Genetic insights into moderate-to-severe asthma
Authors: Rachel Nadif
Journal: The Lancet Respiratory Medicine (2018)

Asthma is a heterogeneous disease, composed of many phenotypes that have common clinical characteristics but which have different risk factors and responses to treatment. 5–10% of people with asthma are considered to have severe asthma, which is often associated with poor control and response to treatment. Severe asthma is itself a heterogeneous disease encompassing several clinical phenotypes that might share common pathophysiological mechanisms, so-called asthma endotypes.1Wenzel SE Asthma phenotypes: the evolution from clinical to molecular approaches.Nat Med. 2012; 18: 716-725Crossref PubMed Scopus (1621) Google Scholar New therapies targeting specific pathways have been approved for severe asthma (eg, anti-IgE and anti-interleukin 5), and others directed against type 2 cytokines are being investigated,2Fajt ML Wenzel SE Development of new therapies for severe asthma.Allergy Asthma Immunol Res. 2017; 9: 3-14Crossref PubMed Scopus (79) Google Scholar but the results have not always met expectations—eg, tralokinumab for interleukin 13.3Russell RJ Chachi L FitzGerald JM et al.Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.Lancet Respir Med. 2018; 6: 499-510Summary Full Text Full Text PDF PubMed Scopus (91) Google Scholar A better understanding of the pathophysiological mechanisms underlying severe asthma is necessary to improve disease management. Asthma is a genetic disease, and, to date, 38 loci and genomic regions have been identified through genome-wide association studies, but they account for a small proportion of the genetic component of asthma.4Willis-Owen SAG Cookson WOC Moffatt MF The genetics and genomics of asthma.Annu Rev Genomics Hum Genet. 2018; 19: 223-246Crossref PubMed Scopus (36) Google Scholar To our knowledge, no study has succeeded in identifying genes associated with severe asthma with genome-wide significance, which could be a step towards the identification of new targets for therapy. In The Lancet Respiratory Medicine, Nick Shrine and colleagues5Shrine N Portelli MA John C et al.Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study.Lancet Respir Med. 2018; (published online Dec 11.)http://dx.doi.org/10.1016/S2213-2600(18)30389-8Summary Full Text Full Text PDF PubMed Scopus (120) Google Scholar report the results of the largest genome-wide association study of moderate-to-severe asthma to date. The study used a two-stage case-control design, including 10 549 cases and 47 146 controls of European ancestry, and identified three novel signals among 24 genome-wide signals that they identified as significant: rs10905284 in GATA3, rs560026225 near KIAA1109, and rs11603634 in the MUC5AC region. The MUC5AC signal was not significant when analyses included mild asthma. The other 21 signals had been identified in previous studies on asthma, which included some focusing on asthma that was severe or difficult to treat. Together with the medical literature, the results of this study suggest that mild and moderate-to-severe asthma share part of the same genetic architecture. Furthermore, by exploiting biological knowledge from various datasets, the results strongly support that the genes underlying the signals are involved in innate or adaptive immunity, type 2 inflammation, and mucin dysregulation pathways. Interestingly, beyond the crucial point of having a sufficient number of cases to detect signals that have genome-wide significance, Shrine and colleagues replicated almost all signals reported in previous studies. This successful replication might be partially explained by their definition of cases as having moderate-to-severe asthma if they were taking appropriate medication. This choice of inclusion criterion might have overcome the limitation of the heterogeneity in the definition of the severity of asthma that is frequently faced by researchers when pooling studies. Severity of asthma is also known to be characterised by comorbidities, especially traits related to allergies. Shrine and colleagues acknowledge that their study design could have enhanced the probability of detecting signals associated with allergic comorbidities. This definition of moderate-to-severe asthma could be thought to be too large and worthy of improvement, but it fits with a multi-dimensional assessment of asthma severity, including comorbidities, such as was done by the authors.6Gibson PG McDonald VM Management of severe asthma: targeting the airways, comorbidities and risk factors.Intern Med J. 2017; 47: 623-631Crossref PubMed Scopus (28) Google Scholar Overall, these results support the hypothesis that different asthma phenotypes share common underlying pathophysiological mechanisms. A focus on risk factors is also important in the study of severe asthma.6Gibson PG McDonald VM Management of severe asthma: targeting the airways, comorbidities and risk factors.Intern Med J. 2017; 47: 623-631Crossref PubMed Scopus (28) Google Scholar The environment has an important role in the occurrence and aggravation of asthma, but the effects of environmental factors differ according to individuals' genetic predispositions. To date, these complex interactions remain poorly understood, and the study of genes via their interactions with their environment should help identify the underlying pathophysiological mechanisms involved in moderate-to-severe asthma. The three signals highlighted in the study by Shrine and colleagues echo the findings of a review7Saco TV Breitzig MT Lockey RF Kolliputi N Epigenetics of mucus hypersecretion in chronic respiratory diseases.Am J Respir Cell Mol Biol. 2018; 58: 299-309Crossref PubMed Scopus (19) Google Scholar published on the interactions between the allergic inflammation, adaptive immune response, and regulation of MUC5AC and MUC5B in chronic respiratory diseases. Based on these results, research needs to go further to understand the interactions between these pathways and identify potential therapeutic targets in moderate-to-severe asthma. Additional study is needed of the connectivity between GATA3, KIAA1109, and MUC5AC with other genes from the literature, which could be done by combining text mining and clustering, as has previously been done for ten genes in asthma.8Ailem M Role F Nadif M Demenais F Unsupervised text mining for assessing and augmenting GWAS results.J Biomed Inform. 2016; 60: 252-259Crossref PubMed Scopus (15) Google Scholar Clustering also allows the identification of specific groups of patients who share common clinical, demographic, and biological characteristics, whose associations with genetic markers can then be studied. Furthermore, research into the interactions between all the genes involved in the three highlighted pathways and risks factors on moderate and severe asthma phenotypes or on specific groups by use of a pathway-based approach could be of interest. Of course, all these approaches are mutually non-exclusive and would supplement the genome-wide association study. Finally, a recently published study9Pavord ID Beasley R Agusti A et al.After asthma: redefining airways diseases.Lancet. 2018; 391: 350-400Summary Full Text Full Text PDF PubMed Scopus (572) Google Scholar on airway diseases recommended deconstructing the disease into its components before planning treatment, focusing on traits that are identifiable and treatable. Endotyping can identify groups of patients with moderate-to-severe asthma who have a good likelihood of therapeutic success. The need to develop therapies based on endotypes has been discussed for patients with chronic rhinosinusitis, a comorbidity of asthma.10Bachert C Zhang N Hellings PW Bousquet J Endotype-driven care pathways in patients with chronic rhinosinusitis.J Allergy Clin Immunol. 2018; 141: 1543-1551Summary Full Text Full Text PDF PubMed Scopus (111) Google Scholar Shrine and colleagues should be congratulated for their well-designed study that gives new insights into the genes and their respective pathways associated with moderate-to-severe asthma. I declare no competing interests. Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association studyWe found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population. Full-Text PDF Open Access