Genetic regulation of IL1RL1 methylation and IL1RL1-a protein levels in asthma

Interleukin-1 receptor-like 1; (; IL1RL1; ) is an important asthma gene. (Epi)genetic regulation of; IL1RL1; protein expression has not been established. We assessed the association between; IL1RL1; single nucleotide polymorphisms (SNPs),; IL1RL1; methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of; IL1RL1; SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA; IL1RL1; methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of; IL1RL1; CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101).; IL1RL1; asthma-risk SNPs strongly associated with; IL1RL1; methylation (rs1420101; p=3.7×10; -16; ) and serum IL1RL1-a levels (p=2.8×10; -56; ).; IL1RL1; methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associated; IL1RL1; SNPs strongly regulate; IL1RL1; methylation and serum IL1RL1-a levels, yet neither these; IL1RL1-; methylation CpG sites nor IL1RL1-a levels are associated with asthma.