Hakonarson Hakon, Bjornsdottir Unnur S, Halapi Eva, Bradfield Jonathan, Zink Florian, Mouy Magali, Helgadottir Hildur, Gudmundsdottir Asta S, Andrason Hjalti, Adalsteinsdottir Asdis E, Kristjansson Kristleifur, Birkisson Illugi, Arnason Thor, Andresdottir Margret, Gislason David, Gislason Thorarinn, Gulcher Jeffrey R, Stefansson Kari
deCODE genetics, Inc., Sturlugata 8, IS-101 Reykjavik, Iceland.
Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14789-94. doi: 10.1073/pnas.0409904102. Epub 2005 Oct 3.
Gene expression profiles were examined in freshly isolated peripheral blood mononuclear cells (PBMC) from two independent cohorts (training and test sets) of glucocorticoid (GC)-sensitive (n = 64) and GC-resistant (n = 42) asthma patients in search of genes that accurately predict responders and nonresponders to inhaled corticosteroids. A total of 11,812 genes were examined with high-density oligonucleotide microarrays in both resting PBMC (106 patients) and cells treated in vitro with IL-1beta and TNF-alpha combined (88 patients), with or without GC. A total of 5,011 genes were expressed at significant levels in the PBMC, and 1,334 of those were notably up-regulated or down-regulated by IL-1beta/TNF-alpha treatment. The expression changes of 923 genes were significantly reversed in GC responders in the presence of GC. The expression pattern of 15 of these 923 genes that most accurately separated GC responders (n = 26) from the nonresponders (n = 18) in the training set, based on the weighted voting algorithm, predicted the independent test set of equal size with 84% accuracy. The expression accuracy of these genes was confirmed by real-time-quantitative PCR, wherein 11 of the 15 genes predicted GC sensitivity at baseline with 84% accuracy, with one gene predicting at 81% in an independent cohort of 79 patients. We conclude that we have uncovered gene expression profiles in PBMC that predict clinical response to inhaled GC therapy with meaningful accuracy. Upon validation in an independent study, these results support the development of a diagnostic test to guide GC therapy in asthma patients.
在两组独立队列（训练集和测试集）的糖皮质激素（GC）敏感型（n = 64）和GC抵抗型（n = 42）哮喘患者的新鲜分离外周血单个核细胞（PBMC）中检测基因表达谱，以寻找能准确预测吸入性糖皮质激素反应者和无反应者的基因。使用高密度寡核苷酸微阵列对106例静息PBMC患者以及88例经白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）联合体外处理（无论有无GC）的细胞中的总共11,812个基因进行了检测。共有5,011个基因在PBMC中显著表达，其中1,334个基因在IL-1β/TNF-α处理后显著上调或下调。在GC存在的情况下，923个基因的表达变化在GC反应者中显著逆转。基于加权投票算法，这923个基因中的15个基因在训练集中最准确地将GC反应者（n = 26）与无反应者（n = 18）区分开来，以84%的准确率预测了相同规模的独立测试集。这些基因的表达准确性通过实时定量PCR得到证实，其中15个基因中的11个在基线时以84%的准确率预测GC敏感性，在一个79例患者的独立队列中，有一个基因的预测准确率为81%。我们得出结论，我们在PBMC中发现了基因表达谱，其能以有意义的准确性预测吸入性GC治疗的临床反应。在独立研究中得到验证后，这些结果支持开发一种诊断测试以指导哮喘患者的GC治疗。
