Atopic asthma lowers nasal mucosal sphingolipids

Genetic variations at the 17q21 asthma-risk locus regulate the expression of gasdermin B (GSDMB) and ORMDL3, influencing inflammatory responses and sphingolipid metabolism. While asthma-associated 17q21 variations are known to affect ORMDL3 expression in immune and airway smooth muscle cells, its role in airway epithelial sphingolipid metabolism remains unclear. We investigated whether asthma and 17q21 genetic variations influence sphingolipid composition in the upper respiratory tract and how immune vs. epithelial cells contribute to this process. Sphingolipid profiles were analyzed in nasal fluid and blood from children with and without asthma. We also examined gene expression and sphingolipid composition in nasal epithelial cells and PBMCs from healthy adults homozygous for the rs7216389 C/C and T/T (asthma-risk) genotypes. Children with atopic asthma exhibited lower nasal fluid sphingolipids, including sphinganine, dihydroceramides, and ceramides, independent of corticosteroid use or allergic rhinitis. Asthma was further associated with higher plasma sphingolipids and lower blood cell sphingolipids, the latter mirroring patterns in nasal fluid. In PBMCs, the T allele increased ORMDL3 expression, suppressing de novo sphingolipid synthesis. However, in nasal epithelial cells, the T allele mainly increased GSDMB and there was no effect on sphingolipid metabolism. These findings establish nasal fluid sphingolipid profiling as a potential marker for atopic asthma and provide evidence of a cell-type-specific effect of 17q21 genetic variants. While ORMDL3-mediated sphingolipid suppression occurs in PBMCs and not airway epithelial cells, its systemic effects may contribute to lower airway sphingolipids in asthma.