Circadian rhythmicity of sphingolipids in allergic asthma

Abstract

Background: Genome-wide association studies have reproducibly linked the Orosomucoid-like 3 (ORMDL3) gene to risk of asthma. ORMDL3 regulates sphingolipid synthesis and is rhythmically expressed. There is mounting evidence supporting the role of sphingolipid metabolism in asthma pathogenesis. Since asthma is a highly rhythmic disease, we investigated whether serum sphingolipids vary by time of day in patients with and without asthma. Method(s): Ten individuals with allergic asthma (AA) and 10 healthy non-smokers (HV) completed overnight visits. Blood samples were taken every 6 hours over 24hr. Targetted lipidomics analysis was performed using ultra performance liquid chromatography with tandem mass spectrometry. Result(s): Five ceramides (CER) at 4am and two at 4pm were significantly higher in AA than HV (p<0.05). Five CER were rhythmic in AA with peak at 4am (p<0.05). No sphingolipids were rhythmic in HV. Eighteen sphingolipids were significantly higher in non-eosinophilic asthmatics (NEA)(<0.3x10^9) (n=5) than non-eosinophilic HV at 4am. There were no difference in sphingolipid levels between eosinophilic asthma (EA)(n=4) and eosinophilic controls (n=3). Five sphingolipids were higher in EA than in NEA at distinct time points. Conclusion(s): Sphingolipids in asthma acquire circadian rhythmicity. Further study is needed to gain mechanistic insight into the role of clock control in ORMDL3-sphingolipid pathway, which may lead to novel therapeutic approach in asthma.