Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment.
Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment.
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DOI：
10.1016/j.jaci.2023.05.021
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发表时间：
2023-09
影响因子：
14.2
通讯作者：
Pino-Yanes, Maria
中科院分区：
文献类型：
--
作者：
Perez-Garcia, Javier;Espuela-Ortiz, Antonio;Hernandez-Perez, Jose M.;Gonzalez-Perez, Ruperto;Poza-Guedes, Paloma;Martin-Gonzalez, Elena;Eng, Celeste;Sardon-Prado, Olaia;Mederos-Luis, Elena;Corcuera-Elosegui, Paula;Sanchez-Machin, Inmaculada;Korta-Murua, Javier;Villar, Jesus;Burchard, Esteban G.;Lorenzo-Diaz, Fabian;Pino-Yanes, Maria
上呼吸道微生物组参与哮喘急性发作，尽管吸入皮质类固醇（ICS）治疗。尽管人类遗传学调节微生物组的组成，但其对哮喘相关气道细菌的影响仍然未知。我们试图确定基因和生物学途径调节参与哮喘急性发作和ICS反应的气道微生物组特征。分析了257例欧洲哮喘患者的唾液、鼻和咽部样本。通过微生物组全基因组关联研究，测试了6，296，951种遗传变异与ICS治疗后急性加重相关微生物组特征的关联。1 × 10−4 < P < 1 × 10−6的变异在基因集富集分析中进行了检测。在114名非洲裔美国人和158名拉丁美洲儿童哮喘和非哮喘的复制寻求显着的结果。将文献中报道的ICS反应相关单核苷酸多态性作为微生物组数量性状基因座进行评价。通过错误发现率调整多重比较。与急性加重相关的气道微生物组特征相关的基因在哮喘合并症（即反流性食管炎、肥胖和吸烟）的发展中富集，并且可能受到阿司他汀A和核因子-κB、糖皮质激素受体和CCAAT/增强子结合蛋白转录因子的调节（7.8 × 10−13 ≤错误发现率≤ 0.022）。在不同人群的唾液样本中，吸烟、前列腺素A、核因子-κB和糖皮质激素受体的富集被复制（4.42 × 10−9 ≤ P ≤ .008）。ICS反应相关单核苷酸多态性rs 5995653（APOBEC 3B-APOBEC 3C）、rs6467778（TRIM 24）和rs 5752429（TPST 2）被确定为上呼吸道链球菌、坦那氏菌和弯曲杆菌的微生物组数量性状位点（0.027 ≤错误发现率≤ 0.050）。与哮喘急性发作相关的微生物组特征相关的基因可能会影响哮喘合并症我们强调了阿伐他汀A、核因子-κB、糖皮质激素受体和CCAAT/增强子结合蛋白在哮喘急性发作中的治疗价值。
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. We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response. Saliva, nasal, and pharyngeal samples from 257 European patients with asthma 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 1 × 10−4 < P < 1 × 10−6 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 single nucleotide polymorphisms reported in the literature were evaluated as microbiome quantitative trait loci. Multiple comparisons were adjusted by the false discovery rate. Genes associated with exacerbation-related airway-microbiome traits were enriched in asthma comorbidities development (ie, reflux esophagitis, obesity, and smoking), and were likely regulated by trichostatin A and the nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein transcription factors (7.8 × 10−13 ≤ false discovery rate ≤ 0.022). Enrichment in smoking, trichostatin A, nuclear factor-κB, and glucocorticosteroid receptor were replicated in the saliva samples from diverse populations (4.42 × 10−9 ≤ P ≤ .008). The ICS-response–associated single nucleotide polymorphisms rs5995653 (APOBEC3B-APOBEC3C), rs6467778 (TRIM24), and rs5752429 (TPST2) were identified as microbiome quantitative trait loci of Streptococcus, Tannerella, and Campylobacter in the upper airway (0.027 ≤ false discovery rate ≤ 0.050). Genes associated with asthma exacerbation–related microbiome traits might influence asthma comorbidities. We reinforced the therapeutic interest of trichostatin A, nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein in asthma exacerbations.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
14.2
作者：
Irizar, Haritz;Chun, Yoojin;Arditi, Zoe;Do, Anh;Grishina, Galina;Grishin, Alexander;Vicencio, Alfin;Bunyavanich, Supinda
通讯作者：
Bunyavanich, Supinda
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
15.5
作者：
Davis, Nicole M;Proctor, Diana M;Callahan, Benjamin J
通讯作者：
Callahan, Benjamin J