Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial.
Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial.
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DOI：
10.1186/s13059-018-1560-8
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发表时间：
2018-10-19
期刊：
影响因子：
12.3
通讯作者：
Raychaudhuri S
中科院分区：
文献类型：
--
作者：
Davenport EE;Amariuta T;Gutierrez-Arcelus M;Slowikowski K;Westra HJ;Luo Y;Shen C;Rao DA;Zhang Y;Pearson S;von Schack D;Beebe JS;Bing N;John S;Vincent MS;Zhang B;Raychaudhuri S
细胞因子对人类疾病至关重要，并且由于其对基因调控和转录的广泛影响而成为有吸引力的治疗靶点。确定受细胞因子影响的下游调控机制是确定药物和疾病机制的核心。一种有前景的策略是利用表达数量性状位点（eqtl）和细胞因子水平之间的相互作用来确定靶基因及其机制。在系统性红斑狼疮患者抗il -6的临床试验中，我们在三个时间点测量干扰素（IFN）状态、抗il -6药物暴露和全血全基因组基因表达。我们发现，与使用单一时间点相比，重复转录组学测量增加了鉴定的顺式eqtl的数量。我们观察到体内eQTL与IFN状态和抗il -6药物暴露的相互作用在统计学上显著增加，并发现许多以前未描述的新相互作用。最后，我们发现转录因子结合基序被eQTL相互作用snp打断，这指出了这些环境刺激的关键调节介质，因此是自身免疫性疾病的潜在治疗靶点。特别是，与IFN相互作用的基因在ISRE结合位点基序上富集，而与抗il -6相互作用的基因在IRF4基序上富集。这项研究强调了利用临床试验数据发现体内eQTL与治疗相关环境变量相互作用的潜力。本文的在线版本（10.1186/s13059-018-1560-8）包含补充资料，仅供授权用户使用。
Cytokines are critical to human disease and are attractive therapeutic targets given their widespread influence on gene regulation and transcription. Defining the downstream regulatory mechanisms influenced by cytokines is central to defining drug and disease mechanisms. One promising strategy is to use interactions between expression quantitative trait loci (eQTLs) and cytokine levels to define target genes and mechanisms. In a clinical trial for anti-IL-6 in patients with systemic lupus erythematosus, we measure interferon (IFN) status, anti-IL-6 drug exposure, and whole blood genome-wide gene expression at three time points. We show that repeat transcriptomic measurements increases the number of cis eQTLs identified compared to using a single time point. We observe a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 drug exposure and find many novel interactions that have not been previously described. Finally, we find transcription factor binding motifs interrupted by eQTL interaction SNPs, which point to key regulatory mediators of these environmental stimuli and therefore potential therapeutic targets for autoimmune diseases. In particular, genes with IFN interactions are enriched for ISRE binding site motifs, while those with anti-IL-6 interactions are enriched for IRF4 motifs. This study highlights the potential to exploit clinical trial data to discover in vivo eQTL interactions with therapeutically relevant environmental variables. The online version of this article (10.1186/s13059-018-1560-8) contains supplementary material, which is available to authorized users.
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
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：
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.
DOI：
10.1073/pnas.1115761109
发表时间：
2012-01-24
影响因子：
11.1
作者：
Barreiro, Luis B.;Tailleux, Ludovic;Gilad, Yoav
通讯作者：
Gilad, Yoav
影响因子：
13.3
作者：
Cui, Jing;Diogo, Dorothee;Raychaudhuri, Soumya
通讯作者：
Raychaudhuri, Soumya