Lower Nasal Sphingolipids in Pediatric Asthma and Cell-Type-Specific Effects of 17q21 Variants

Genetic variations at the 17q21 asthma-risk locus regulate GSDMB and ORMDL3, influencing inflammatory pathways and sphingolipid metabolism. Although 17q21 variants such as rs7216389 and rs12936231 are associated with ORMDL3 expression in immune and airway smooth muscle cells, their effects on airway epithelial sphingolipids remain unclear.

To determine whether asthma or 17q21 asthma genotypes alter sphingolipid composition in the upper respiratory tract in children, and to define contributions of epithelial versus immune cells.

Sphingolipids were quantified by mass spectrometry in nasal fluid and plasma from children with and without asthma. Nasal epithelial cells and PBMCs from healthy adults homozygous for rs7216389 C/C or T/T (risk) were analyzed for sphingolipid levels and ORMDL3/GSDMB associated gene expression.

Children with atopic asthma had significantly lower nasal dihydroceramides, ceramides, and sphingosine independent of inhaled corticosteroids and allergic rhinitis. Asthma was associated with increased plasma sphingolipids but decreased sphingolipids in blood cells, mirroring nasal findings. In PBMCs, the rs7216389 T allele was associated with increased ORMDL3 expression and suppressed de-novo sphingolipid synthesis. In nasal epithelial cells, the T allele predominantly increased GSDMB expression and did not alter sphingolipid metabolism.

Nasal mucosal sphingolipids are reduced in children with atopic asthma and sphingolipids generated by de-novo sphingolipid synthesis may serve as a noninvasive biomarker of disease. 17q21 risk alleles can exert cell-type-specific effects: ORMDL3-mediated suppression of sphingolipid synthesis occurs in immune cells but not in airway epithelial cells. Systemic immune or inflammatory cell-driven alterations may contribute to reduced airway sphingolipids in asthma.