Fitzmaurice Karen, Hurst Jacob, Dring Megan, Rauch Andri, McLaren Paul J, Günthard Huldrych F, Gardiner Clair, Klenerman Paul
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Nuffield Department of Medicine, University of Oxford, Oxford, UK Institute of Emerging Infection, The Oxford Martin School, University of Oxford, Oxford, UK.
Gut. 2015 May;64(5):813-9. doi: 10.1136/gutjnl-2013-306287. Epub 2014 Jul 4.
Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes.
This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3.
We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound.
Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A03 (OR 0.36 (0.15 to 0.89), p=0.027) -B27 (OR 0.12 (0.03 to 0.45), p=<0.001), -DRB101:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB104:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 'T' allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome.
This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.
慢性丙型肝炎病毒（HCV）感染是全球肝脏相关疾病的主要病因。先天免疫和适应性免疫反应被认为在决定病毒感染结果中起重要作用。与IFNL3（IL28B）基因相关的多态性与病毒的自发清除及治疗结果密切相关。
本研究探讨在与先天免疫基因IFNL3和KIR2DS3相关的基因变异背景下，人类白细胞抗原（HLA）基因的重要性。
我们评估了HLA和先天免疫基因对一组爱尔兰女性队列（n = 319）以及一个更具异质性的队列（瑞士队列，n = 461）中病毒感染结果的综合影响。在爱尔兰队列中，一些HLA等位基因与不同的感染结果相关，且IFNL3相关多态性的影响显著。
对爱尔兰队列的数据进行逻辑回归分析，结果显示HLA - A03（比值比[OR] 0.36[0.15至0.89]，p = 0.027）、- B27（OR 0.12[0.03至0.45]，p < 0.001）、- DRB101:01（OR 0.2[0.07至0.61]，p = 0.005）、- DRB104:01（OR 0.31[0.12至0.85]，p = 0.02）以及IFNL3 rs12979860基因型CC（OR 0.1[0.04至0.23]，p < 0.001）与病毒清除显著相关。此外，DQB1*02:01（OR 4.2[2.04至8.66]，p = 0.008）、KIR2DS3（OR 4.36[1.62至11.74]，p = 0.004）以及rs12979860 IFNL3的'T'等位基因与慢性感染相关。本研究未发现IFNL3与这些I类和II类等位基因在病毒清除方面存在交互作用。然而，存在明显的累加效应。瑞士队列的数据也证实了HLA I类、II类基因和IFNL3基因在预测病毒感染结果方面具有独立和累加效应。
该数据支持适应性免疫反应与先天免疫反应协同在控制HCV感染中起关键作用。
