基因调控的炎症蛋白与哮喘风险：MMP-10的关键作用
2025/10/27
背景和目的：蛋白质定量性状位点（pQTLs）在哮喘中的研究仍然较少，但它们可能为揭示潜在的分子机制提供有价值的见解。作者旨在探讨遗传变异与炎症相关的血浆蛋白之间的关联，并评估在具有2型炎症和/或哮喘特征的受试者中，遗传决定性蛋白质水平的差异。
方法：本研究对来自瑞典BAMSE队列的成年人（n = 1538）进行了92种炎症相关血浆蛋白的pQTL定位。尝试对标志性pQTL进行复制，并利用公开数据研究pQTL与表达定量性状位点（eQTLs）的重叠和共定位情况。对具有显著pQTL的蛋白质进行了与2型炎症标志的关联性检验，2型炎症标志定义为高水平的呼气一氧化氮、血嗜酸性粒细胞和/或对空气传播过敏原的敏感性，研究对象包括有或没有哮喘的BAMSE受试者。
结果：共识别出39种炎症相关蛋白的45个标志性pQTL（33个顺式、12个反式）（p ≤ 7.14 × 10−11），并且其中大部分在独立人群中得到了验证。在不同组织中，19种蛋白质的顺式pQTL与顺式eQTL之间观察到高度的共定位可能性。39种具有显著pQTL的循环蛋白中，有6种与2型炎症标志和/或哮喘相关，其中基质金属蛋白酶-10（MMP-10）显示出最显著的关联。
结论：本研究表明，炎症蛋白的血浆水平由遗传因素决定。其中，MMP-10作为一个受遗传影响的关键因子，在哮喘患者的高水平2型炎症中发挥着重要作用，这使其成为一个潜在的治疗靶点。
关键词：哮喘；遗传学；炎症；蛋白质；2型特征
Abstract
Background: Protein quantitative trait loci (pQTLs) remain underexplored in asthma but might provide valuable insights into the underlying molecular mechanisms. This study aimed to investigate associations between genetic variation and inflammation-related plasma proteins and to assess differences in the levels of genetically determined proteins in subjects with signatures of type-2 inflammation and/or asthma.
Methods: A pQTL mapping of 92 inflammation-related plasma proteins was conducted in young adults from the Swedish BAMSE cohort (n = 1538). Replication of sentinel pQTLs was attempted, and the overlap and colocalization of pQTLs with expression quantitative trait loci (eQTLs) were investigated using publicly available data. Proteins with significant pQTLs were tested for association with type-2 signatures defined as high levels of fractional exhaled nitric oxide, blood eosinophils, and/or sensitization to airborne allergens in subjects with or without asthma in BAMSE.
Results：Forty-five sentinel pQTLs (33 cis, 12 trans) for 39 inflammation-related proteins were identified (p ≤ 7.14 × 10−11), and a high proportion of these were validated in independent populations. A high likelihood for colocalization of cis-pQTLs and cis-eQTLs was observed for 19 proteins in different tissues. Six of the 39 circulating proteins with significant pQTLs were associated with type-2 signatures and/or asthma, and matrix metalloproteinase-10 (MMP-10) showed the most significant associations.
Conclusion：These findings underscore the existence of a genetic component influencing the plasma levels of proteins involved in inflammatory processes, including MMP-10, which is suggested to have a role in high type-2 inflammation in asthma subjects.
Key words: asthma; genetics; inflammation; proteins; type-2 signatures
方法：本研究对来自瑞典BAMSE队列的成年人（n = 1538）进行了92种炎症相关血浆蛋白的pQTL定位。尝试对标志性pQTL进行复制，并利用公开数据研究pQTL与表达定量性状位点（eQTLs）的重叠和共定位情况。对具有显著pQTL的蛋白质进行了与2型炎症标志的关联性检验，2型炎症标志定义为高水平的呼气一氧化氮、血嗜酸性粒细胞和/或对空气传播过敏原的敏感性，研究对象包括有或没有哮喘的BAMSE受试者。
结果：共识别出39种炎症相关蛋白的45个标志性pQTL（33个顺式、12个反式）（p ≤ 7.14 × 10−11），并且其中大部分在独立人群中得到了验证。在不同组织中，19种蛋白质的顺式pQTL与顺式eQTL之间观察到高度的共定位可能性。39种具有显著pQTL的循环蛋白中，有6种与2型炎症标志和/或哮喘相关，其中基质金属蛋白酶-10（MMP-10）显示出最显著的关联。
结论：本研究表明，炎症蛋白的血浆水平由遗传因素决定。其中，MMP-10作为一个受遗传影响的关键因子，在哮喘患者的高水平2型炎症中发挥着重要作用，这使其成为一个潜在的治疗靶点。
关键词：哮喘；遗传学；炎症；蛋白质；2型特征
（南方医科大学南方医院 黄海伦 龚钊乾 赵海金）
（Hernandez‐Pacheco N, Björkander S, Merid S K, et al. Genetically determined inflammation‐related proteins in asthma and type‐2 signatures[J]. Allergy, 2025, 80(6): 1702-1714. DOI: 10.1111/all.16608.）
（Hernandez‐Pacheco N, Björkander S, Merid S K, et al. Genetically determined inflammation‐related proteins in asthma and type‐2 signatures[J]. Allergy, 2025, 80(6): 1702-1714. DOI: 10.1111/all.16608.）
Abstract
Background: Protein quantitative trait loci (pQTLs) remain underexplored in asthma but might provide valuable insights into the underlying molecular mechanisms. This study aimed to investigate associations between genetic variation and inflammation-related plasma proteins and to assess differences in the levels of genetically determined proteins in subjects with signatures of type-2 inflammation and/or asthma.
Methods: A pQTL mapping of 92 inflammation-related plasma proteins was conducted in young adults from the Swedish BAMSE cohort (n = 1538). Replication of sentinel pQTLs was attempted, and the overlap and colocalization of pQTLs with expression quantitative trait loci (eQTLs) were investigated using publicly available data. Proteins with significant pQTLs were tested for association with type-2 signatures defined as high levels of fractional exhaled nitric oxide, blood eosinophils, and/or sensitization to airborne allergens in subjects with or without asthma in BAMSE.
Results：Forty-five sentinel pQTLs (33 cis, 12 trans) for 39 inflammation-related proteins were identified (p ≤ 7.14 × 10−11), and a high proportion of these were validated in independent populations. A high likelihood for colocalization of cis-pQTLs and cis-eQTLs was observed for 19 proteins in different tissues. Six of the 39 circulating proteins with significant pQTLs were associated with type-2 signatures and/or asthma, and matrix metalloproteinase-10 (MMP-10) showed the most significant associations.
Conclusion：These findings underscore the existence of a genetic component influencing the plasma levels of proteins involved in inflammatory processes, including MMP-10, which is suggested to have a role in high type-2 inflammation in asthma subjects.
Key words: asthma; genetics; inflammation; proteins; type-2 signatures
上一篇：
精准预测生物制剂疗效：重度哮喘治疗前FeNO水平指导抗IL-4Rα用药
下一篇：
儿童早期喘息模式预示独特的基因表达谱
