Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis.
Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis.
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DOI：
10.1186/s12967-018-1387-9
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发表时间：
2018-01-29
影响因子：
7.4
通讯作者：
Goodyear CS
中科院分区：
文献类型：
--
作者：
Carini C;Hunter E;Scottish Early Rheumatoid Arthritis Inception cohort Investigators;Ramadass AS;Green J;Akoulitchev A;McInnes IB;Goodyear CS
类风湿性关节炎(RA)迫切需要确定哪些患者对一线抗风湿药物(DMARD)无效。我们探讨了甲氨蝶呤(MTX)治疗前早期RA患者血液中染色体构象特征(CCS)所代表的基因组结构的差异是否有助于识别对DMARD的无反应，以及这种特征与RA特异性表达数量性状基因座(EQTL)之间是否存在关联。我们使用EpiSwitch™捕获的染色体构象从早期RA患者的血液中寻找CCS的存在。使用来自MTX应答者、非应答者和健康对照的血液样本，定制设计的生物标记物发现阵列被改进为5标记CCS，可以区分MTX应答者和非应答者。我们交叉验证了CCS的预测能力，在MTX治疗前产生了59名早期RA患者(30名应答者和29名无应答者)的150个随机组。CCS使用19名早期RA患者(9名应答者和10名无应答者)的盲法独立队列进行验证。最后，将CCS标记定位于RA特异的eQTL。我们确定了一个5标记CCS，它可以在基线上识别MTX的应答者和无应答者。CCS由位于IFNAR1、IL-21R、IL-23、CXCL13和IL-17A基因组区域的二元染色体构象组成。当对59名RA患者进行队列测试时，CCS对MTX反应的阴性预测值为90.0%。当在19名早期RA患者的盲目独立验证队列上进行测试时，该签名显示真正的阴性应答率为86，对于检测对MTX无反应者的敏感性为90%。只有响应者中的构象被映射到RA特定的eQTL。在这里，我们证明在早期RA的血液中检测CCS能够高度准确地预测对MTX的反应不足。我们的结果提供了一个原则证据，即对MTX的反应是可能的先验分层，提供了一种机制，为疾病早期对MTX无应答者提供替代治疗。本文的在线版本(10.1186/s12967-0181387-9)包含补充材料，可供授权用户使用。
There is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to first-line disease-modifying anti-rheumatic drugs (DMARD). We explored whether differences in genomic architecture represented by a chromosome conformation signature (CCS) in blood taken from early RA patients before methotrexate (MTX) treatment could assist in identifying non-response to DMARD and, whether there is an association between such a signature and RA specific expression quantitative trait loci (eQTL). We looked for the presence of a CCS in blood from early RA patients commencing MTX using chromosome conformation capture by EpiSwitch™. Using blood samples from MTX responders, non-responders and healthy controls, a custom designed biomarker discovery array was refined to a 5-marker CCS that could discriminate between responders and non-responders to MTX. We cross-validated the predictive power of the CCS by generating 150 randomized groups of 59 early RA patients (30 responders and 29 non-responders) before MTX treatment. The CCS was validated using a blinded, independent cohort of 19 early RA patients (9 responders and 10 non-responders). Last, the loci of the CCS markers were mapped to RA-specific eQTL. We identified a 5-marker CCS that could identify, at baseline, responders and non-responders to MTX. The CCS consisted of binary chromosome conformations in the genomic regions of IFNAR1, IL-21R, IL-23, CXCL13 and IL-17A. When tested on a cohort of 59 RA patients, the CCS provided a negative predictive value of 90.0% for MTX response. When tested on a blinded independent validation cohort of 19 early RA patients, the signature demonstrated a true negative response rate of 86 and a 90% sensitivity for detection of non-responders to MTX. Only conformations in responders mapped to RA-specific eQTL. Here we demonstrate that detection of a CCS in blood in early RA is able to predict inadequate response to MTX with a high degree of accuracy. Our results provide a proof of principle that a priori stratification of response to MTX is possible, offering a mechanism to provide alternative treatments for non-responders to MTX earlier in the course of the disease. The online version of this article (10.1186/s12967-018-1387-9) contains supplementary material, which is available to authorized users.
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影响因子：
5.5
作者：
Barrera, P;van der Maas, A;van Riel, PLCM
通讯作者：
van Riel, PLCM
DOI：
10.1126/science.1260793
发表时间：
2015-02-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Battle A;Khan Z;Wang SH;Mitrano A;Ford MJ;Pritchard JK;Gilad Y
通讯作者：
Gilad Y
影响因子：
30.8
作者：
Fairfax, Benjamin P.;Makino, Seiko;Radhakrishnan, Jayachandran;Plant, Katharine;Leslie, Stephen;Dilthey, Alexander;Ellis, Peter;Langford, Cordelia;Vannberg, Fredrik O.;Knight, Julian C.
通讯作者：
Knight, Julian C.
影响因子：
4
作者：
Christova, Rossitza;Jones, Tania;Sheer, Denise
通讯作者：
Sheer, Denise
影响因子：
7
作者：
Garge, Nikhil;Pan, Huaqin;Bunger, Maureen K.
通讯作者：
Bunger, Maureen K.