人类遗传学影响下的与吸入皮质类固醇治疗后哮喘恶化相关的微生物组组分研究
2023/06/25
摘要
背景：尽管吸入皮质类固醇（ICS）治疗，上呼吸道微生物组仍参与哮喘恶化。虽然人类遗传学因素可以调节微生物的组成，但其对哮喘相关的气道细菌的影响尚不清楚。
目的：我们旨在确定调控哮喘急性发作和ICS反应的气道微生物组特征的基因和生物学途径。
方法：对257例欧洲哮喘患者的唾液样本、鼻腔采集样本和咽部采集样本进行分析。通过微生物组全基因组关联研究，测试并分析6296951个遗传变异点与接受了ICS治疗后哮喘患者病情仍恶化的微生物组特征的关联。在基因集富集分析中检查了1x104<p<1x10-6的变异型。在患有和未患哮喘的114名非裔美国人和158名拉丁裔儿童等实验样本组之中取得显著的重复性结果。将文献中报告的ics反应相关snp作为微生物组数量性状位点(mbQTL)进行评估。通过错误发现率（FDR）调整多重比较。有关详细方法，请参阅本文在线存储库中的方法部分，网址为www.jacionline.org。
结果：与哮喘恶化相关的气道微生物组特征的相关基因在哮喘合并症易感性（即反流性食管炎，肥胖和吸烟）中富集，并可能受曲古抑素A和NF-κB，NR3C1，和CEBP转录因子（7.8x10-13≤FDR≤0.022）调控。曲古抑素A、NF-κB和NR3C1富集于吸烟人群唾液样本中，并在其他不同人群的唾液样本中均有发现（4.42x10-9≤p≤0.008）.ICS反应相关SNP rs5995653（APOBEC3B-APOBEC3C），rs6467778（TRIM24）和rs5752429（TPST2），被鉴定为上气道中链球菌，坦纳菌和弯曲杆菌（0.027≤FDR≤0.050）。
结论：与哮喘恶化相关的微生物组特征相关的基因可能影响哮喘合并症。我们强化了曲古抑素A、NF-κB、NR3C1和CEBP可能作为治疗哮喘恶化的靶点。
Perez-Garcia J, Espuela-Ortiz A, Hernández-Pérez JM
Abstrast
Background: The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown.
Objective：We aimed to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response.
Methods: Saliva, nasal, and pharyngeal samples from 257 European asthma patients were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1x104<p<1x10-6 were examined in gene-set enrichment analyses. Significant results were sought for replication in 114 African American and 158 Latino children with and without asthma. ICS-response-associated SNPs reported in the literature were evaluated as microbiome quantitative trait loci (mbQTLs). Multiple comparisons were adjusted by the false discovery rate (FDR). For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org.
Results: Genes associated with exacerbation-related airway microbiome traits were enriched in asthma comorbidities susceptibility (i.e., reflux esophagitis, obesity, and smoking), and were likely regulated by trichostatin A and the NF-κB, NR3C1, and CEBP transcription factors (7.8x10-13≤FDR≤0.022). Enrichment in smoking, trichostatin A, NF-κB, and NR3C1 were replicated in the saliva samples from diverse populations (4.42x10-9≤p≤0.008). The ICS-response-associated SNPs rs5995653 (APOBEC3B-APOBEC3C), rs6467778 (TRIM24), and rs5752429 (TPST2), were identified as mbQTLs of Streptococcus, Tannerella, and Campylobacter in the upper-airway (0.027≤FDR≤0.050).
Conclusions: Genes associated with asthma exacerbation-related microbiome traits might influence asthma comorbidities. We reinforced the therapeutic interest of trichostatin A, NF-κB, NR3C1, and CEBP in asthma exacerbations.
