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. 2024 Mar;153(3):809-820.
doi: 10.1016/j.jaci.2023.10.023. Epub 2023 Nov 7.

Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma

Selene Clay  1 , Jehan Alladina  2 , Neal P Smith  3 , Cynthia M Visness  4 , Robert A Wood  5 , George T O'Connor  6 , Robyn T Cohen  6 , Gurjit K Khurana Hershey  7 , Carolyn M Kercsmar  8 , Rebecca S Gruchalla  9 , Michelle A Gill  10 , Andrew H Liu  11 , Haejin Kim  12 , Meyer Kattan  13 , Leonard B Bacharier  14 , Deepa Rastogi  15 , Katherine Rivera-Spoljaric  16 , Rachel G Robison  17 , Peter J Gergen  18 , William W Busse  19 , Alexandra-Chloe Villani  3 , Josalyn L Cho  20 , Benjamin D Medoff  2 , James E Gern  21 , Daniel J Jackson  21 , Carole Ober  22 , Matthew Dapas  22
Affiliations

Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma

Selene Clay et al. J Allergy Clin Immunol. 2024 Mar.

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.

Keywords: Whole-genome sequencing; eosinophils; neutrophils; total IgE.

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Conflict of interest statement

All authors, with the exception of P. J. Gergen, report grants from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases during the conduct of study. S. Clay, J. Alladina, N. P. Smith, C. M. Visness, M. Dapas, M. Kattan, P. J. Gergen, and J. L. Cho have nothing to disclose outside the submitted work. W. W. Busse reports consulting fees from Novartis, GlaxoSmithKline, Genentech, Sanofi, AstraZeneca, and Regeneron and royalties from Elsevier outside the submitted work. M. A. Gill reports an honorarium for and support for travel to the 2017 AAAAI meeting during the conduct of study and monetary compensation from the American Academy of Pediatrics for her work teaching the biannual Pediatrics board review course, PREP The Course. G. K. K. Hershey reports grants from Adare during the conduct of the study. D. J. Jackson reports personal fees from Novartis, Pfizer, Regeneron, AstraZeneca, Sanofi, and Vifor Pharma, grants and personal fees from GlaxoSmithKline, and grants from NIH/National Heart, Lung, and Blood Institute, outside the submitted work. R. S. Gruchalla reports government employment from the Center for Biologics Evaluation and Research as well as personal fees from Consulting Massachusetts Medical Society, outside the submitted work. A. H. Liu reports personal fees from Phadia ThermoFisher as consulting honoraria, grants and nonfinancial support from ResMed/Propeller Health, nonfinancial support from Revenio, grants and personal fees from Avillion, and personal fees from Labcorp, outside the submitted work. L. B. Bacharier reports book royalties from Elsevier, consulting fees from Sanofi, Regeneron, Genentech, GlaxoSmithKline, DBV Technologies, Teva, Medscape, Kinaset, OM Pharma, and AstraZeneca, honoraria from Sanofi, Regeneron, and GlaxoSmithKline, participation in advisory board for DBV Technologies, AstraZeneca, and Vertex, leadership role in the American Academy of Allergy, Asthma & Immunology and the American Board of Allergy and Immunology, and medical writing services for Sanofi/Regeneron. J. E. Gern reports consulting fees from AstraZeneca and Meissa Vaccines and 2 patents related to the methods to enhance the production of rhinoviruses and stock options with Meissa Vaccines. C. M. Kercsmar reports royalties from UpToDate. R. A. Wood reports grants from DBV, Aimmune, Regeneron, Genentech, Novartis, Food Allergy Research & Education (FARE), and Genentech and royalties from UpToDate. R. G. Robison received grant support from DBV Technologies and Aimmune Therapeutics. A.-C. Villani has a financial interest in 10X Genomics; the company designs and manufactures gene sequencing technology for use in research, and such technology is being used in this research. Dr Villani’s interests were reviewed by The Massachusetts General Hospital and Mass General Brigham in accordance with their institutional policies. B. D. Medoff receives research funding from and served as a consultant for Sanofi and Regeneron. C. C. Ober reports personal fees from the American Association of Asthma, Allergy and Immunology.

Figures

FIG 1.
FIG 1.
USF1 and neutrophil count. A, Manhattan plot for gene set associations with blood neutrophil count. Each point represents a gene. The red line is the Bonferroni significance threshold. B, Marginal associations and locations of variants in the USF1 variant set. Variants are color coded green if they are noncoding and orange if coding in either USF1 or its neighboring gene, ARHGAP30. C, USF1 association with other traits. FENO, Fractional exhaled nitric oxide; FVC, forced vital capacity.
FIG 2.
FIG 2.
TNFRSF21 and total IgE. A, Manhattan plot for total IgE levels. Red line is Bonferroni significance and blue is suggestive significance (1.00 × 10−5). B, Marginal associations of variants in the TNFRSF21 variant set. C, TNFRSF21 association with the other traits before and after conditioning on total IgE. FENO, Fractional exhaled nitric oxide; FVC, forced vital capacity.
FIG 3.
FIG 3.
PIK3R6 and eosinophil count. A, Manhattan plot for blood eosinophil count. B, Marginal associations of variants in variant set. C, PIK3R6 association with the other traits.
FIG 4.
FIG 4.
TNFRSF21 and 3-gene score with URECA and APIC phenotypes. Boxplots show the log10-transformed total number of rare variants in (A) TNFRSF21 and (B) the 3-gene score for each individual in URECA phenotypes LW-LA (low wheeze/low atopy) vs LW-HA (low wheeze/high atopy) and for APIC phenotypes A (minimally symptomatic asthma and rhinitis; low allergy/inflammation) vs E (highest levels of symptomatic asthma and rhinitis; highest degree of allergy and allergic inflammation). For all results, see Fig E8 and Table E7. Sample sizes for each phenotype are also shown.
FIG 5.
FIG 5.
TNFRSF21 expression in airway epithelial cells (AECs) in individuals with AA and AC. Uniform manifold approximation and projection (UMAP) of 20,410 AECs from a publicly available database in (A) with 14 AEC subclusters obtained from endobronchial brush sampling of third-to fourth-generation airway segments from patients with AA and ACs before and 24 hours after segmental allergen challenge. Feature plots in (B) AA (red) and (C) AC (blue) using pseudocoloring to depict TNFRSF21 expression at baseline and after allergen challenge. Cell number and percentages (%) represent gene expression across all AEC subclusters and scaled gene expression in log(CPM).
See this image and copyright information in PMC

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