IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype

Abstract

Background

Genetic markers of susceptibility to asthma exacerbations in adults remain unclear.

Objective

To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype.

Methods

In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors were determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis.

Results

Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV₁ <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval, 2.37 to 18.6; P = 0.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% confidence interval, 1.47 to 11.0; P = 0.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% confidence interval, 1.05 to 7.67; P = 0.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations.

Conclusions and Clinical Relevance

IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.

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