Upper airway microbiome interacts with GSDMB and ORMDL3 asthma risk SNPs to influence early-life wheeze risk.
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 (rs7216389TT) were compared to the heterozygous (rs7216389CT) line using bulk RNA sequencing. RESULTS: SNPs, particularly those in the ORMDL3 (rs8076131; odds ratio [OR]: 1.72; 95% CI: 1.09-2.71; Pint = .031) and GSDMB (rs2305480; OR: 1.72; 95% CI: 1.09-2.71; Pint = 0.042; and rs7216389; OR: 1.73; 95% CI: 1.09-2.70; Pint = .047) genes, interact with MSH microbiota to increase early-life wheeze risk (false discovery rate Pint = .016 for all), while interactions with CDSB reduce risk. A549 airway epithelial cells homozygous for rs7216389TT 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.