High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis.
High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis.
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DOI：
10.1186/s13073-016-0374-0
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发表时间：
2016-11-22
期刊：
影响因子：
12.3
通讯作者：
Ekström TJ
中科院分区：
文献类型：
--
作者：
Gomez-Cabrero D;Almgren M;Sjöholm LK;Hensvold AH;Ringh MV;Tryggvadottir R;Kere J;Scheynius A;Acevedo N;Reinius L;Taub MA;Montano C;Aryee MJ;Feinberg JI;Feinberg AP;Tegnér J;Klareskog L;Catrina AI;Ekström TJ
双生子研究是阐明基因-环境相互作用引起的表观遗传修饰的有力模型。然而，通常有限数量的临床双胞胎样本是可用的，导致受假阳性困扰的动力不足的情况，并受到低灵敏度的阻碍。我们研究了两组代表类风湿性关节炎（RA）进展不同阶段的单卵双胞胎的全基因组DNA甲基化数据，以寻找新的基因进行进一步研究。我们实施了一种稳健的统计学方法，旨在研究少量样本，以利用综合CHARM平台鉴定差异甲基化，其中全血细胞DNA来自ACPA（瓜氨酸化蛋白抗原抗体）阳性RA与ACPA阴性健康人或ACPA阳性健康人（RA前期）与ACPA阴性健康人不一致的两组双胞胎对。为了解卷积细胞类型依赖性差异甲基化，我们分析了分选细胞的甲基化模式，并使用计算算法来解析不同细胞类型的相对贡献，并将它们用作协变量。为了鉴定甲基化生物标志物，对5对ACPAs不一致的健康双胞胎进行了分析，揭示了一个差异甲基化区域（DMR）。7对双胞胎不一致的ACPA阳性RA显示6个显着的DMR。在细胞类型比例的去卷积后，健康ACPA不一致双胞胎的分析显示了17个全基因组显著的DMR。当根据细胞类型调整ACPA阳性RA双胞胎对的甲基化谱时，分析揭示了一个与EXOSC 1基因相关的显著DMR。此外，从我们的方法的结果表明，原钙粘素β-14基因的时间连接ACPA阳性与临床RA。我们的生物统计学方法，优化了低样本双胞胎设计，揭示了与RA的两个不同阶段相关的非遗传连锁基因。功能性证据仍然缺乏，但结果加强了对影响RA进展的表观遗传修饰的进一步研究。我们的研究设计和方法可能被证明在双胞胎研究中普遍有用。本文的在线版本（doi：10.1186/s13073-016-0374-0）包含补充材料，可供授权用户使用。
Twin studies are powerful models to elucidate epigenetic modifications resulting from gene–environment interactions. Yet, commonly a limited number of clinical twin samples are available, leading to an underpowered situation afflicted with false positives and hampered by low sensitivity. We investigated genome-wide DNA methylation data from two small sets of monozygotic twins representing different phases during the progression of rheumatoid arthritis (RA) to find novel genes for further research. We implemented a robust statistical methodology aimed at investigating a small number of samples to identify differential methylation utilizing the comprehensive CHARM platform with whole blood cell DNA from two sets of twin pairs discordant either for ACPA (antibodies to citrullinated protein antigens)-positive RA versus ACPA-negative healthy or for ACPA-positive healthy (a pre-RA stage) versus ACPA-negative healthy. To deconvolute cell type-dependent differential methylation, we assayed the methylation patterns of sorted cells and used computational algorithms to resolve the relative contributions of different cell types and used them as covariates. To identify methylation biomarkers, five healthy twin pairs discordant for ACPAs were profiled, revealing a single differentially methylated region (DMR). Seven twin pairs discordant for ACPA-positive RA revealed six significant DMRs. After deconvolution of cell type proportions, profiling of the healthy ACPA discordant twin-set revealed 17 genome-wide significant DMRs. When methylation profiles of ACPA-positive RA twin pairs were adjusted for cell type, the analysis disclosed one significant DMR, associated with the EXOSC1 gene. Additionally, the results from our methodology suggest a temporal connection of the protocadherine beta-14 gene to ACPA-positivity with clinical RA. Our biostatistical methodology, optimized for a low-sample twin design, revealed non-genetically linked genes associated with two distinct phases of RA. Functional evidence is still lacking but the results reinforce further study of epigenetic modifications influencing the progression of RA. Our study design and methodology may prove generally useful in twin studies. The online version of this article (doi:10.1186/s13073-016-0374-0) contains supplementary material, which is available to authorized users.
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影响因子：
27.4
作者：
Gerlag DM;Raza K;van Baarsen LG;Brouwer E;Buckley CD;Burmester GR;Gabay C;Catrina AI;Cope AP;Cornelis F;Dahlqvist SR;Emery P;Eyre S;Finckh A;Gay S;Hazes JM;van der Helm-van Mil A;Huizinga TW;Klareskog L;Kvien TK;Lewis C;Machold KP;Rönnelid J;van Schaardenburg D;Schett G;Smolen JS;Thomas S;Worthington J;Tak PP
通讯作者：
Tak PP
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
27.4
作者：
Karlson EW;Chang SC;Cui J;Chibnik LB;Fraser PA;De Vivo I;Costenbader KH
通讯作者：
Costenbader KH
影响因子：
4.9
作者：
Clark, Peter M.;Dawany, Noor;Tozeren, Aydin
通讯作者：
Tozeren, Aydin
影响因子：
14.9
作者：
Edgar, R;Domrachev, M;Lash, AE
通讯作者：
Lash, AE