Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznań, Przybyszewskiego 49, Poland.
Department of Ophthalmology and Optometry, Poznan University of Medical Sciences, 60-780 Poznań, Grunwaldzka 16/18, Poland.
Vaccine. 2018 Jul 16;36(30):4454-4461. doi: 10.1016/j.vaccine.2018.06.034. Epub 2018 Jun 20.
Indoleamine 2,3-dioxygenase (IDO) contributes to maintaining immune homeostasis. Polymorphisms (SNPs) of the IDO encoding gene (IDO1) influence the IDO activity. Interferon (IFN)-λ3 induces IDO expression. We aimed to investigate whether IDO1 variants are associated with anti-HBs production in response to HBV vaccination or infection, interact with IFN-λ3 associated variants of IFNL4, and influence survival of hemodialysis (HD) patients. We also tested circulating IDO concerning IDO1 SNPs and plasma IFN-λ3 and anti-HBs levels.
The study included HD patients who had established status concerning responsiveness to HBV vaccination (n = 1022) or were exposed to HBV (n = 315). Ability to generate anti-HBs was diagnosed if anti-HBs after vaccination or infection exceeded 10 IU/L. Genotyping of IDO1 (rs3739319 A < G, rs9657182 C < T), IFNL4 rs8099917 G < T and IFNL4 rs12979860 C > T polymorphisms was carried out by high-resolution melting curve analysis. Circulating IDO and IFN-λ3 were measured with ELISA in 57 subjects. Survival probability was analyzed using the Kaplan-Meier method.
IDO1 SNPs did not correlate with the ability to produce anti-HBs after vaccination or infection. Anti-HBs titers, including a frequency of anti-HBs ≥ 1000 IU/l, also did not associate with IDO1 SNPs, but there was an epistatic interaction between rs9657182, rs8099917, and rs12979860 concerning anti-HBs titers (P = 0.028). Significant associations between IDO1 SNPs and circulating IDO were not demonstrated. Anti-HBs titers negatively correlated with plasma IDO (r = -0.358, P = 0.006), and positively with circulating IFN-λ3 (r = 0.498, P = 0.00008). IDO and IFN-λ3 did not correlate. Patients possessing the rs9657182 TT genotype showed higher infection-related mortality, also in multivariate analysis (HR 2.073, 1.221-3.518, P = 0.007).
IDO1 rs9657182, IFNL4 rs8099917, and IFNL4 rs12979860 show epistatic interaction concerning anti-HBs titers. Overreacting immune responses to HBsAg occur in patients with lower IDO but simultaneously higher IFN-λ3 levels. The rs9657182 TT genotype associates with infection-related mortality of HD patients.
吲哚胺 2,3-双加氧酶（IDO）有助于维持免疫稳态。IDO 编码基因（IDO1）的多态性（SNP）影响 IDO 活性。干扰素（IFN）-λ3 诱导 IDO 表达。我们旨在研究 IDO1 变体是否与乙型肝炎病毒（HBV）疫苗接种或感染后抗-HBs 的产生有关，是否与 IFN-λ3 相关的 IFNL4 变体相互作用，以及是否影响血液透析（HD）患者的存活。我们还检测了循环 IDO 与 IDO1 SNP 以及血浆 IFN-λ3 和抗-HBs 水平的关系。
该研究纳入了已确定对 HBV 疫苗接种有反应（n=1022）或已接触 HBV（n=315）的 HD 患者。如果接种疫苗或感染后抗-HBs 超过 10IU/L，则诊断出产生抗-HBs 的能力。通过高分辨率熔解曲线分析对 IDO1（rs3739319 A<G，rs9657182 C<T）、IFNL4 rs8099917 G<T 和 IFNL4 rs12979860 C>T 多态性进行基因分型。在 57 名受试者中，用 ELISA 法检测循环 IDO 和 IFN-λ3。采用 Kaplan-Meier 法分析生存概率。
IDO1 SNP 与接种或感染后产生抗-HBs 的能力无关。抗-HBs 滴度，包括抗-HBs≥1000IU/L 的频率，也与 IDO1 SNP 无关，但 rs9657182、rs8099917 和 rs12979860 之间存在与抗-HBs 滴度的上位性相互作用（P=0.028）。未显示 IDO1 SNP 与循环 IDO 之间存在显著相关性。抗-HBs 滴度与血浆 IDO 呈负相关（r=-0.358，P=0.006），与循环 IFN-λ3 呈正相关（r=0.498，P=0.00008）。IDO 和 IFN-λ3 不相关。携带 rs9657182 TT 基因型的患者感染相关死亡率更高，多因素分析也如此（HR 2.073，1.221-3.518，P=0.007）。
IDO1 rs9657182、IFNL4 rs8099917 和 IFNL4 rs12979860 与抗-HBs 滴度存在上位性相互作用。对 HBsAg 的过度免疫反应发生在 IDO 较低但同时 IFN-λ3 水平较高的患者中。rs9657182 TT 基因型与 HD 患者的感染相关死亡率有关。
