Genome-wide analysis of oxylipins and oxylipin profiles in a pediatric population.

ABSTRACT

Background: Oxylipins are inflammatory biomarkers derived from omega-3 and-6 fatty acids implicated in inflammatory diseases but have not been studied in a genome-wide association study (GWAS). The aim of this study was to identify genetic loci associated with oxylipins and oxylipin profiles to identify biologic pathways and therapeutic targets for oxylipins. Methods: We conducted a GWAS of plasma oxylipins in 316 participants in the Diabetes Autoimmunity Study in the Young (DAISY). DNA samples were genotyped using the TEDDY-T1D Exome array, and additional variants were imputed using the Trans-Omics for Precision Medicine (TOPMed) multi-ancestry reference panel. Principal components analysis of 36 plasma oxylipins was used to capture oxylipin profiles. PC1 represented linoleic acid (LA)- and alpha-linolenic acid (ALA)-related oxylipins, and PC2 represented arachidonic acid (ARA)-related oxylipins. Oxylipin PC1, PC2, and the top five loading oxylipins from each PC were used as outcomes in the GWAS (genome-wide significance: p < 5×10-8). Results: The SNP rs143070873 was associated with (p < 5×10-8) the LA-related oxylipin 9-HODE, and rs6444933 (downstream of CLDN11) was associated with the LA-related oxylipin 13 S-HODE. A locus between MIR1302-7 and LOC100131146, rs10118380 and an intronic variant in TRPM3 were associated with the ARA-related oxylipin 11-HETE. These loci are involved in inflammatory signaling cascades and interact with PLA2, an initial step to oxylipin biosynthesis. Conclusion: Genetic loci involved in inflammation and oxylipin metabolism are associated with oxylipin levels.