Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction.

TitleLung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction.
Publication TypeJournal Article
Year of Publication2020
AuthorsC Y Mak, A, Sajuthi, S, Joo, J, Xiao, S, Sleiman, PM, White, MJ, Lee, EY, Saef, B, Hu, D, Gui, H, Keys, KL, Lurmann, F, Jain, D, Abecasis, G, Kang, HMin, Nickerson, DA, Germer, S, Zody, MC, Winterkorn, L, Reeves, C, Huntsman, S, Eng, C, Salazar, S, Oh, SS, Gilliland, FD, Chen, Z, Kumar, R, Martínez, FD, Wu, AChen, Ziv, E, Hakonarson, H, Himes, BE, L Williams, K, Seibold, MA, Burchard, EG
JournalGenetics
Volume215
Issue3
Pagination869-886
Date Published2020 Jul
ISSN1943-2631
Abstract

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV), 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 FEV on chromosome 12 in 867 African American children with asthma ( = 1.26 × 10, 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 nine variants as the most likely candidates responsible for the association with FEV Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with (KIT ligand, also known as ), and their minor alleles were associated with increased expression of the 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 ( = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV, possibly mediated through , in African American children with asthma. This is the first study that has identified a genetic association between lung function and , which has established a role in orchestrating allergic inflammation in asthma.

DOI10.1534/genetics.120.303231
Alternate JournalGenetics
PubMed ID32327564
PubMed Central IDPMC7337089
Grant ListR01 ES015794 / ES / NIEHS NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
HHSN268201600032C / ES / NIEHS NIH HHS / United States
R01 HL141992 / HL / NHLBI NIH HHS / United States
R01 DK113003 / DK / NIDDK NIH HHS / United States
K01 HL140218 / HL / NHLBI NIH HHS / United States
R01 AI079139 / AI / NIAID NIH HHS / United States
UM1 HG008901 / HG / NHGRI NIH HHS / United States
U01 HG009080 / HG / NHGRI NIH HHS / United States
R01 HL128439 / HL / NHLBI NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
R01 HL118267 / HL / NHLBI NIH HHS / United States
R01 MD010443 / MD / NIMHD NIH HHS / United States
R01 HL135156 / HL / NHLBI NIH HHS / United States
R01 HD085993 / HD / NICHD NIH HHS / United States
R01 HL133433 / HL / NHLBI NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
R01 HL117004 / HL / NHLBI NIH HHS / United States
P60 MD006902 / MD / NIMHD NIH HHS / United States