Upper airway microbiome interacts with GSDMB and ORMDL3 asthma risk SNPs to influence early-life wheeze risk

Holly M Steininger; Kathryn E McCauley; Gabe E Braga; Andréanne Morin; Kristine E Lee; Cynthia M Visness; Douglas W Fadrosh; Matthew Dapas; George T O'Connor; Leonard B Bacharier; Katherine Rivera-Spoljaric; Meyer Kattan; Robert F Lemanske Jr; Edward M Zoratti; Fernando D Martinez; Diane R Gold; Tina V Hartert; Christine C Johnson; Rachel L Miller; Christine M Seroogy; Robert A Wood; Alkis Togias; Daniel J Jackson; James E Gern; Carole Ober; Susan V Lynch; CADRE Investigators

doi:10.1016/j.jaci.2026.05.021

Upper airway microbiome interacts with GSDMB and ORMDL3 asthma risk SNPs to influence early-life wheeze risk

J Allergy Clin Immunol. 2026 Jun 4:S0091-6749(26)00405-7. doi: 10.1016/j.jaci.2026.05.021. Online ahead of print.

Authors

Holly M Steininger¹, Kathryn E McCauley¹, Gabe E Braga¹, Andréanne Morin², Kristine E Lee³, Cynthia M Visness⁴, Douglas W Fadrosh¹, Matthew Dapas⁵, George T O'Connor⁶, Leonard B Bacharier⁷, Katherine Rivera-Spoljaric⁸, Meyer Kattan⁹, Robert F Lemanske Jr¹⁰, Edward M Zoratti¹¹, Fernando D Martinez¹², Diane R Gold¹³, Tina V Hartert¹⁴, Christine C Johnson¹⁵, Rachel L Miller¹⁶, Christine M Seroogy¹⁰, Robert A Wood¹⁷, Alkis Togias¹⁸, Daniel J Jackson¹⁰, James E Gern¹⁰, Carole Ober², Susan V Lynch¹⁹; CADRE Investigators

Affiliations

¹ Benioff Center for Microbiome Medicine, Department of Medicine, University of California, San Francisco, Calif.
² Department of Human Genetics, University of Chicago, Chicago, Ill.
³ Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
⁴ Rho, Inc, Federal Research Operations, Durham, NC.
⁵ Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
⁶ Pulmonary Center, Boston University, Boston, Mass.
⁷ Division of Pediatric Allergy, Immunology and Pulmonary Medicine, Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, Tenn.
⁸ Department of Pediatrics, Washington University School of Medicine, St Louis, Mo.
⁹ Department of Pediatrics, Columbia University Medical Center, New York, NY.
¹⁰ Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
¹¹ Department of Medicine, Henry Ford Health System, Detroit, Mich.
¹² Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz.
¹³ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass; Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Mass.
¹⁴ Departments of Medicine and Pediatrics, Vanderbilt University Medical Center, Nashville, Tenn.
¹⁵ Department of Public Health Sciences, Henry Ford Health System, Detroit, Mich.
¹⁶ Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY.
¹⁷ School of Medicine, Johns Hopkins University, Baltimore, Md.
¹⁸ National Institute of Allergy and Infectious Diseases, Bethesda, Md.
¹⁹ Benioff Center for Microbiome Medicine, Department of Medicine, University of California, San Francisco, Calif; Department of Pediatrics, University of California, San Francisco, Calif. Electronic address: susan.lynch@ucsf.edu.

PMID: 42248217
DOI: 10.1016/j.jaci.2026.05.021

Abstract

Background: Single-nucleotide polymorphisms (SNPs) in the chromosome 17q12-q21 region and, independently, early-life nasal microbiota dominated by Moraxella, Streptococcus, or Haemophilus (MSH) increase risk of chronic wheeze and asthma development.

Objective: We sought to determine whether 17q12-q21 risk SNPs and nasal microbiota interact to modulate childhood wheeze risk.

Methods: Nasal wash samples from 12-month-old infants in 2 birth cohorts, COAST (Childhood Origins of Asthma; n = 180) and URECA (Urban Environment and Childhood Asthma; n = 139), underwent 16S ribosomal RNA variable region 4 sequencing. Nasal microbiota dominated by MSH or Corynebacterium, Dolosigranulum, Staphylococcus, or Bacillus (CDSB) were assessed. Paired blood was genotyped for 9 17q12-q21 risk SNPs. Logistic regression tested interactions between 17q12-q21 SNPs and MSH or CDSB on wheeze risk in the first 3 years of life. A549 lung epithelial cells, CRISPR-edited to encode the rs7216389 risk genotype (rs7216389^TT) were compared to the heterozygous (rs7216389^CT) line using bulk RNA sequencing.

Results: SNPs, particularly those in the ORMDL3 (rs8076131; odds ratio [OR]: 1.72; 95% CI: 1.09-2.71; P_int = .031) and GSDMB (rs2305480; OR: 1.72; 95% CI: 1.09-2.71; P_int = 0.042; and rs7216389; OR: 1.73; 95% CI: 1.09-2.70; P_int = .047) genes, interact with MSH microbiota to increase early-life wheeze risk (false discovery rate P_int = .016 for all), while interactions with CDSB reduce risk. A549 airway epithelial cells homozygous for rs7216389^TT exhibited decreased expression of genes involved in antimicrobial responses and neutrophil recruitment and evidence increased microbial adherence compared with the heterozygous cell line.

Conclusion: Airway microbiota interact with SNPs at the 17q12-q21 locus in genes involved in sphingolipid metabolism and intracellular antimicrobial responses, to modulate wheeze risk.

Keywords: 17q12-q21 risk loci; Airway microbiota; wheeze.