Risk factors for inhibitors in hemophilia A based on RNA-seq and DNA methylation.
Risk factors for inhibitors in hemophilia A based on RNA-seq and DNA methylation.
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基于RNA-seq和DNA甲基化的血友病A抑制剂的危险因素
DOI：
10.1002/rth2.12794
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发表时间：
2022-08
影响因子：
4.6
通讯作者：
Yang, Renchi
中科院分区：
文献类型：
--
作者：
Liu, Wei;Lyu, Cuicui;Wang, Wentian;Xue, Feng;Chen, Lingling;Li, Huiyuan;Chi, Ying;Ma, Yueshen;Wu, Runhui;Fang, Yunhai;Zhang, Lei;Yang, Renchi
因子VIII （FVIII）抑制剂的发展是血友病a患者替代治疗期间的严重并发症。基于全基因组RNA测序和亚硫酸氢盐全基因组测序分析，我们研究了FVIII抑制剂形成的潜在危险因素。对17份F8内含子22倒置的血液样本进行了RNA测序和亚硫酸氢盐全基因组测序分析，其中7份含有抑制剂，10份没有。总共有344个mRNA转录本和20个长链非编码rna （lncRNA）转录本差异表达。在差异表达的转录本中，200个mrna和12个lncrna上调，144个mrna和8个lncrna下调。差异表达mrna的基因本体富集分析显示，与免疫刺激相关的基因，特别是与T细胞活化相关的基因，表达上调，而与免疫负性反应相关的基因表达下调。共表达分析显示，差异表达lncRNA的靶向上调基因与免疫激活，尤其是T细胞激活相似密切相关。甲基化分析显示，抑制剂患者在CpG岛、5 '非翻译区和外显子区域的甲基化状态略低（p < 0.01）。具有差异甲基化区域的基因也与T细胞活化有关。在A型血友病患者的抑制剂中，参与免疫系统激活的基因上调。lncRNA和甲基化修饰可能在抑制剂的产生中起重要作用。这些发现有可能揭示预防和治疗抑制剂的新治疗靶点。
The development of factor VIII (FVIII) inhibitor is a severe complication during replacement therapy for hemophilia A patients. We investigated the potential risk factors for FVIII inhibitor formation based on genome‐wide RNA‐sequencing and whole‐genome bisulfite sequencing analysis. RNA‐sequencing and whole‐genome bisulfite sequencing analysis were applied on 17 blood samples with F8 intron 22 inversion, including seven with inhibitors and 10 without. Altogether, 344 mRNA transcripts and 20 long noncoding RNAs (lncRNA) transcripts were differentially expressed. Among the differentially expressed transcripts, 200 mRNAs and 12 lncRNAs were upregulated, and 144 mRNAs and eight lncRNAs were downregulated. Gene ontology enrichment analysis of differentially expressed mRNAs showed that genes involved in immune stimulation, especially those for T‐cell activation, were upregulated, whereas genes involved in negative immune response regulation were downregulated. Coexpression analysis revealed that the targeted upregulated genes of differentially expressed lncRNA were similarly closely related to immune activation, especially T‐cell activation. Methylation analysis showed inhibitor patients exhibited a slightly lower methylation status in the CpG islands, 5′ untranslated region, and exon regions (p < 0.01). Genes with differentially methylated regions were also related to T‐cell activation. There is an upregulation of genes involved in activation of the immune system in hemophilia A patients with inhibitors. The lncRNA and methylation modifications may play important roles in inhibitor production. These findings are potentially to reveal novel therapeutic targets for prevention and treatment of inhibitors.
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影响因子：
6.7
作者：
Kroetz DN;Allen RM;Schaller MA;Cavallaro C;Ito T;Kunkel SL
通讯作者：
Kunkel SL
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Miggin, Sinead M.
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通讯作者：
Geha, Raif S.
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7.4
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通讯作者：
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20.3
作者：
Allacher, Peter;Baumgartner, Christina K.;Reipert, Birgit M.
通讯作者：
Reipert, Birgit M.