Kevin L. Keys, Fred Lurmann, Deepti Jain, Gonçalo Abecasis, Hyun Min Kang, Deborah A. Nickerson, Soren Germer, Michael C. Zody, Lara Winterkorn, Catherine ReevesScott Huntsman, Celeste Eng, Sandra Salazar, Sam S. Oh, Frank D. Gilliland, Zhanghua Chen, Rajesh Kumar, Fernando D. Martínez, Ann Chen Wu, Elad Ziv, Hakon Hakonarson, Blanca E. Himes, L. Keoki Williams, Max A. Seibold, Esteban G. Burchard

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV1 on chromosome 12 in 867 African American children with asthma (P = 1.26 3 1028, b = 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 nine variants as the most likely candidates responsible for the association with FEV1. Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with KITLG (KIT ligand, also known as SCF), and their minor alleles were associated with increased expression of the KITLG gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure (P = 0.003, b = 0.32). This study identified a novel protective genetic association with FEV1, possibly mediated through KITLG, in African American children with asthma. This is the first study that has identified a genetic association between lung function and KITLG, which has established a role in orchestrating allergic inflammation in asthma.

Original languageEnglish (US)
Pages (from-to)869-886
Number of pages18
JournalGenetics
Volume215
Issue number3
DOIs
StatePublished - Jul 2020

Keywords

  • African American
  • Air pollution
  • FEV gene-by-environment interaction
  • GWAS
  • GxE
  • KITLG
  • SCF

ASJC Scopus subject areas

  • Genetics

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