Although dysregulated sphingolipid metabolism has been linked to the risk of childhood asthma, the precise sphingolipid classes and/or mechanisms responsible for this association are uncertain. The multifaceted role of sphingolipids in conjunction with other known risk factors for asthma may partially account for the complexity of this relationship.

To identify relationships between sphingolipid metabolism, childhood asthma, and known asthma risk factors.

We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two diverse independent cohorts (VDAART and COPSAC2010). We examined the association of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given the racial differences between two childhood cohorts, association analyses were performed separately and then meta-analyzed.

Overall, elevated circulatory sphingolipids were associated with asthma phenotypes and increased risk factors; however, sphingolipid classes had differential associations with clinical outcomes and/or risk factors. While elevations from ceramides recycling and catabolic pathways were associated with asthma and worse lung function (meta p-value: 1.86E-04 to 2.24E-3), increased ceramide levels were associated with asthma risk factors (meta p-value: 7.75E-5 to 0.013), but not asthma. Further investigation identified interactions between these risk factors and ceramides to affect asthma outcomes.

This study clarifies the complex role of sphingolipid subclasses on asthma and asthma risk factors.