A Large-Scale, Consortium-Based Genomewide Association Study of Asthma

Abstract

BACKGROUND Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. METHODS We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. RESULTS We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P =3×10−9); rs9273349 on chromosome 6, implicating HLA-DQ (P = 7×10−14); rs1342326 on chromosome 9, flanking IL33 (P = 9×10−10); rs744910 on chromosome 15 in SMAD3 (P = 4×10−9); and rs2284033 on chromosome 22 in IL2RB (P = 1.1×10−8). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P = 6×10−23). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. CONCLUSIONS Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)

Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children

“…A subgroup of BAMSE children were also included in the multinational GABRIEL study, and based on genome-wide data, only 3.7% of the children were removed from the GABRIEL study because of potential extra-European ancestry. 28 Taken together, this indicates that population stratification very likely is a minor problem in BAMSE (although subtle stratification could still occur).…”

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

“…12,13 We were curious if an allergic phenotype could be playing a role in the antitumor response observed. Accordingly, we analyzed the cytokine expression patterns from the peritoneal cells derived from IL-33 treated vs control mice.…”

“…30 Increased secretion of IL-33 is a characteristic finding in the pathogenesis of allergy 12,31 and asthma. 13,32,33 In our ovarian cancer tumor model the local increase in IL-33 resulted in a IL5 + IL-13 + skewing of CD4 + T-cells and recruitment and activation of eosinophils, similar to allergic disease. This allergic response differed from a classical regulatory Th2 response in that there was a general downregulation of IL-10.…”

17q21 variant increases the risk of exacerbations in asthmatic children despite inhaled corticosteroids use

“…Variation within the 17q21 locus is the strongest genetic determinant for childhood‐onset asthma 2. Recently, the influence of this locus on treatment outcomes has been shown in several studies 3, 4.…”

“…Altered expression of ORMDL3 and GSDMB by 17q21 locus variants may play a key role in childhood asthma onset 2, 7. Two 17q21 asthma‐risk variants (rs4065275 and rs12936231) in high linkage disequilibrium (LD) with rs7216389 were reported to switch CTCF‐binding sites that resulted in increased expression of ORMDL3 in CD4+ T cells which subsequently reduced interleukin‐2 production 8…”