Genome-wide association study to identify genetic determinants of severe asthma

Abstract

BackgroundThe genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p¼1.03310 (À8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p¼5.59310 (À8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Clinically relevant subgroups in COPD and asthma

“…Nevertheless, it is clear that certain asthma subgroups, which vary with age, will require different treatment. Early-onset asthma is often more atopic/allergic, and ORMDL3 polymorphisms exhibit a stronger association with childhood and severe asthma [129,130]. These observations suggest that there are different disease mechanisms in younger patients, which have been partly proven by studies of airway cells.…”

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

“…5), is relevant to the pathophysiology of severe asthma. Single-nucleotide polymorphisms in the genes of IL-33 and T1/ST2, a receptor for IL-33, are associated with severe asthma 6,7 . IL-33 immunoreactivity in the airway smooth muscles cells is enhanced in the patients with severe asthma 8 .…”

Integrated approaches in diagnostics and therapy of allergic diseases

“…Результаты широкомас-штабных геномных исследований доступны на сайте www.genome.gov. Было обнаружено, что мутации в локусе l7q21 связаны с астмой [18], причем эти данные были подтверждены раз-личными исследовательскими коллективами [19][20][21]. Расположенные в локусе l7q21 гены ORMDL3, GSDMB, ZPBP2, и IKZF3 влияют на фолдинг белков, ответственных за поддержа-ние уровня внутриклеточного Ca 2+ , и являются эндогенными индукторами воспаления [22].…”