背景：尽管吸入皮质类固醇（ICS）治疗，上呼吸道微生物组仍参与哮喘恶化。虽然人类遗传学因素可以调节微生物的组成，但其对哮喘相关的气道细菌的影响尚不清楚。
目的：我们旨在确定调控哮喘急性发作和ICS反应的气道微生物组特征的基因和生物学途径。
方法：对257例欧洲哮喘患者的唾液样本、鼻腔采集样本和咽部采集样本进行分析。通过微生物组全基因组关联研究，测试并分析6296951个遗传变异点与接受了ICS治疗后哮喘患者病情仍恶化的微生物组特征的关联。在基因集富集分析中检查了1x104<p<1x10-6的变异型。在患有和未患哮喘的114名非裔美国人和158名拉丁裔儿童等实验样本组之中取得显著的重复性结果。将文献中报告的ics反应相关snp作为微生物组数量性状位点(mbQTL)进行评估。通过错误发现率（FDR）调整多重比较。有关详细方法，请参阅本文在线存储库中的方法部分，网址为www.jacionline.org。
结果：与哮喘恶化相关的气道微生物组特征的相关基因在哮喘合并症易感性（即反流性食管炎，肥胖和吸烟）中富集，并可能受曲古抑素A和NF-κB，NR3C1，和CEBP转录因子（7.8x10-13≤FDR≤0.022）调控。曲古抑素A、NF-κB和NR3C1富集于吸烟人群唾液样本中，并在其他不同人群的唾液样本中均有发现（4.42x10-9≤p≤0.008）.ICS反应相关SNP rs5995653（APOBEC3B-APOBEC3C），rs6467778（TRIM24）和rs5752429（TPST2），被鉴定为上气道中链球菌，坦纳菌和弯曲杆菌（0.027≤FDR≤0.050）。
结论：与哮喘恶化相关的微生物组特征相关的基因可能影响哮喘合并症。我们强化了曲古抑素A、NF-κB、NR3C1和CEBP可能作为治疗哮喘恶化的靶点。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(J Allergy Clin Immunol 2023 Jun 08; doi: 10.1016/j.jaci.2023.05.021.IF：10.228.)
Human Genetics Influences Microbiome Composition Involved in Asthma Exacerbations despite Inhaled Corticosteroid Treatment.(J Allergy Clin Immunol 2023 Jun 08; doi: 10.1016/j.jaci.2023.05.021.IF：10.228.)
Perez-Garcia J, Espuela-Ortiz A, Hernández-Pérez JM
Abstrast
Background: The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown.
Objective：We aimed to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response.
Methods: Saliva, nasal, and pharyngeal samples from 257 European asthma patients were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1x104<p<1x10-6 were examined in gene-set enrichment analyses. Significant results were sought for replication in 114 African American and 158 Latino children with and without asthma. ICS-response-associated SNPs reported in the literature were evaluated as microbiome quantitative trait loci (mbQTLs). Multiple comparisons were adjusted by the false discovery rate (FDR). For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org.
Results: Genes associated with exacerbation-related airway microbiome traits were enriched in asthma comorbidities susceptibility (i.e., reflux esophagitis, obesity, and smoking), and were likely regulated by trichostatin A and the NF-κB, NR3C1, and CEBP transcription factors (7.8x10-13≤FDR≤0.022). Enrichment in smoking, trichostatin A, NF-κB, and NR3C1 were replicated in the saliva samples from diverse populations (4.42x10-9≤p≤0.008). The ICS-response-associated SNPs rs5995653 (APOBEC3B-APOBEC3C), rs6467778 (TRIM24), and rs5752429 (TPST2), were identified as mbQTLs of Streptococcus, Tannerella, and Campylobacter in the upper-airway (0.027≤FDR≤0.050).
Conclusions: Genes associated with asthma exacerbation-related microbiome traits might influence asthma comorbidities. We reinforced the therapeutic interest of trichostatin A, NF-κB, NR3C1, and CEBP in asthma exacerbations.
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顺式和反式eQTM分析揭示气道上皮中特应性哮喘的新表观遗传学和转录组免疫标志物
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组胺释放因子在严重哮喘和鼻病毒相关性哮喘加重中的作用
