Nasal sphingolipids are decreased in children with asthma

<bold>Rationale:</bold> Asthma-associated genetic variations at the 17q21 locus can affect sphingolipid de novo synthesis through increased expression of ORMDL3, as a regulator of sphingolipid synthesis. Altered sphingolipid de novo synthesis may contribute to the pathogenesis of childhood asthma. It is unclear if ORMDL3 is relevant in the respiratory tract as asthma-associated 17q21 polymorphisms affect mainly the expression of gasdermin B (GSDMB) in respiratory epithelial cells. However, there is limited data on the sphingolipid composition in the respiratory tract of children. <bold>Methods:</bold> Nasal epithelial lining fluid was collected from 216 children (133 with asthma, 83 without asthma) ages 5 to 18 years. Thirty-two sphingolipids were analyzed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) in the nasal fluid, in nasal epithelial cells grown at air-liquid interface and peripheral blood mononuclear cells from individuals homozygous for asthma-risk and non-risk alleles of the 17q21 single nucleotide polymorphism rs7216389 that affects sphingolipid de novo synthesis. <bold>Results:</bold> Sphinganine and dihydroceramides that are exclusively generated through de novo synthesis were decreased in children with asthma compared to healthy controls. Expression of GSDMB in nasal epithelial cells grown at air-liquid interface and peripheral blood mononuclear cells from individuals homozygous for asthma-risk alleles was increased 2-fold compared to cell homozygous for the non-risk allele whereas ORMDL3 expression was increased by 10%. <bold>Conclusion:</bold> Nasal fluid sphingolipids can distinguish children with and without asthma, suggestive of an effect of ORMDL3 on airway sphingolipids.