IL4Rα和ADAM33作为哮喘急性加重和2型炎症内型的遗传标志物。
IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype.
作者信息
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
机构信息
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kinki Hokuriku Airway disease Conference (KiHAC), Sayama, Japan.
出版信息
Clin Exp Allergy. 2017 Aug;47(8):998-1006. doi: 10.1111/cea.12927. Epub 2017 Apr 21.
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 (%FEV <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.
背景
成人哮喘急性加重易感性的遗传标志物仍不明确。
目的
确定哮喘急性加重的遗传标志物，尤其是在2型炎症内型患者中。
方法
在这项对参加近畿北陆气道疾病会议多中心研究的患者进行的观察性研究中，确定了入组后2年内需要全身使用糖皮质激素的急性加重频率及相关危险因素。对于遗传标志物分析，纳入了白细胞介素-4受体α（IL4RA）rs8832以及解整合素和金属蛋白酶33（ADAM33）的S_2（rs528557）、T_1（rs2280091）、T_2（rs2280090）和V_4（rs2787094）变体。分析中考虑了入组时血清骨膜蛋白水平升高（≥95 ng/mL，定义为2型炎症内型）。
结果
在入组后成功随访2年的217例患者中，60例在这2年内至少出现1次哮喘急性加重。气流受限（%FEV<80%）和近期急性加重被确定为急性加重的风险标志物，而非遗传变体。共有27例患者表现为2型炎症内型（入组时血清骨膜蛋白≥95 ng/mL）及随后的急性加重；这些患者的危险因素经多因素分析为气流受限（比值比，6.51；95%置信区间（CI）：2.37 - 18.6；P = 0.0003）、IL4RA rs8832的GG基因型（比值比，4.01；95%CI：1.47 - 11.0；P = 0.007）以及ADAM33 T_2的A等位基因（比值比，2.81；95%CI：1.05 - 7.67；P = 0.04）。此外，IL4RA rs8832的GG基因型与2型内型相关，而ADAM33 T_2的A等位基因与嗜酸性粒细胞/2型和中性粒细胞炎症的混合类型相关。
结论及临床意义
IL4RA和ADAM33变体可能是2型炎症内型哮喘急性加重的风险标志物。精确的内型分型可能有助于识别哮喘急性加重的遗传风险标志物。
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