Hexosyl C6-phytoCeramide at birth is a risk factor for atopic dermatitis in boys in two consecutive birth cohorts

Background Serum levels of metabolites, nutrients, and toxins (MNTs) have been associated with atopic dermatitis (AD). We aimed to identify and replicate associations between AD manifestations across multiple follow-ups in two consecutive cohorts and their association with MNTs in maternal serum (generation F0) and MNTs in cord blood serum (generation F2). Methods Across two generations (F1: n = 583; F2: n = 236), we tested 6,908 MNTs for associations with the occurrence of AD, stratifying by sex. AD was defined as chronically relapsing, itchy dermatitis assessed from age 1–18 years in F1 and age 1–10 years in F2. To explore the underlying mechanisms, we additionally investigated genetic polymorphisms, gene expression, and DNA methylation. Results We identified and replicated one specific MNT, hexosyl C6-phytoCeramide (H6pCer), which conferred an approximately twofold increased AD risk in males across both generations (Risk Ratio [95% CI] F1: 2.46 [1.27, 4.77]; F2: 1.84 [1.06, 3.17]), but not in females. Furthermore, three SPTLC3 SNPs were associated with increased AD risk only in male participants (F1 and F2). Adjusting for genetic polymorphisms did not attenuate the association between H6pCer and AD, suggesting that H6pCer may result from outside the analyzed genetic framework, potentially from the microbiome. Conclusion Elevated birth levels of a short-chain ceramide and variations in related genes independently predict increased AD risk in males, but not females. Although microbiome profiles were not directly evaluated, these findings highlight sex-specific sphingolipid pathways and generate hypotheses regarding potential microbial influence in AD pathogenesis.