Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma
Year: 2023
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. RESULTS: ) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.
Authors: Selene Clay, Jehan Alladina, Neal P. Smith, Cynthia M. Visness, Robert A. Wood, George T. O’Connor, Robyn T. Cohen, Gurjit K. Khurana Hershey, Carolyn M. Kercsmar, Rebecca S. Gruchalla, Michelle A. Gill, Andrew H. Liu, Haejin Kim, Meyer Kattan, Leonard B. Bacharier, Deepa Rastogi, Katherine Rivera-Spoljaric, Rachel G. Robison, Peter J. Gergen, William W. Busse, Alexandra-Chloe Villani, Josalyn L. Cho, Benjamin D. Medoff, James E. Gern, Daniel J. Jackson, Carole Ober, Matthew Dapas
Institutions: University of Chicago, Harvard University, Massachusetts General Hospital, Broad Institute, Massachusetts Institute of Technology, Rho (United States), Johns Hopkins University, Boston University, Cincinnati Children's Hospital Medical Center, The University of Texas Southwestern Medical Center, St. Louis Children's Hospital, Children's Hospital Colorado, Henry Ford Health, Henry Ford Hospital, Columbia University Irving Medical Center, Columbia University, Monroe Carell Jr. Children's Hospital, Vanderbilt University Medical Center, Children's National, Washington University in St. Louis, Lurie Children's Hospital, National Institutes of Health, National Institute of Allergy and Infectious Diseases, University of Wisconsin–Madison, University of Iowa, University of Iowa Health Care
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
Funders: U.S. Department of Defense, GlaxoSmithKline, Regeneron Pharmaceuticals, Vifor Pharma, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1133076894, G11701374, G1260873166, Wisconsin Infant Study Cohort (WISC) ECHO Pediatric Follow-Up, G1314613728, G1346455397, G1655252654, G1663837155, G1830311252, THE GPCR-CARMA3 SIGNALING AXIS MEDIATES INFLAMMATION IN ASTHMA, Deciphering the Achilles Heel of Cancer Immunotherapy, G2340152788, G2358412042, G277117613, G2797270607, G3138919099, G336615015, G3395997892, Airway Dendritic Cells in the Allergic Asthma Phenotype, Clinical and Translational Science Institute at Children's National, G4325039693, G473988448, G475936976, G477853788, Northwestern University Clinical and Translational Science Institute (NUCATS), G4867537966, G491532010, G498997782, Inner City Asthma consortium 3 (ICAC3), G6267435838, G629043820, Institute for Clinical and Translational Research, Genetics and Regulation, G715742319, G7480681299, Clinical and Translational Science Award, G9000001959, G9000018693, G9000023784, G9000037139, G9000038034, G9000047020, G9000047280, G9000049237, G9000056172, G9000056855, G9000070888, G9000119642, G9000122439, G9000235735, G9000241600, G9000248469, G9000305379, Environmental Health Sciences Research Center, Integrated genetic, omic, and immunologic studies to identify endotypes and novel drug targets for asthma and allergic diseases, FITting noninvasive testing into Lynch syndrome colorectal cancer surveillance: a multicenter, prospective trial, J. NRSA Training Core
OpenAlex ID: W4388452138