Evidence map›Paper›PMID 40950420›Full record

ArticlemedRxiv : the preprint server for health sciences2025

Epigenetic patient stratification reveals a sub-endotype of type 2 asthma with altered B-cell response.

Aditya Gorla, Jonathan Witonsky, Zeyuan Johnson Chen, Jennifer R Elhawary, Joel Mefford, Javier Perez-Garcia, Anne-Marie Madore, Scott Huntsman, Donglei Hu, Celeste Eng and 10 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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3 · Its place in the literature

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0 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

20 authors.

Aditya GorlaDepartment of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.ORCID 0000-0003-0849-7894
Jonathan WitonskyDivision of Allergy, Immunology, and Bone Marrow Transplant, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Zeyuan Johnson ChenDepartment of Computer Science, University of California Los Angeles, Los Angeles, CA, USA.
Jennifer R ElhawaryDepartment of Medicine, University of California San Francisco, San Francisco, CA, USA.ORCID 0000-0003-3326-1680
Joel MeffordDepartment of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Javier Perez-GarciaDepartment of Epidemiology and Population Health, Stanford University, Stanford, CA, USA.
Anne-Marie MadoreCentre intersectoriel en santé durable of the Université du Québec à Chicoutimi, Saguenay, Québec, Canada.
Scott HuntsmanDepartment of Medicine, University of California San Francisco, San Francisco, CA, USA.
Donglei HuDepartment of Medicine, University of California San Francisco, San Francisco, CA, USA.
Celeste EngDepartment of Medicine, University of California San Francisco, San Francisco, CA, USA.
Nirav R BhaktaDepartment of Medicine, University of California San Francisco, San Francisco, CA, USA.
Prescott G WoodruffDepartment of Medicine, University of California San Francisco, San Francisco, CA, USA.
Catherine LapriseCentre intersectoriel en santé durable of the Université du Québec à Chicoutimi, Saguenay, Québec, Canada.
Sriram SankararamanDepartment of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Jonathan FlintDepartment of Psychiatry and Behavioral Sciences, Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA.ORCID 0000-0002-9427-4429
Christopher D C AllenCardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
Elad ZivDepartment of Medicine, University of California San Francisco, San Francisco, CA, USA.
Noah ZaitlenDepartment of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Esteban BurchardDepartment of Medicine, University of California San Francisco, San Francisco, CA, USA.
Elior RahmaniDepartment of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Funding

The Airway Functional Genomics of Bronchodilator Drug Response in Minority Children with AsthmaR01HL117004 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AHITUV, NADAV, SEIBOLD, MAX A · 2013 to 2022
$9.3M
Gene-environments and Admixture in Latino Asthmatics (GALA 2)R01ES015794 · NIEHS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BURCHARD, ESTEBAN GONZALEZ · 2008 to 2012
$5.4M
Transcriptomic and Pharmacogenetic Asthma Endotypes in Minority ChildrenR01HL135156 · NHLBI · NATIONAL JEWISH HEALTH · PI SEIBOLD, MAX A, ZIV, ELAD · 2017 to 2021
$4.1M
Genes, air pollution, and asthma severity in minority childrenR01MD010443 · NIMHD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SEIBOLD, MAX A, ZIV, ELAD · 2016 to 2020
$3.8M
Combining Voice and Genetic Information to Detect Heterogeneity in Major Depressive DisorderR01MH122569 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI FLINT, JONATHAN · 2020 to 2024
$3.4M
Genetic Control of Airway Epithelium Gene Expression in Childhood AsthmaticsR01HL128439 · NHLBI · NATIONAL JEWISH HEALTH · PI SEIBOLD, MAX A · 2015 to 2019
$3.1M
Epigenomics of asthma risk factors and clinical subtypes in minority childrenR01HL155024 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BORRELL, LUISA N, ZAITLEN, NOAH A · 2021 to 2024
$2.9M
Improving the interpretability of genetic studies of major depressive disorder to identify risk genesR01MH130581 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI JONATHAN FLINT, KENNETH SEEDMAN KENDLER · 2022 to 2026
$2.8M
Improving Prediction of Asthma-related Outcomes with Genetic Ancestry-informed Lung Function EquationsK23HL169911 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Jonathan Witonsky · 2023 to 2026
$688k
Gene-Environment Analyses of Early Life Exposures and Asthma in Ethnically Diverse ChildrenR21ES024844 · NIEHS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BURCHARD, ESTEBAN GONZALEZ, GAUDERMAN, WILLIAM JAMES · 2015 to 2017
$509k
Epigenetics of Socio-Environmental Effects on Asthma in MinoritiesR56MD013312 · NIMHD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BURCHARD, ESTEBAN GONZALEZ, ZAITLEN, NOAH A · 2018 to 2018
$458k
Subtyping complex phenotypes via constrastive learning by leveraging electronic health recordsR21HG013393 · NHGRI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI RAHMANI, ELIOR · 2023 to 2023
$428k
NHGRI NIH HHS R21 HG013393NHLBI NIH HHS K23 HL169911NHLBI NIH HHS R01 HL117004NHLBI NIH HHS R01 HL128439NHLBI NIH HHS R01 HL135156NHLBI NIH HHS R01 HL155024NIEHS NIH HHS R01 ES015794NIEHS NIH HHS R21 ES024844NIMHD NIH HHS R01 MD010443NIMHD NIH HHS R56 MD013312NIMH NIH HHS R01 MH122569NIMH NIH HHS R01 MH130581
6 · The paper itself

Abstract

Despite biomarker-guided treatment strategies, clinical outcomes among patients with type 2 (T2)-high asthma remain heterogeneous, with some patients responding poorly to T2-targeted biologic therapies. We developed a contrastive machine learning method for patient stratification based on whole-blood DNA methylation (DNAm), applying it to pediatric asthma cohorts of Latino (discovery; n=1,016) and African American (replication; n=429) children. The resulting DNAm stratification score revealed a continuum of clinical severity and drug response within the T2-high asthma endotype. Molecular profiling of high-score asthma patients identified eosinophil-specific hypermethylation-validated in an independent Canadian adult cohort using purified eosinophil DNAm-as well as upregulation of canonical T2-associated genes. Transcriptomic analysis of elevated DNAm scores within T2-high patients further uncovered a gene signature linked to B-cell lineage activity, predominantly reflecting plasma cell activity orthogonal to canonical T2 inflammation programs. This defines a previously unrecognized sub-endotype, which we term T2-high asthma with Altered B Cell response (T2ABC). In a randomized controlled trial of the anti-IgE biologic omalizumab in primarily White adult T2-high asthmatic patients (n=300), the T2ABC gene expression signature was prognostic of poor outcomes, including a 24% mean increase in disease exacerbation rates compared to the trial baseline (P=0.004), which could not be explained by treatment or placebo assignment. Patients treated with omalizumab showed better outcomes than patients in the placebo arm within the T2ABC-low group (P=0.019) but not within the T2ABC-high group (P=0.48), suggesting that IgE blockade does not adequately target the pathogenic mechanisms active in T2ABC-high disease. Single-cell transcriptomic analysis demonstrated that the T2ABC signature reflects heightened activity of non-IgE plasma cells, consistent with the presence of additional antibody isotype responses in a form of severe asthma arising within a T2-high immunologic context. Our findings, replicated and validated across four ancestrally and ethnically diverse pediatric and adult cohorts, support the use of DNAm- and transcriptome-based patient stratification to refine drug development, eligibility, and administration strategies for improving precision in T2 asthma therapy.

Identifiers

PMID40950420
PMCPMC12424920

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