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

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

doi:10.1016/j.jaci.2023.10.023

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

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. BusseAlexandra Chloe Villani, Josalyn L. Cho, Benjamin D. Medoff, James E. Gern, Daniel J. Jackson, Carole Ober, Matthew Dapas

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Pages (from-to)	809-820
Number of pages	12
Journal	Journal of Allergy and Clinical Immunology
Volume	153
Issue number	3
DOIs	https://doi.org/10.1016/j.jaci.2023.10.023
State	Published - Mar 2024

Funding

Disclosure of potential conflict of interest: 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. This work was supported by the National Institutes of Health (NIH) (grant nos. U19 AI62310, R01 HL104608, UG3/UH3 OD023282, HHSN272200900052C, HHSN272201000052I, UM1 AI114271, UM1 AI160040, DP2 CA247831, and UH2 AI4434); the Department of Defense (grant no. PR150903/W81XWH-16-1-0493), and funding from Sanofi and Regeneron. Site data collection was supported by the following NIH grants: RR00052 and UL1 TR001079 (Baltimore); M01 RR00533, UL1 RR025771, and 1 UL1 TR001430 (Boston); UL1 TR000150 (Chicago); UL1 TR000451 and UL1 TR001105 (Dallas); Ul1 RR025780 (Denver); UL1 TR000040, M01 RR00071, and UL1 TR001873 (New York); UL1 TR000075 (DC); and UL1 TR000077 (Cincinnati). S.M.C. was supported by NIH grant number T32 GM007197. J.A. was supported by NIH grant number KL2 TR002542. M.D. was supported by NIH grant numbers TL1 TR002388 and T32 HL007605. Single-cell sequencing studies were supported by the NIH (grant no. KL2 TR002452 to J.A., grant no. DP2 CA247831 to A.-C.V., and grant no. UH2 AI44434 to J.L.C.), and a DOD grant PR150903/W81XWH-16-1-0493 and Sanofi iAward (B.D.M).

Keywords

Whole-genome sequencing
eosinophils
neutrophils
total IgE

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaci.2023.10.023

Cite this

Clay, S., Alladina, J., Smith, N. P., Visness, C. M., Wood, R. A., O'Connor, G. T., Cohen, R. T., Khurana Hershey, G. K., Kercsmar, C. M., Gruchalla, R. S., Gill, M. A., Liu, A. H., Kim, H., Kattan, M., Bacharier, L. B., Rastogi, D., Rivera-Spoljaric, K., Robison, R. G., Gergen, P. J., ... Dapas, M. (2024). 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, 153(3), 809-820. https://doi.org/10.1016/j.jaci.2023.10.023

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

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",

author = "Selene Clay and Jehan Alladina and Smith, {Neal P.} and Visness, {Cynthia M.} and Wood, {Robert A.} and O'Connor, {George T.} and Cohen, {Robyn T.} and {Khurana Hershey}, {Gurjit K.} and Kercsmar, {Carolyn M.} and Gruchalla, {Rebecca S.} and Gill, {Michelle A.} and Liu, {Andrew H.} and Haejin Kim and Meyer Kattan and Bacharier, {Leonard B.} and Deepa Rastogi and Katherine Rivera-Spoljaric and Robison, {Rachel G} and Gergen, {Peter J.} and Busse, {William W.} and Villani, {Alexandra Chloe} and Cho, {Josalyn L.} and Medoff, {Benjamin D.} and Gern, {James E.} and Jackson, {Daniel J.} and Carole Ober and Matthew Dapas",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

month = mar,

doi = "10.1016/j.jaci.2023.10.023",

language = "English (US)",

volume = "153",

pages = "809--820",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "3",

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Clay, S, Alladina, J, Smith, NP, Visness, CM, Wood, RA, O'Connor, GT, Cohen, RT, Khurana Hershey, GK, Kercsmar, CM, Gruchalla, RS, Gill, MA, Liu, AH, Kim, H, Kattan, M, Bacharier, LB, Rastogi, D, Rivera-Spoljaric, K, Robison, RG, Gergen, PJ, Busse, WW, Villani, AC, Cho, JL, Medoff, BD, Gern, JE, Jackson, DJ, Ober, C & Dapas, M 2024, '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, no. 3, pp. 809-820. https://doi.org/10.1016/j.jaci.2023.10.023

TY - JOUR

T1 - Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma

AU - Clay, Selene

AU - Alladina, Jehan

AU - Smith, Neal P.

AU - Visness, Cynthia M.

AU - Wood, Robert A.

AU - O'Connor, George T.

AU - Cohen, Robyn T.

AU - Khurana Hershey, Gurjit K.

AU - Kercsmar, Carolyn M.

AU - Gruchalla, Rebecca S.

AU - Gill, Michelle A.

AU - Liu, Andrew H.

AU - Kim, Haejin

AU - Kattan, Meyer

AU - Bacharier, Leonard B.

AU - Rastogi, Deepa

AU - Rivera-Spoljaric, Katherine

AU - Robison, Rachel G

AU - Gergen, Peter J.

AU - Busse, William W.

AU - Villani, Alexandra Chloe

AU - Cho, Josalyn L.

AU - Medoff, Benjamin D.

AU - Gern, James E.

AU - Jackson, Daniel J.

AU - Ober, Carole

AU - Dapas, Matthew

PY - 2024/3

Y1 - 2024/3

N2 - 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.

AB - 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.

KW - Whole-genome sequencing

KW - eosinophils

KW - neutrophils

KW - total IgE

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

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UN SDGs

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