A novel TRIM22 gene polymorphism promotes the response to PegIFNα therapy through cytokine-cytokine receptor interaction signaling pathway in chronic hepatitis B.
A novel TRIM22 gene polymorphism promotes the response to PegIFNα therapy through cytokine-cytokine receptor interaction signaling pathway in chronic hepatitis B.
复制标题
DOI：
10.1128/spectrum.02247-23
复制
发表时间：
2023-12-12
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
目的：聚乙二醇干扰素α（PegIFNα）治疗慢性B型肝炎（CH B）疗效有限。由于已知单核苷酸多态性（SNPs）可赋予疾病易感性并影响治疗反应，因此我们旨在鉴定与慢性乙型肝炎患者接受聚乙二醇干扰素α治疗后的疗效相关的新型含三联体基序的22（TRIM 22）SNPs。使用亚洲筛选阵列基因芯片对107例CHB患者的样本进行基因分型。通过细胞实验和RNA测序方法对筛选出的SNPs的相关机制进行了探讨。TRIM 22在用PegIFNα刺激后上调最多。具体而言，TRIM 22中的SNP rs 10838543 CC基因型被发现与对PegIFNα治疗的阳性应答相关。TRIM 22中SNP rs 10838543 CC基因型与TT基因型相比在HepAD 38细胞中更稳定且更稳健地抑制B型肝炎病毒（HBV）复制。从机制上讲，我们发现，与TT基因型相比，在PegIFNα处理后，稳定表达TRIM 22的SNP rs 10838543 CC基因型的HepAD 38细胞中，精氨酸-细胞因子受体相互作用信号通路显著上调，TRIM 22中的SNP rs 10838543 CC基因型通过诱导IFNL 1、CCL 3和CCL 5的分泌增强了PegIFNα诱导的抗HBV活性。TRIM 22中的SNP rs 10838543 CC基因型通过调节丝氨酸-细胞因子受体相互作用信号通路增加肝细胞分泌细胞因子IFNL 1、CCL 3和CCL 5，并与CHB患者中PegIFNα诱导的治疗应答呈正相关。我们的研究结果表明，CHB患者TRIM 22中SNP rs 10838543的基因分型可能是一种有用的生物标志物，可帮助医生识别最有可能从PegIFNα治疗中获益的患者。聚乙二醇干扰素α（PegIFNα）治疗慢性B型肝炎（CH B）疗效有限。尽管已经提出了许多与B型肝炎病毒（HBV）相关的生物标志物来对患者进行分层，但对聚乙二醇干扰素α的应答率仍不令人满意。在此，我们的数据表明，TRIM 22中的单核苷酸多态性（SNP）rs 10838543通过增加IFN L1、CCL 3和CCL 5的水平，增强了B e抗原阳性CH B肝炎患者对PegIFNα治疗的阳性临床应答。这些观察结果有助于指导CHB患者的治疗决策，以提高对PegIFNα的应答率。
Objectives: Pegylated interferon alfa (PegIFNα) has limited efficacy in patients with chronic hepatitis B (CHB). Because single-nucleotide polymorphisms (SNPs) are known to confer disease susceptibility and influence treatment response, we aimed to identify novel tripartite motif-containing 22 (TRIM22) SNPs that were associated with therapeutic efficacy in patients with CHB after PegIFNα treatment. Samples from 107 patients with CHB were genotyped using Asian Screening Array gene chips. The related mechanisms of SNPs screened were explored through both cell experiments and RNA sequence methods. TRIM22 was the most upregulated upon stimulation with PegIFNα. Specifically, the SNP rs10838543 CC genotype in TRIM22 was found to be associated with the positive response to PegIFNα treatment. The SNP rs10838543 CC genotype in TRIM22 was more stable and more robustly inhibited hepatitis B virus (HBV) replication in HepAD38 cells compared to the TT genotype. Mechanistically, we showed that the cytokine-cytokine receptor interaction signaling pathway was significantly upregulated in HepAD38 cells stably expressing the SNP rs10838543 CC genotype of TRIM22 compared to the TT genotype after PegIFNα treatment and that the SNP rs10838543 CC genotype in TRIM22 enhanced PegIFNα-induced anti-HBV activity by inducing the secretion of IFNL1, CCL3, and CCL5. The SNP rs10838543 CC genotype in TRIM22 increased the secretion of the cytokines IFNL1, CCL3, and CCL5 from hepatocytes by regulating the cytokine-cytokine receptor interaction signaling pathway and was positively correlated with the PegIFNα-induced treatment response in patients with CHB. Our findings suggest that genotyping patients with CHB for the SNP rs10838543 in TRIM22 may be a useful biomarker to help physicians identify patients who are most likely to benefit from PegIFNα treatment. Pegylated interferon alfa (PegIFNα) has limited efficacy in the treatment of chronic hepatitis B (CHB). Although many biomarkers related to hepatitis B virus (HBV) have been proposed to stratify patients, the response rate to PegIFNα is still unsatisfactory. Herein, our data suggest that the single-nucleotide polymorphism (SNP) rs10838543 in TRIM22 potentiates a positive clinical response to PegIFNα treatment in patients with hepatitis B e antigen-positive CHB by increasing the levels of IFNL1, CCL3, and CCL5. These observations can help guide treatment decisions for patients with CHB to improve the response rate to PegIFNα.
登录
查看更多内容
DOI：
10.1038/nri2413
发表时间：
2008-11
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Ozato K;Shin DM;Chang TH;Morse HC 3rd
通讯作者：
Morse HC 3rd
DOI：
10.3390/v9030056
发表时间：
2017-03-21
期刊：
Viruses
影响因子：
--
作者：
Hu J;Liu K
通讯作者：
Liu K
影响因子：
12.6
作者：
Choi, Hannah S. J.;van Campenhout, Margo J. H.;Janssen, Harry L. A.
通讯作者：
Janssen, Harry L. A.
Kir3Ds1/HLA-B Bw4-80lle 基因型与乙型肝炎 e 抗原阳性慢性乙型肝炎的 IFN-α 治疗反应相关
影响因子：
7.3
作者：
Li W;Shen X;Fu B;Guo C;Liu Y;Ye Y;Sun R;Li J;Tian Z;Wei H
通讯作者：
Wei H
影响因子：
24.3
作者：
Krug, Jasmin;Kiefer, Alexander;Finotto, Susetta
通讯作者：
Finotto, Susetta