IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype.
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
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.
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.
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http://orcid.org/0000-0002-4617-2348
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Sunadome
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.
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Matsumoto
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Petrova
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.
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Kanemitsu
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Respiratory Medicine and Allergology, Faculty of Medicine, Kinki University, Sayama, Japan.
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Tohda
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Respiratory Internal Medicine, Fujita Health University Second Educational Hospital, Nagoya, Japan.
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Horiguchi
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Respiratory Medicine, Takatsuki Red Cross Hospital, Takatsuki, Japan.
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Kita
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Respiratory Internal Medicine, Fujita Health University Second Educational Hospital, Nagoya, Japan.
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Kuwabara
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.
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Tomii
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.
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Otsuka
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
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Fujimura
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
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Ohkura
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Respiratory Medicine and Allergology, Faculty of Medicine, Kinki University, Sayama, Japan.
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Tomita
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Hematology and Respiratory Medicine, Kochi University, Kochi, Japan.
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Yokoyama
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Department of Hematology and Respiratory Medicine, Kochi University, Kochi, Japan.
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Ohnishi
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.
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Nakano
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.
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Oguma
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Hiroshima Allergy and Respiratory Clinic, Hiroshima, Japan.
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Hozawa
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Nagasaki
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Ito
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Oguma
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Inoue
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Tajiri
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Iwata
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Izuhara
Shino-Test Corporation, Sagamihara, Japan.
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Ono
Department of Laboratory Medicine, Saga Medical School, Saga, Japan.
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Ohta
Laboratory for Respiratory and Allergic Diseases, Core for Genomic Medicine, Center for Integrative Medical Sciences, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
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Hirota
Laboratory for Respiratory and Allergic Diseases, Core for Genomic Medicine, Center for Integrative Medical Sciences, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
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Tamari
Department of Health Promotion, National Institute of Public Health, Wako, Japan.
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Yokoyama
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.|Division of Respiratory Medicine, Department of Medical Oncology and Immunology, Nagoya City University School of Medical Sciences, Nagoya, Japan.
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Niimi
Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.
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Izuhara
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.
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Mishima
D051722:ADAM Proteins / Q000097:blood / Q000235:genetics; D000328:Adult; D000368:Aged; D001249:Asthma / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D005500:Follow-Up Studies; D005819:Genetic Markers; D006801:Humans; D053662:Interleukin-4 Receptor alpha Subunit / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D012307:Risk Factors
D005819:Genetic Markers; C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; D051722:ADAM Proteins; C450441:ADAM33 protein, human
asthma; clinical immunology; genetics