Journal article
Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma
Journal of allergy and clinical immunology, Vol.153(3), pp.809-820
03/2024
DOI: 10.1016/j.jaci.2023.10.023
PMCID: PMC10939893
PMID: 37944567
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
Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10−7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10−6) and PIK3R6 with eosinophil count (P = 4.10 × 10−5) 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.
Details
- Title: Subtitle
- Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma
- Creators
- Selene Clay - University of ChicagoJehan Alladina - Massachusetts General HospitalNeal P. Smith - Massachusetts General HospitalCynthia M. Visness - RhoRobert A. Wood - Bloomberg (United States)George T. O’Connor - Boston UniversityRobyn T. Cohen - Boston UniversityGurjit K. Khurana HersheyCarolyn M. Kercsmar - Cincinnati Children's Hospital Medical CenterRebecca S. Gruchalla - The University of Texas Southwestern Medical CenterMichelle A. Gill - St. Louis Children's HospitalAndrew H. Liu - University of Colorado DenverHaejin KimMeyer Kattan - Columbia University Irving Medical CenterLeonard B. Bacharier - Monroe Carell Jr. Children's HospitalDeepa Rastogi - Children's NationalKatherine Rivera-Spoljaric - Washington University in St. LouisRachel G. Robison - Lurie Children's HospitalPeter J. Gergen - National Institute of Allergy and Infectious DiseasesWilliam W. Busse - University of Wisconsin–MadisonAlexandra-Chloe VillaniJosalyn L. Cho - University of IowaBenjamin D. Medoff - Massachusetts General HospitalJames E. Gern - Washington University in St. LouisDaniel J. Jackson - Washington University in St. LouisCarole C. Ober - University of ChicagoMatthew Dapas - University of Chicago
- Resource Type
- Journal article
- Publication Details
- Journal of allergy and clinical immunology, Vol.153(3), pp.809-820
- DOI
- 10.1016/j.jaci.2023.10.023
- PMID
- 37944567
- PMCID
- PMC10939893
- ISSN
- 0091-6749
- eISSN
- 1097-6825
- Grant note
- DOI: 10.13039/100000002, name: NIH; DOI: 10.13039/100000005, name: US Department of Defense
- Language
- English
- Electronic publication date
- 11/2023
- Date published
- 03/2024
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
- Record Identifier
- 9984506358902771
Metrics
5 Record Views