medwireNews: A genome-wide association study (GWAS) has identified novel genetic variants associated with the risk of developing moderate-to-severe asthma, a substantial proportion of which are also associated with mild asthma susceptibility.
“[T]o our knowledge, this is the largest genome-wide association study of moderate-to-severe asthma published to date”, say Ian Sayers (University of Nottingham, UK) and fellow researchers in The Lancet Respiratory Medicine.
Using a two-stage case-control study design, the team carried out a GWAS using data from 5135 patients with moderate-to-severe asthma and 25,675 controls – defined as individuals without physician-diagnosed asthma, rhinitis, eczema, allergy, emphysema or chronic bronchitis – from two UK cohorts in stage 1, and independent variants were validated in a separate UK cohort of 5414 cases and 21,471 controls in stage 2.
Sayers and colleagues identified a total of 24 signals that were significantly associated with moderate-to-severe asthma risk, including “several signals” in genes related to innate or adaptive immunity. Three novel variants were reported: rs10905284 in the GATA3 gene; rs11603634 in the MUC5AC region; and rs560026225 in a region including KIAA1109.
The investigators note that the remaining 21 (88%) of the 24 signals “have previously been reported in studies that predominantly assessed samples from patients with mild asthma, suggesting a substantial shared genetic architecture between mild and moderate-to-severe asthma.”
While two of the novel variants were significantly associated with all types of asthma, there was no significant association between the MUC5AC variant and asthma risk in a previous GWAS that included patients with mild asthma, indicating that “[t]he rs11603634 signal is specific to moderate-to-severe asthma”, say the researchers.
They also identified an association between the rs11603634 variant and elevated expression of MUC5AC messenger (m)RNA in bronchial epithelial brush samples, and levels of MUC5AC mRNA were significantly increased among patients with severe asthma relative to controls.
These findings “[add] to evidence of alterations in the airway epithelium and mucin dysregulation in more severe forms of asthma, and potentially [support] specific targeting of MUC5AC expression and induction in severe asthma”, remark Sayers and colleagues.
Writing in an accompanying comment, Rachel Nadif (INSERM, Villejuif, France) says that the “well-designed study […] gives new insights into the genes and their respective pathways associated with moderate-to-severe asthma.”
She believes that research now “needs to go further to understand the interactions between these pathways and identify potential therapeutic targets in moderate-to-severe asthma.”
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