Open AccessRisk factors for inhibitors in hemophilia A based on RNA ‐seq and DNA methylation
Author(s) -
Liu Wei,
Lyu Cuicui,
Wang Wentian,
Xue Feng,
Chen Lingling,
Li Huiyuan,
Chi Ying,
Ma Yueshen,
Wu Runhui,
Fang Yunhai,
Zhang Lei,
Yang Renchi
Publication year - 2022
Publication title -
research and practice in thrombosis and haemostasis
Language(s) - English
Resource type - Journals
ISSN - 2475-0379
DOI - 10.1002/rth2.12794
Subject(s) - biology , dna methylation , gene , methylation , cpg site , downregulation and upregulation , exon , microbiology and biotechnology , intron , rna , differentially methylated regions , gene expression , genetics
Background The development of factor VIII (FVIII) inhibitor is a severe complication during replacement therapy for hemophilia A patients. Objectives We investigated the potential risk factors for FVIII inhibitor formation based on genome‐wide RNA‐sequencing and whole‐genome bisulfite sequencing analysis. Methods 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. Results 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. Conclusions 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.