Novel Il33 gene polymorphisms associated with asthma are associated with resistance to schistosoma mansoni

Abstract

Rationale IL33 is one of the most consistently associated candidate genes for asthma identified by GWAS in diverse ethnic groups. We previously demonstrated GWAS SNPs associated with asthma were also associated with asthma and schistosomiasis in African-ancestry Brazilians (356 nuclear families) living in Conde, Bahia, a region endemic for Schistosoma mansoni. We expanded these studies to include an additional set of variants selected from a recently completed deep-resequencing study in an African American asthma cohort.

Methods Targeted resequencing in 77 kb around the IL33 gene in 183 asthmatic cases and 192 controls yielded 9 SNPs associated with asthma, these were genotyped in 772 Brazilian samples using TaqMan. Hardy-Weinberg testing was performed using PLINK and pairwise linkage disequilibrium was estimated using Haploview. Genetic association tests were performed using generalized estimating equation under a dominant model on the soluble adult worm antigen (SWAP)-specific IgE:IgG4 ratio (a measure of S. mansoniresistance) adjusting for age, gender, water contact index, and African admixture.

Results Three SNPs were associated with higher SWAP-specific IgE:IgG4 (P=0.001, 0.004, 0.020, respectively). The most significant SNP mapped to intron 1, and the allele conferring asthma risk in the African American cohort also conferred protection against schistosomiasis. This intronic variant is independent from the previously reported GWAS co-associations (R2=0.133).

Conclusions Additional genotyping of IL33 variants identified by targeted sequencing demonstrated a novel locus that co-associates with both asthma and schistosomiasis in populations of African ancestry.