H Sunadome1,2, H Matsumoto1,2, G Petrova1, Y Kanemitsu1,2, Y Tohda2,3, T Horiguchi2,4, H Kita2,5, K Kuwabara2,4, K Tomii2,6, K Otsuka2,6, M Fujimura2,7, N Ohkura2,7, K Tomita2,3, A Yokoyama2,8, H Ohnishi2,8, Y Nakano2,9, T Oguma1, S Hozawa2,10, 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 Niimi1,2,15, K Izuhara16, M Mishima1,2. 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.
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.
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 IL4RArs8832 (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 IL4RArs8832 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.
Authors: Anet Kivihall; Alar Aab; Jerzy Soja; Krzysztof Sładek; Marek Sanak; Alan Altraja; Bogdan Jakiela; Grazyna Bochenek; Ana Rebane Journal: Clin Transl Allergy Date: 2019-11-27 Impact factor: 5.871