Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia

Abstract

Genome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt to replicate the association with four loci reported previously (ORMDL3, PDE4D, DENND1B and IL1RL1). Genome-wide association analyses of individual single nucleotide polymorphisms (SNPs), rare copy number variants (CNVs) and overall CNV burden were carried out in 986 asthma cases and 1846 asthma-free controls from Australia. The most-associated locus in the SNP analysis was ORMDL3 (rs6503525, P¼4.8Â10 À7 ). Five other loci were associated with Po10 À5 , most notably the chemokine CXC motif ligand 14 (CXCL14) gene (rs31263, P¼7.8Â10 À6 ). We found no evidence for association with the specific risk variants reported recently for PDE4D, DENND1B and ILR1L1. However, a variant in IL1RL1 that is in low linkage disequilibrium with that reported previously was associated with asthma risk after accounting for all variants tested (rs10197862, gene wide P¼0.01). This association replicated convincingly in an independent cohort (P¼2.4Â10 À4 ). A 300-kb deletion on chromosome 17q21 was associated with asthma risk, but this did not reach experiment-wide significance. Asthma cases and controls had comparable CNV rates, length and number of genes affected by deletions or duplications. In conclusion, we confirm the association between asthma risk and variants in ORMDL3 and identify a novel risk variant in IL1RL1. Follow-up of the 17q21 deletion in larger cohorts is warranted.

Relationship between the 17q21 locus and adult asthma in a Czech population

“…Since then, further studies have replicated associations with SNPs on 17q21 and asthma [1-3,9 -15,25-27] (Table S1) showing that the association is primarily with childhood-onset asthma [3,14,26,28] and is more pronounced in children with exacerbations, respiratory viral infections, severe asthma, and exposure to environmental tobacco smoke in infancy [3,10,[25][26][29][30]. This case-control study tested the association of the four selected SNPs (rs17608925, rs12603332, rs8076131, and rs3169572) with atopic asthma and a number of quantitative asthma/atopy traits in the adult Czech Caucasian population.…”

17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells

“…Originally the 17q21 locus was strongly linked to asthma susceptibility, which was confirmed by multiple other GWAS studies in diverse ethnic populations151617181920 and in a large study of individuals with severe asthma21. Subsequently, various other autoimmune diseases such as type 1 diabetes, Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus and primary biliary cirrhosis were all found to share the same 17q21 risk locus, suggesting its broader implication in several diseases234567822; however, an important distinction is that the risk alleles for asthma paradoxically have a protective effect for the autoimmune diseases studied2345622.…”

Stress and asthma: Novel insights on genetic, epigenetic, and immunologic mechanisms

“…This “missing heritability” of asthma may be explained by unaccounted phenotypic heterogeneity 19 , structural variation (e.g. copy number variants) 20 , rare genetic variants with strong effects 21 , gene-by-gene interactions (epistasis) 21 gene-by-environment interactions 22,23 or epigenetic mechanisms such as DNA methylation 24 or microRNAs 25 . Few studies have examined the role of genetic or epigenetic mechanisms on stress-related asthma.…”