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

H Sunadome; H Matsumoto; G Petrova; Y Kanemitsu; Y Tohda; T 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

Clin Exp Allergy. 2017 Aug;47(8):998-1006. doi: 10.1111/cea.12927. Epub 2017 Apr 21.

Authors

H Sunadome^{1

2}, H Matsumoto^{1

2}, G Petrova¹, Y Kanemitsu^{1

2}, Y Tohda^{2

3}, T Horiguchi^{2

4}, H Kita^{2

5}, K Kuwabara^{2

4}, K Tomii^{2

6}, K Otsuka^{2

6}, M Fujimura^{2

7}, N Ohkura^{2

7}, K Tomita^{2

3}, A Yokoyama^{2

8}, H Ohnishi^{2

8}, Y Nakano^{2

9}, T Oguma^{2

9}, S Hozawa^{2

10}, T Nagasaki¹, I Ito¹, T Oguma¹, H Inoue¹, T Tajiri¹, T Iwata¹, Y Izuhara¹, J Ono¹¹, S Ohta¹², T Hirota¹³, M Tamari¹³, T Yokoyama¹⁴, A Niimi^{1

2

15}, K Izuhara¹⁶, M Mishima^{1

2}

Affiliations

¹ Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.
³ Department of Respiratory Medicine and Allergology, Faculty of Medicine, Kinki University, Sayama, Japan.
⁴ Department of Respiratory Internal Medicine, Fujita Health University Second Educational Hospital, Nagoya, Japan.
⁵ Department of Respiratory Medicine, Takatsuki Red Cross Hospital, Takatsuki, Japan.
⁶ Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.
⁷ Department of Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
⁸ Department of Hematology and Respiratory Medicine, Kochi University, Kochi, Japan.
⁹ Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.
¹⁰ Hiroshima Allergy and Respiratory Clinic, Hiroshima, Japan.
¹¹ Shino-Test Corporation, Sagamihara, Japan.
¹² Department of Laboratory Medicine, Saga Medical School, Saga, Japan.
¹³ Laboratory for Respiratory and Allergic Diseases, Core for Genomic Medicine, Center for Integrative Medical Sciences, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
¹⁴ Department of Health Promotion, National Institute of Public Health, Wako, Japan.
¹⁵ Division of Respiratory Medicine, Department of Medical Oncology and Immunology, Nagoya City University School of Medical Sciences, Nagoya, Japan.
¹⁶ Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.

PMID: 28326636
DOI: 10.1111/cea.12927

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.

Keywords: asthma; clinical immunology; genetics.

Publication types

Clinical Trial
Multicenter Study
Observational Study

MeSH terms

ADAM Proteins* / blood
ADAM Proteins* / genetics
Adult
Aged
Asthma / blood*
Asthma / drug therapy
Asthma / genetics*
Follow-Up Studies
Genetic Markers
Humans
Interleukin-4 Receptor alpha Subunit* / blood
Interleukin-4 Receptor alpha Subunit* / genetics
Middle Aged
Risk Factors

Substances

Genetic Markers
IL4R protein, human
Interleukin-4 Receptor alpha Subunit
ADAM Proteins
ADAM33 protein, human