Department of Science and Technology, The Hebei Key Laboratory of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Social Medicine and Health Care Management, Hebei Medical University, Shijiazhuang, China.
Cytokine. 2018 Mar;103:10-14. doi: 10.1016/j.cyto.2017.12.017. Epub 2017 Dec 26.
BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is a global health problem and the outcome are associated with both viral factors and host genetic factors. High Throughput Sequencing (HTS) technology were used to identify variants associated with liver disease.
Fifty-five Chronic hepatitis B (CHB) patients, fifty-three self-healing HBV (SH) patients and 53 healthy controls (HC) were recruited, 404 cytokine and cytokine receptor related genes were captured and sequenced at high depth (>900X), both variant (Fischer's exact test, P value < 0.05) and gene (SKAT-O gene level test, adjust P value < 0.05) level association were used to identify variants and genes associated with CHB.
Total 5083 variants have been detected, fifty-four variants were found associated with CHB, most (29/32) variants were located in HLA region, including HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DQB2, HLA-DRB1 and HLA-DRB5. Several missense variants were found associated with CHB, including p.E226K in PVR (poliovirus receptor), p.E400A and p.C431R in IL4R (interleukin 4 receptor). Four variants located in 3'UTR (untranslated region) have also been found associated with CHB.
Our study revealed that high through target region sequencing, combined with association analysis at variant and gene level, would be a good way to found variants and genes associated with CHB even at small sample size. Our data implied that chronic hepatitis B patients who carry these variants need intensive monitoring.
慢性乙型肝炎病毒（HBV）感染是一个全球性的健康问题，其结果既与病毒因素有关，也与宿主遗传因素有关。高通量测序（HTS）技术被用于鉴定与肝病相关的变异体。
招募了 55 名慢性乙型肝炎（CHB）患者、53 名自限性乙型肝炎（SH）患者和 53 名健康对照（HC），对 404 个细胞因子和细胞因子受体相关基因进行了高通量测序（深度>900X），采用变异体（Fisher 精确检验，P 值<0.05）和基因（SKAT-O 基因水平检验，调整 P 值<0.05）水平关联分析鉴定与 CHB 相关的变异体和基因。
共检测到 5083 个变异体，其中 54 个变异体与 CHB 相关，大多数（29/32）变异体位于 HLA 区域，包括 HLA-B、HLA-C、HLA-DQA1、HLA-DQB1、HLA-DQB2、HLA-DRB1 和 HLA-DRB5。还发现了几个错义变异体与 CHB 相关，包括 PVR（脊髓灰质炎病毒受体）中的 p.E226K、IL4R（白细胞介素 4 受体）中的 p.E400A 和 p.C431R。还发现了 4 个位于 3'UTR（非翻译区）的变异体与 CHB 相关。
我们的研究表明，即使在小样本量的情况下，通过高通量靶向区域测序，结合变异体和基因水平的关联分析，是发现与 CHB 相关的变异体和基因的一种很好的方法。我们的数据表明，携带这些变异体的慢性乙型肝炎患者需要进行强化监测。
