New genetic variants associated with eosinophil cationic protein and eosinophil-derived neurotoxin levels identified through bivariate genome-wide association study

Background: Eosinophils play a key role in the allergic response in asthma by the release of cytotoxic molecules such as eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) that generate epithelium damages. Objective: Our goal was to identify genetic variants influencing ECP and EDN levels. Methods: We conducted univariate and bivariate genome-wide association analyses of ECP and EDN levels measured in plasma in 1018 adults (451 with asthma) from the EGEA cohort using 1000-Genomes imputed SNPs. Results: The univariate analyses detected two genome-wide significant loci associated with ECP on chromosomes 14q11 (rs7141958 located between RNASE3 and RNASE2, P=3.9x10-13) and 18q21 near MC4R (rs9959588, P=1.7x10-9) and one significant locus at 14q11 associated with EDN near RNASE2 (rs67049014, P=1.6x10-12). The bivariate analysis detected the two previous loci plus a third one on 1p31 (rs57716204 in AK4, P=1.6x10-8). Fine-mapping of these regions, based on bivariate conditional analysis, showed that the 14q11 region contained three distinct signals located 76kb apart: the lead SNP rs67049014 and two other SNPs, rs76185655 and rs28525131. Interrogation of eQTL databases showed that the lead SNP was associated with the expression of RNASE2, RNASE3 and METTL17 (P Conclusion: The joint analysis of biomarkers involved in the same pathway can increase power to detect new loci and can help refining associated regions. Replication of these results is ongoing.