Chu Xu, Han Zhifa, Li Baicun, Yang Ting
National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, P.R. China.
Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Henan University of Science & Technology, Luoyang, P.R. China.
Medicine (Baltimore). 2025 May 9;104(19):e42409. doi: 10.1097/MD.0000000000042409.
Several studies have reported a strong association between plasma proteins and chronic obstructive pulmonary disease (COPD). However, the directionality and causality of the association and whether proteins effected COPD remain unclear. Therefore, we used Proteome-wide Mendelian randomization (MR) study and co-localization analyses to estimate the casual relationship between them. Summary-level data of 2923 plasma protein levels were extracted from a large-scale protein quantitative trait loci study including 54,219 individuals by the UK Biobank Pharma Proteomics Project. The outcome data for COPD and its subtypes were sourced from the FinnGen study. MR analysis was conducted to estimate the associations between protein and COPD and its subtypes risk. Additionally, phenome-wide MR analysis, and candidate drug prediction were employed to identify potential causal circulating proteins and novel drug targets. STROBE MR guidelines are followed for the study. We assessed the effect of 1929 plasma proteins on COPD. We found that Seven proteins, 4 proteins, and 3 proteins were associated with overall COPD, early-onset COPD, and later-onset COPD risk, respectively. MHC class I polypeptide-related sequence B_A (MICB_MICA) and tyrosine-protein kinase receptor tie-1 (TIE-1) would increase 8% and 27% COPD risk (MICB_MICA: odds ratios [OR], 1.08; 95% CI, 1.05-1.10; PFDR = 2.53 × 10-5; TIE-1: OR, 1.27; 95% CI, 1.13-1.43; PFDR = .012). There was negative association of Septin-8 and Butyrophilin subfamily 1 member A1 (BTN1A1) with overall COPD risk (Septin-8: OR, 0.68; 95% CI, 0.57-0.79; PFDR = 8.00 × 10-4 BTN1A1: OR, 0.82; 95% CI, 0.75-0.90; PFDR = .010). There was a protective effect of BTN1A1 on early COPD incidence (OR, 0.72; 95% CI, 0.63-0.83; PFDR = .002). However, there was no evidence indicating a shared causal variant between the other proteins and COPD and its subtypes in these regions (all posterior probability.H4 < .8). The study revealed the causal relationship between several plasma proteins and COPD and its subtypes, providing new theoretical support for understanding COPD.
多项研究报告了血浆蛋白与慢性阻塞性肺疾病（COPD）之间存在密切关联。然而，这种关联的方向性和因果关系以及蛋白质是否影响COPD仍不清楚。因此，我们使用全蛋白质组孟德尔随机化（MR）研究和共定位分析来估计它们之间的因果关系。通过英国生物银行药物蛋白质组学项目，从一项包括54219名个体的大规模蛋白质定量性状位点研究中提取了2923种血浆蛋白水平的汇总数据。COPD及其亚型的结局数据来自芬兰基因研究。进行MR分析以估计蛋白质与COPD及其亚型风险之间的关联。此外，还采用了全表型组MR分析和候选药物预测来识别潜在的因果循环蛋白和新的药物靶点。本研究遵循STROBE MR指南。我们评估了1929种血浆蛋白对COPD的影响。我们发现分别有7种蛋白、4种蛋白和3种蛋白与总体COPD、早发型COPD和晚发型COPD风险相关。主要组织相容性复合体I类多肽相关序列B_A（MICB_MICA）和酪氨酸蛋白激酶受体tie-1（TIE-1）会使COPD风险分别增加8%和27%（MICB_MICA：优势比[OR]，1.08；95%置信区间，1.05 - 1.10；PFDR = 2.53×10⁻⁵；TIE-1：OR，1.27；95%置信区间，1.13 - 1.43；PFDR = 0.012）。Septin-8和嗜乳脂蛋白亚家族1成员A1（BTN1A1）与总体COPD风险呈负相关（Septin-8：OR，0.68；95%置信区间，0.57 - 0.79；PFDR = 8.00×10⁻⁴；BTN1A1：OR, 0.82；）。BTN1A1对早期COPD发病率有保护作用（OR，0.72；95%置信区间，0.63 - 0.83；PFDR = 0.002）。然而，没有证据表明这些区域中的其他蛋白质与COPD及其亚型之间存在共同的因果变异（所有后验概率.H4 < 0.8）。该研究揭示了几种血浆蛋白与COPD及其亚型之间的因果关系，为理解COPD提供了新理论支持。
