A Large-Scale Genomewide Association Study of Asthma

Asthma is a disease with a high prevalence and a chronic relapsing course. There are therapies available to treat mild asthma, but severe asthma remains difficult to treat. The societal cost of the disease is substantial, including direct medical costs as well as indirect costs such as lost productivity. According to researchers, asthma runs in families; the inheritability of asthma has been estimated as 60%. Genetic studies provide a means of identifying the causes of asthma as well as targets that can be used to treat it. The GABRIEL (Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community) Consortium found in an earlier, small genomewide association study that multiple markers on chromosome 17q21 were strongly and reproducibly associated with childhood-onset asthma. That first-generation study was followed by a study utilizing a sample 10 times larger. Results of the larger study, including analyses of later-onset and occupational asthma in addition to childhood-onset asthma, were reported in the New England Journal of Medicine [2010;363(13):1211-1221]. The genomewide association study utilized data on 10,365 case studies and 16,110 controls recruited from 23 previous studies. The study used random effects pooled analysis to test for association in the overall study population and in subgroups of patients with childhood-onset asthma (asthma that developed prior to 16 years of age), later-onset asthma, severe asthma, and occupational asthma. The researchers genotyped 582,892 single-nucleotide polymorphisms (SNPs) associated with asthma and SNPs associated with total serum immunoglobulin (Ig)E levels. The strongest association on chromosome 2 was with an SNP within the IL18R1 gene (rs3771166) (P=3.4×10–9; odds ratio, 0.87). IL18R1 is in close proximity to IL1RL1, which also contained SNPs, showing significant association with asthma. There was also strong evidence of association in the overall sample in a locus centered on rs9273349 in the HLA-DQ region of the major histocompatibility complex gene (P=7×10–14; odds ratio, 1.18). Significant association between disease and rs1342326 (on chromosome 9), flanking the IL33 gene, was also observed (P=9×10–10; odds ratio, 1.20). Other SNPs showing significant association with disease were rs744910 on chromosome 15 (P=4×10–9; odds ratio, 0.89), within the SMAD3 gene, and rs2284033, within IL2RB on chromosome 22 (P=1×10–8; odds ratio, 0.89). Generally, the odds ratios for the observed loci suggested more pronounced effects in childhood-onset asthma compared with later-onset asthma. Association with the ORMDL3/GSDMB locus on chromosome 17q12 was specific to childhood-onset asthma (rs2305480, P=6×10–23; odds ratio, 0.76). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration. Loci strongly associated with IgE levels were not associated with asthma. The researchers did not observe any significant associations that were specific to patients with severe or occupational asthma. Likewise, they did not find any evidence of dominance, or interactions with sex, for any of the loci. In summary, the researchers said that “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.... Elevation of total serum IgE levels has a minor role in the development of asthma.”