IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype
IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype
复制标题
DOI：
10.1111/cea.12927
复制
发表时间：
2017-08-01
影响因子：
6.1
通讯作者：
Mishima, M.
中科院分区：
文献类型：
--
作者：
Sunadome, H.;Matsumoto, H.;Mishima, M.
背景：成人哮喘加重易感性的遗传标记尚不清楚。目的：确定哮喘加重的遗传标记，特别是在2型炎症内型患者中。方法：在这项观察性研究中，纳入了近畿北陆气道疾病会议多中心研究的患者，确定了入组后2年内需要全身皮质类固醇的发作频率和相关危险因素。遗传标记分析包括白细胞介素-4受体a (IL4RA) rs8832和分解素和金属蛋白酶33 (ADAM33) S_2 （rs528557）、T_1 （rs2280091）、T_2 （rs2280090）和V_4 （rs2787094）变异。在分析中考虑了入组时血清骨膜素水平升高（>= 95 ng/mL，定义为2型炎症内型）。结果：入选后成功随访2年的217例患者中，60例患者在2年内至少出现一次哮喘发作。气流受限（入组时% FEV1 = 95 ng/mL）和随后的加重；这些患者的危险因素是气流受限(优势比，6.51；95%可信区间（CI）： 2.37-18.6；P= 0.0003)、IL4RA rs8832 GG基因型（优势比4.01;95% CI: 1.47 ~ 11.0； P= 0.007）、ADAM33 T_2 A等位基因（优势比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/ 2型和嗜中性粒细胞炎症混合型相关。结论及临床意义：IL4RA和ADAM33变异可能是2型炎性内型患者哮喘加重的危险标志。精确的内分型可能有助于识别哮喘恶化的遗传风险标记。
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 a (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 = 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.