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

H. Sunadome; H. Matsumoto; G. Petrova; Y. Kanemitsu; Y. Tohda; Takahiko Horiguchi; H. Kita; K. Kuwabara; K. Tomii; K. Otsuka; M. Fujimura; N. Ohkura; K. Tomita; A. Yokoyama; H. Ohnishi; Y. Nakano; T. Oguma; S. Hozawa; T. Nagasaki; I. Ito; T. Oguma; H. Inoue; T. Tajiri; T. Iwata; Y. Izuhara; J. Ono; S. Ohta; T. Hirota; M. Tamari; T. Yokoyama; A. Niimi; K. Izuhara; M. Mishima

doi:10.1111/cea.12927

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

H. Sunadome
, H. Matsumoto
, G. Petrova
, Y. Kanemitsu
, Y. Tohda
, Takahiko Horiguchi
, H. Kita
, K. Kuwabara
, K. Tomii
, K. Otsuka
, M. Fujimura
, N. Ohkura
, K. Tomita
, A. Yokoyama
, H. Ohnishi
, Y. Nakano
, T. Oguma
, S. Hozawa
, T. Nagasaki
, I. Ito

T. Oguma, H. Inoue, T. Tajiri, T. Iwata, Y. Izuhara, J. Ono, S. Ohta, T. Hirota, M. Tamari, T. Yokoyama, A. Niimi, K. Izuhara, M. Mishima

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	998-1006
Number of pages	9
Journal	Clinical and Experimental Allergy
Volume	47
Issue number	8
DOIs	https://doi.org/10.1111/cea.12927
Publication status	Published - 08-2017

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

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10.1111/cea.12927

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Sunadome, H., Matsumoto, H., Petrova, G., Kanemitsu, Y., Tohda, Y., Horiguchi, T., Kita, H., Kuwabara, K., Tomii, K., Otsuka, K., Fujimura, M., Ohkura, N., Tomita, K., Yokoyama, A., Ohnishi, H., Nakano, Y., Oguma, T., Hozawa, S., Nagasaki, T., ... Mishima, M. (2017). IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype. Clinical and Experimental Allergy, 47(8), 998-1006. https://doi.org/10.1111/cea.12927

@article{0f739454eae74731a0965047fed3135d,

title = "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 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{\textendash}18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95\% CI: 1.47{\textendash}11.0; P=.007), and A allele of ADAM33 T\_2 (odds ratio, 2.81; 95\% CI: 1.05{\textendash}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.",

keywords = "asthma, clinical immunology, genetics",

author = "H. Sunadome and H. Matsumoto and G. Petrova and Y. Kanemitsu and Y. Tohda and Takahiko Horiguchi and H. Kita and K. Kuwabara and K. Tomii and K. Otsuka and M. Fujimura and N. Ohkura and K. Tomita and A. Yokoyama and H. Ohnishi and Y. Nakano and T. Oguma and S. Hozawa and T. Nagasaki and I. Ito and T. Oguma and H. Inoue and T. Tajiri and T. Iwata and Y. Izuhara and J. Ono and S. Ohta and T. Hirota and M. Tamari and T. Yokoyama and A. Niimi and K. Izuhara and M. Mishima",

note = "Publisher Copyright: {\textcopyright} 2017 John Wiley \& Sons Ltd",

year = "2017",

month = aug,

doi = "10.1111/cea.12927",

language = "English",

volume = "47",

pages = "998--1006",

journal = "Clinical and Experimental Allergy",

issn = "0954-7894",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "8",

}

Sunadome, H, Matsumoto, H, Petrova, G, Kanemitsu, Y, Tohda, Y, Horiguchi, T, Kita, H, Kuwabara, K, Tomii, K, Otsuka, K, Fujimura, M, Ohkura, N, Tomita, K, Yokoyama, A, Ohnishi, H, Nakano, Y, Oguma, T, Hozawa, S, Nagasaki, T, Ito, I, Oguma, T, Inoue, H, Tajiri, T, Iwata, T, Izuhara, Y, Ono, J, Ohta, S, Hirota, T, Tamari, M, Yokoyama, T, Niimi, A, Izuhara, K & Mishima, M 2017, 'IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype', Clinical and Experimental Allergy, vol. 47, no. 8, pp. 998-1006. https://doi.org/10.1111/cea.12927

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, Takahiko

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.

KW - asthma

KW - clinical immunology

KW - genetics

UR - https://www.scopus.com/pages/publications/85018630765

UR - https://www.scopus.com/pages/publications/85018630765#tab=citedBy

U2 - 10.1111/cea.12927

DO - 10.1111/cea.12927

M3 - Article

C2 - 28326636

AN - SCOPUS:85018630765

SN - 0954-7894

VL - 47

SP - 998

EP - 1006

JO - Clinical and Experimental Allergy

JF - Clinical and Experimental Allergy

IS - 8

ER -

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

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