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
Year: 2020
Type: article
Study design: Observational Study
Abstract: ABSTRACT Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV 1 ), 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 FEV 1 on chromosome 12 in 867 African American children with asthma (p = 1.26 × 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 FEV 1 . 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 SO 2 exposure (p = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV 1 , possibly mediated through KITLG , in African American children with asthma.
Source: Genetics
Authors: Angel CY 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 Reeves, Scott 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
Institutions: University of California, San Francisco, National Jewish Health, University of Pennsylvania, Henry Ford Health, Henry Ford Hospital, Children's Hospital of Philadelphia, University of California, Berkeley, Sonoma Technology (United States), University of Washington, University of Michigan, Brotman Baty Institute, New York Genome Center, University of Southern California, Lurie Children's Hospital, University of Arizona, Harvard University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Robert Wood Johnson Foundation, Alfred P. Sloan Foundation, Gordon and Betty Moore Foundation, Tobacco-Related Disease Research Program, Kaiser Permanente, Northwestern University, Texas Children's Hospital, American Asthma Foundation, National Institutes of Health, University of California, San Francisco, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Eye Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Institute on Minority Health and Health Disparities, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1268573537, G1278681517, CEBPD-Mediated Mechanisms of Glucocorticoid Insensitivity in Severe Asthma, G1461185250, Age-Dependent Pharmacogenomics of Asthma Treatment (ADAPT), G1678129981, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2189466114, Addressing disparities in chronic disease with a teen and young adult focus, G2305281594, G2317004092, G232264632, G2589338529, G2816736420, G2976884267, G2986409096, G3194560040, G3256118428, G330094603, Poly-omic Study of Asthma Exacerbations in Diverse Populations, G3520747131, G4091723164, G4183848059, G4432600228, G457392980, G4765065348, G5272449015, G5337788423, Genetic Control of Airway Epithelium Gene Expression in Childhood Asthmatics, PHARMACOGENOMICS OF INHALED CORTICOSTEROID RESPONSIVENESS IN PATIENTS WITH ASTHMA, G6460128660, Integrative Genetics and Genomics of Obese-Asthma in Minority Children, Combined Transcriptomics and Genomics to Find Asthma Genes in Admixed Populations, Data Science Environment, G7307112236, Genes, air pollution, and asthma severity in minority children, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, G86930896, NHGRI Genome Sequencing Program Coordinating Center, G9000025080, G9000032667, G9000094210, G9000151446, G9000227757, Southwest Environmental Health Sciences Center, Center of Excellence in Environmental Toxicology, G955715661
OpenAlex ID: W3018079806