He Dengming, Tao Shiqi, Guo Shimin, Li Maoshi, Wu Junqiu, Huang Hongfei, Guo Xinwu, Yan Guohua, Zhu Peng, Wang Yuming
Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, Chongqing, China.
Liver Disease Diagnoses and Treatment Center of Chinese PLA, The 88th Hospital of Chinese PLA, Tai'an, Shandong Province, China.
Liver Int. 2015 Aug;35(8):1941-9. doi: 10.1111/liv.12756. Epub 2015 Jan 21.
BACKGROUND & AIMS: The toll-like receptor-interferon (TLR-IFN) signalling pathway plays a crucial role in HBV infection. Human leucocyte antigen (HLA) polymorphisms are associated with chronic HBV infection by genome wide association study (GWAS). We aimed to explore interaction between TLR-IFN and HLA gene polymorphisms in susceptibility of chronic HBV infection.
In the Chinese Southwest Han population, 1191 chronic HBV infection patients and 273 HBV clearance were selected. A total of 39 single nucleotide polymorphism loci in 23 genes of the TLR-IFN pathway and four HLA polymorphism loci associated with chronic HBV infection identified by GWAS were selected for genotyping. SNPStats, QVALUE, and multifactor dimensionality reduction were used for statistical analysis.
A significant association was seen in several of the TLR-IFN pathway genes, TLR9 rs352140 (OR = 0.70, P = 0.0088), IL1B rs16944 (OR = 0.67, P = 0.016), IL12B rs3212227 (OR = 1.38, P = 0.021), IFNGR1 rs3799488 (OR = 1.48, P = 0.0048), IFNGR2 rs1059293 (OR = 0.27, P = 0.011), MX1 rs467960 (OR = 0.68, P = 0.022), as well as four loci in HLA, rs3077 (OR = 0.55, P < 0.0001), rs2856718 (OR = 0.60, P = 4e-04), rs9277535 (OR = 0.54, P < 0.0001) and rs7453920 (OR = 0.43, P < 0.0001). A synergistic relationship was seen between rs9277535 and rs16944 (0.13%), rs1143623 and rs6613 (0.10%). The combination of rs9277535 in HLA and rs16944 in IL1B was the best model to predict chronic HBV infection (testing accuracy = 0.6040, P = 0.0010, cross-validation consistency = 10/10).
TLR-IFN pathway gene polymorphisms are associated with chronic HBV infection. Interactions with polymorphisms in these genes may be one mechanism by which HLA polymorphisms influence susceptibility to chronic HBV infection, as specific single nucleotide polymorphism combinations are highly predictive of chronic HBV infection.
Toll样受体-干扰素（TLR-IFN）信号通路在乙肝病毒（HBV）感染中起关键作用。通过全基因组关联研究（GWAS）发现，人类白细胞抗原（HLA）多态性与慢性HBV感染相关。我们旨在探讨TLR-IFN与HLA基因多态性在慢性HBV感染易感性中的相互作用。
在中国西南汉族人群中，选取1191例慢性HBV感染患者和273例HBV清除者。选择TLR-IFN通路23个基因中的39个单核苷酸多态性位点以及GWAS鉴定的与慢性HBV感染相关的4个HLA多态性位点进行基因分型。使用SNPStats、QVALUE和多因素降维法进行统计分析。
在多个TLR-IFN通路基因中发现显著关联，包括TLR9 rs352140（比值比[OR]=0.70，P=0.0088）、IL1B rs16944（OR=0.67，P=0.016）、IL12B rs3212227（OR=1.38，P=0.021）、IFNGR1 rs3799488（OR=1.48，P=0.0048）、IFNGR2 rs1059293（OR=0.27，P=0.011）、MX1 rs467960（OR=0.68，P=0.022），以及HLA中的4个位点，rs3077（OR=0.55，P<0.0001）、rs2856718（OR=0.60，P=4×10⁻⁴）、rs9277535（OR=0.54，P<0.0001）和rs7453920（OR=0.43，P<0.0001）。rs9277535与rs16944之间（0.13%）、rs1143623与rs6613之间（0.10%）存在协同关系。HLA中的rs9277535与IL1B中的rs16944组合是预测慢性HBV感染的最佳模型（检验准确性=0.6040，P=0.0010，交叉验证一致性=10/10）。
TLR-IFN通路基因多态性与慢性HBV感染相关。这些基因多态性之间的相互作用可能是HLA多态性影响慢性HBV感染易感性的一种机制，因为特定的单核苷酸多态性组合对慢性HBV感染具有高度预测性。
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