Tejwani Vickram, Wang Yifan, Tremblay Lauren Munoz, Azzato Elizabeth, Baldomero Arianne K, Wendt Christine, Attaway Amy, Bowler Russell, Hatipoglu Umur, Hutton Rebecca, Strange Charlie, Wang Xiaofeng, Ortega Victor E, Zein Joe, Stoller James K
Department of Pulmonary and Critical Care Medicine, Integrated Hospital Care Institute, Cleveland Clinic, Cleveland, USA.
Genomic Sciences and Systems Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
Respir Res. 2025 Jul 11;26(1):243. doi: 10.1186/s12931-025-03322-6.
The best described endotype of COPD is alpha-1 antitrypsin (AAT) deficiency, due to a genetic abnormality in the SERPINA1 gene. Common deficient PI variants are the Z and S variants. Homozygotes for the Z allele (PIZZ individuals) carry the genotype most commonly associated with severe AAT deficiency (AATD), but a highly prevalent endotype is the heterozygous state (PIMZ individuals). The effect of PI*MZ status on exacerbations and health care utilization is unknown.
Cleveland electronic health record data was examined to compare healthcare utilization between PIMZ and PIMM individuals. Three outcomes were assessed: moderate COPD exacerbation (defined as short-term steroid prescription), any emergent care (defined as an express care, urgent care, or emergency department visit), and any hospitalization. Models were adjusted for age, sex, race, BMI, smoking status, comorbidity count, liver disease, zip code median income.
4,148 individuals had the PIMM genotype and 308 PIMZ. PIMZ was associated with increased risk for moderate COPD exacerbations (HR [95% CI]: 1.66 [1.27, 2.17]) and hospitalizations (HR [95% CI]: 1.44 [1.19, 1.75]) compared to PIMM. The risk of hospitalization was higher among PIMZ individuals with AAT levels < 90 mg/dL (HR [95% CI]: 1.59 [1.14, 2.23]) but not in those with AAT levels > 90 mg/dL, as compared to PIMM.
Given the high prevalence, PIMZ represents a COPD phenotype that is associated with worse outcomes, inviting additional investigation to identify predictive biomarkers of worse disease and treatable traits. Future prospective studies to better characterize the longitudinal course and healthcare utilization among individuals with a PIMZ genotype.
慢性阻塞性肺疾病（COPD）最典型的内型是α-1抗胰蛋白酶（AAT）缺乏症，这是由SERPINA1基因的遗传异常所致。常见的缺陷性蛋白酶抑制物（PI）变体是Z和S变体。Z等位基因的纯合子（PIZZ个体）携带的基因型最常与严重的AAT缺乏症（AATD）相关，但一种高度普遍的内型是杂合状态（PIMZ个体）。PI*MZ状态对病情加重和医疗保健利用的影响尚不清楚。
对克利夫兰电子健康记录数据进行检查，以比较PIMZ个体和PIMM个体之间的医疗保健利用情况。评估了三个结果：中度COPD加重（定义为短期使用类固醇处方）、任何急诊护理（定义为快速护理、紧急护理或急诊就诊）以及任何住院治疗。模型根据年龄、性别、种族、体重指数、吸烟状况、合并症数量、肝病、邮政编码中位数收入进行了调整。
4148人具有PIMM基因型，308人具有PIMZ基因型。与PIMM相比，PIMZ与中度COPD加重风险增加（风险比[95%置信区间]：1.66[1.27，2.17]）和住院风险增加（风险比[95%置信区间]：1.44[1.19，1.75]）相关。与PI*MM相比，AAT水平<90mg/dL的PI*MZ个体住院风险更高（风险比[95%置信区间]：1.59[1.14，2.23]），但AAT水平>90mg/dL的个体则不然。
鉴于PIMZ的高患病率，它代表了一种与更差预后相关的COPD表型，需要进一步研究以确定疾病预后更差的预测生物标志物和可治疗特征。未来需要进行前瞻性研究，以更好地描述PIMZ基因型个体的疾病纵向病程和医疗保健利用情况。
