Xu Jingran, Tao Li, Shi Yanyan, Gong Hui, Abudureheman Zulipikaer, Zheng Aifang, Zhong Xuemei, Xue Lexin, Zou Xiaoguang, Li Li
Department of Respiratory and Critical Care Medicine, First People's Hospital of Kashi, Kashi, China.
The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Sci Rep. 2025 Apr 25;15(1):14515. doi: 10.1038/s41598-025-98599-4.
The etiology of chronic obstructive pulmonary disease (COPD) is multifaceted. This study aims to explore the association between the bactericidal/permeability-increasing bold-containing family B member 4 (BPIFB4) rs4339026 A > G (NC_000,020.11: g.33083793 A > G) polymorphism and COPD susceptibility in Kashi population, and investigate the potential role of BPIFB4 in COPD. A total of 541 unrelated COPD patients and 534 healthy controls were enrolled from the First People's Hospital and Kashi village. The association between rs4339026 A > G polymorphism and COPD risk were assessed by multivariable logistic regression. BPIFB4 expression and associated pathways were analyzed through bioinformatics approaches using human peripheral blood and bronchoalveolar lavage fluid (BALF) datasets from the GEO database (GSE13896 and GSE42057). Experimental validation was performed in a cigarette smoke (CS)-induced COPD mouse model. BPIFB4 rs4339026 G/G genotype was associated with significantly increased COPD risk across all genetic models: genotype model [adjusted odds ratios (aOR) = 2.52, corresponding 95% confidence interval (95% CI): 1.34-4.71], recessive model (aOR = 2.32, 95% CI: 1.25-4.31), dominant model (aOR = 1.39, 95% CI: 1.07-1.81), allele model (aOR = 1.42, 95% CI: 1.13-1.77), and additive model (aOR = 1.40, 95% CI: 1.12-1.75). Stratified analysis based on smoking status revealed that BPIFB4 rs4339026 G/G genotype was also associated with an increased risk of COPD, regardless of smoking status. However, the risk was more pronounced in smokers compared to non-smokers, as evidenced by the dominant model (aOR = 2.52, 95% CI: 1.23-5.15), additive model (aOR = 2.61, 95% CI: 1.37-4.97), and allele model (aOR = 2.68, 95% CI: 1.41-5.08). In non-smokers, the association remained significant, with the genotype model (aOR = 1.99, 95% CI: 1.03-3.85), additive model (aOR = 1.28, 95% CI: 1.01-1.62), and allele model (aOR = 1.29, 95% CI: 1.01-1.64). The bioinformatics analysis demonstrated a decrease in BPIFB4 expression in peripheral blood and BALF of COPD patients, with pathway enrichment analysis implicating PI3K/AKT signaling. Consistently, COPD mice exhibited significant BPIFB4 downregulation (P < 0.0001), accompanied by upregulation of PI3K, p-PI3K, and p-AKT was upregulated (P < 0.001 vs. controls). We confirmed that BPIFB4 rs4339026 A > G increased the risk of COPD. BPIFB4 might contribute to COPD pathogenesis through the PI3K/AKT pathway.
慢性阻塞性肺疾病（COPD）的病因是多方面的。本研究旨在探讨含杀菌/通透性增加蛋白B家族成员4（BPIFB4）rs4339026 A＞G（NC_000,020.11: g.33083793 A＞G）多态性与喀什地区人群COPD易感性之间的关联，并研究BPIFB4在COPD中的潜在作用。从喀什地区第一人民医院和喀什村招募了541例无亲缘关系的COPD患者和534例健康对照。通过多变量逻辑回归评估rs4339026 A＞G多态性与COPD风险之间的关联。利用来自基因表达综合数据库（GEO数据库，GSE13896和GSE42057）的人类外周血和支气管肺泡灌洗液（BALF）数据集，通过生物信息学方法分析BPIFB4表达及相关通路。在香烟烟雾（CS）诱导的COPD小鼠模型中进行实验验证。在所有遗传模型中，BPIFB4 rs4339026 G/G基因型与COPD风险显著增加相关：基因型模型[调整优势比（aOR）=2.52，相应的95%置信区间（95%CI）：1.34 - 4.71]，隐性模型（aOR = 2.32，95%CI：1.25 - 4.31），显性模型（aOR = 1.39，95%CI：1.07 - 1.81），等位基因模型（aOR = 1.42，95%CI：1.13 - 1.77）和加性模型（aOR = 1.40，95%CI：1.12 - 1.75）。基于吸烟状态的分层分析显示，无论吸烟状态如何，BPIFB4 rs4339026 G/G基因型也与COPD风险增加相关。然而，与非吸烟者相比，吸烟者的风险更为明显，显性模型（aOR = 2.52，95%CI：1.23 - 5.15）、加性模型（aOR = 2.61，95%CI：1.37 - 4.97）和等位基因模型（aOR = 2.68，95%CI：1.41 - 5.08）均证实了这一点。在非吸烟者中，这种关联仍然显著，基因型模型（aOR = 1.99，95%CI：1.03 - 3.85）、加性模型（aOR = 1.28，95%CI：1.01 - 1.62）和等位基因模型（aOR = 1.29，95%CI：1.01 - 1.64）均显示了这一点。生物信息学分析表明，COPD患者外周血和BALF中BPIFB4表达降低，通路富集分析表明PI3K/AKT信号通路参与其中。同样，COPD小鼠表现出显著的BPIFB4下调（P＜0.0001），同时PI3K、p - PI3K和p - AKT上调（与对照组相比，P＜0.001）。我们证实BPIFB4 rs4339026 A＞G增加了COPD风险。BPIFB4可能通过PI3K/AKT通路参与COPD的发病机制。
