Prediction and characterization of genetically regulated expression of asthma tissues from African-ancestry populations

Sarah D Slack¹, Erika Esquinca², Christopher H Arehart³, Meher Preethi Boorgula⁴, Brooke Szczesny⁵, Alex Romero¹, Monica Campbell⁴, Sameer Chavan¹, Nicholas Rafaels⁶, Harold Watson⁷, R Clive Landis⁸, Nadia N Hansel⁹, Charles N Rotimi¹⁰, Christopher O Olopade¹¹, Camila A Figueiredo¹², Carole Ober¹³, Andrew H Liu¹⁴, Eimear E Kenny¹⁵, Kai Kammers¹⁶, Ingo Ruczinski¹⁷, Margaret A Taub¹⁸, Michelle Daya¹, Christopher R Gignoux¹, Katerina Kechris¹⁹, Kathleen C Barnes⁴, Rasika A Mathias⁵, Randi K Johnson²⁰

Affiliations

¹ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colo.
² Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colo; Department of Biostatistics & Informatics, Colorado School of Public Health, Aurora, Colo.
³ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colo; Department of Ecology & Evolutionary Biology, University of Colorado Boulder, Boulder, Colo.
⁴ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colo.
⁵ Genomics and Precision Health Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
⁶ Colorado Center for Personalized Medicine, University of Colorado School of Medicine, Aurora, Colo.
⁷ Faculty of Medical Sciences, The University of the West Indies, Queen Elizabeth Hospital, St Michael, Bridgetown, Barbados.
⁸ Edmund Cohen Laboratory for Vascular Research, George Alleyne Chronic Disease Research Centre, Caribbean Institute for Health Research, The University of the West Indies, Cave Hill Campus, Wanstead, Barbados.
⁹ Department of Medicine, Johns Hopkins University, Baltimore, Md.
¹⁰ Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
¹¹ Department of Medicine, University of Chicago, Chicago, Ill.
¹² Instituto de Ciências de Saúde, Universidade Federal da Bahia, Salvador, Brazil; Program for Control of Asthma in Bahia (ProAR), Salvador, Brazil.
¹³ Department of Human Genetics, University of Chicago, Chicago, Ill.
¹⁴ Department of Pediatrics, Childrens Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, Colo.
¹⁵ Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY.
¹⁶ Department of Oncology, Johns Hopkins University, Baltimore, Md.
¹⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md.
¹⁸ Department of Epidemiology, Colorado School of Public Health, Aurora, Colo.
¹⁹ Department of Biostatistics & Informatics, Colorado School of Public Health, Aurora, Colo.
²⁰ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colo; Department of Epidemiology, Colorado School of Public Health, Aurora, Colo. Electronic address: randi.johnson@cuanschutz.edu.

PMID: 40930298
DOI: 10.1016/j.jaci.2025.07.035

Free article

Prediction and characterization of genetically regulated expression of asthma tissues from African-ancestry populations

Sarah D Slack et al. J Allergy Clin Immunol. 2025.

Free article

. 2025 Sep 8:S0091-6749(25)00938-8.

doi: 10.1016/j.jaci.2025.07.035. Online ahead of print.

Authors

Affiliations

¹ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colo.
² Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colo; Department of Biostatistics & Informatics, Colorado School of Public Health, Aurora, Colo.
³ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colo; Department of Ecology & Evolutionary Biology, University of Colorado Boulder, Boulder, Colo.
⁴ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colo.
⁵ Genomics and Precision Health Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
⁶ Colorado Center for Personalized Medicine, University of Colorado School of Medicine, Aurora, Colo.
⁷ Faculty of Medical Sciences, The University of the West Indies, Queen Elizabeth Hospital, St Michael, Bridgetown, Barbados.
⁸ Edmund Cohen Laboratory for Vascular Research, George Alleyne Chronic Disease Research Centre, Caribbean Institute for Health Research, The University of the West Indies, Cave Hill Campus, Wanstead, Barbados.
⁹ Department of Medicine, Johns Hopkins University, Baltimore, Md.
¹⁰ Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
¹¹ Department of Medicine, University of Chicago, Chicago, Ill.
¹² Instituto de Ciências de Saúde, Universidade Federal da Bahia, Salvador, Brazil; Program for Control of Asthma in Bahia (ProAR), Salvador, Brazil.
¹³ Department of Human Genetics, University of Chicago, Chicago, Ill.
¹⁴ Department of Pediatrics, Childrens Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, Aurora, Colo.
¹⁵ Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY.
¹⁶ Department of Oncology, Johns Hopkins University, Baltimore, Md.
¹⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md.
¹⁸ Department of Epidemiology, Colorado School of Public Health, Aurora, Colo.
¹⁹ Department of Biostatistics & Informatics, Colorado School of Public Health, Aurora, Colo.
²⁰ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colo; Department of Epidemiology, Colorado School of Public Health, Aurora, Colo. Electronic address: randi.johnson@cuanschutz.edu.

