Genetic regulation of<i>IL1RL1</i>methylation and IL1RL1-a protein levels in asthma

Abstract

<i>Interleukin-1 receptor-like 1</i> (<i>IL1RL1</i>) is an important asthma gene. (Epi)genetic regulation of <i>IL1RL1</i> protein expression has not been established. We assessed the association between <i>IL1RL1</i> single nucleotide polymorphisms (SNPs), <i>IL1RL1</i> methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of <i>IL1RL1</i> 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 <i>IL1RL1</i> 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 <i>IL1RL1</i> 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).<i>IL1RL1</i> asthma-risk SNPs strongly associated with <i>IL1RL1</i> methylation (rs1420101; p=3.7×10^-16) and serum IL1RL1-a levels (p=2.8×10^-56). <i>IL1RL1</i> 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 <i>IL1RL1</i> SNPs strongly regulate <i>IL1RL1</i> methylation and serum IL1RL1-a levels, yet neither these <i>IL1RL1-</i>methylation CpG sites nor IL1RL1-a levels are associated with asthma.