TY - JOUR
T1 - IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype
AU - Sunadome, H.
AU - Matsumoto, H.
AU - Petrova, G.
AU - Kanemitsu, Y.
AU - Tohda, Y.
AU - Horiguchi, T.
AU - Kita, H.
AU - Kuwabara, K.
AU - Tomii, K.
AU - Otsuka, K.
AU - Fujimura, M.
AU - Ohkura, N.
AU - Tomita, K.
AU - Yokoyama, A.
AU - Ohnishi, H.
AU - Nakano, Y.
AU - Oguma, T.
AU - Hozawa, S.
AU - Nagasaki, T.
AU - Ito, I.
AU - Oguma, T.
AU - Inoue, H.
AU - Tajiri, T.
AU - Iwata, T.
AU - Izuhara, Y.
AU - Ono, J.
AU - Ohta, S.
AU - Hirota, T.
AU - Tamari, M.
AU - Yokoyama, T.
AU - Niimi, A.
AU - Izuhara, K.
AU - Mishima, M.
PY - 2017/8
Y1 - 2017/8
N2 - 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 was 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 (CI): 2.37–18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47–11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05–7.67; P=.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.
AB - 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 was 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 (CI): 2.37–18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47–11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05–7.67; P=.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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U2 - 10.1111/cea.12927
DO - 10.1111/cea.12927
M3 - Article
C2 - 28326636
AN - SCOPUS:85018630765
VL - 47
SP - 998
EP - 1006
JO - Clinical and Experimental Allergy
JF - Clinical and Experimental Allergy
SN - 0954-7894
IS - 8
ER -