PMID: 40930298
DOI: 10.1016/j.jaci.2025.07.035

Abstract

Background: Genetic control of gene expression in asthma-related tissues is not well characterized, particularly for African-ancestry populations, limiting advancement in our understanding of the increased prevalence and severity of asthma in these populations.

Objective: We sought to create novel transcriptome prediction models for asthma tissues (nasal epithelium and CD4⁺ T cells) and apply them in a transcriptome-wide association study (TWAS) to discover candidate asthma genes.

Methods: We developed and validated gene expression prediction databases for unstimulated CD4⁺ T cells and nasal epithelium using an elastic net framework. Combining these with existing prediction databases (N = 51), we performed a TWAS of 9284 individuals of African ancestry to identify tissue-specific and cross-tissue candidate genes for asthma.

Results: Novel databases for CD4⁺ T cells and nasal epithelial gene expression prediction contain 8,351 and 10,296 genes, respectively, including 4 asthma loci (SCGB1A1, MUC5AC, ZNF366, and LTC4S) not predictable with existing public databases. Prediction performance was comparable to existing databases and was most accurate for populations sharing ancestry with the training set (eg, African ancestry). From the TWAS, we identified 17 candidate causal asthma genes (adjusted P < .1), including genes with tissue-specific (IL33 in nasal epithelium) and cross-tissue (CCNC and FBXW7) effects.

Conclusions: Expression of IL33, CCNC, and FBXW7 may affect asthma risk in African- ancestry populations by mediating inflammatory responses. The addition of CD4⁺ T cell and nasal epithelium prediction databases to the public sphere will improve ancestry representation and power to detect novel gene-trait associations from TWAS.

Keywords: CD4(+)T; TWAS; ancestry; asthma; eQTL; gene expression; nasal epithelium.

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Conflict of interest statement

Disclosure statement This work was supported by the National Institutes of Health (grant nos. R01HL104608, R01HL104608-10S1, R01AI114555, and R01AI132476), and a National Heart, Lung, and Blood Institute BioData Catalyst Fellowship. The funding sources were not involved in the study design; data collection, analysis, or interpretation; writing the report; or in the decision to submit the article for publication. Disclosure of potential conflict of interest: A. H. Liu has research grants with National Institutes of Health, ResMed and OM Pharma, receives nonmonetary research support from ResMed and Revenio, and is a Consultant for ThermoFisher Scientific, AstraZeneca, and OM Pharma. All funds are paid to the University of Colorado. C. R. Gignoux owns stock in 23andMe, Inc. K. C. Barnes declares royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.

Update of

Prediction and Characterization of Genetically Regulated Expression of Target Tissues in Asthma.
Slack SD, Esquinca E, Arehart CH, Boorgula MP, Szczesny B, Romero A, Campbell M, Chavan S, Rafaels N, Watson H, Landis RC, Hansel NN, Rotimi CN, Olopade CO, Figueiredo CA, Ober C, Liu AH, Kenny EE, Kammers K, Ruczinski I, Taub MA, Daya M, Gignoux CR, Kechris K, Barnes KC, Mathias RA, Johnson RK. Slack SD, et al. medRxiv [Preprint]. 2025 Feb 8:2025.02.06.25321273. doi: 10.1101/2025.02.06.25321273. medRxiv. 2025. Update in: J Allergy Clin Immunol. 2025 Sep 8:S0091-6749(25)00938-8. doi: 10.1016/j.jaci.2025.07.035. PMID: 39974046 Free PMC article. Updated. Preprint.

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Prediction and characterization of genetically regulated expression of asthma tissues from African-ancestry populations

Affiliations

Prediction and characterization of genetically regulated expression of asthma tissues from African-ancestry populations

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

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