Stelma F, Jansen L, Sinnige M J, van Dort K A, Takkenberg R B, Janssen H L A, Reesink H W, Kootstra N A
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.
Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands.
J Viral Hepat. 2016 Aug;23(8):652-9. doi: 10.1111/jvh.12525. Epub 2016 Mar 4.
Current treatment for chronic hepatitis B infection (CHB) consists of interferon-based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA-C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA-C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa-2a + adefovir. Genotyping of killer immunoglobin-like receptors (KIRs) was performed by SSP-PCR. One SNP in HLA-C (rs2308557) was significantly associated with combined response in HBeAg-positive CHB patients (P = 0.003). This SNP is linked to the HLA-C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA-C2 was observed significantly more often in HBeAg-positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1-C2 predicted response independent of HBV genotype and ALT at baseline. HLA-C and KIR genotype is strongly associated with response in HBeAg-positive CHB patients treated with interferon-based therapy. In combination with other known response markers, HLA-C/KIR genotype could enable the selection of patients more likely to respond to interferon-based therapy.
慢性乙型肝炎感染（CHB）的当前治疗方法包括基于干扰素的疗法。然而，由于不明原因，很大一部分CHB患者对这种治疗无反应。因此，迫切需要建立反应标志物，以选择能从治疗中获益的患者，并使潜在的无反应者免受抗病毒治疗不必要的副作用。在此，我们评估了HLA-C和KIR基因型是否与CHB的治疗结果相关。对86例接受聚乙二醇干扰素α-2a +阿德福韦治疗的CHB患者（41例HBeAg阳性；45例HBeAg阴性）进行了HLA-C基因内部或附近12个单核苷酸多态性（SNP）的基因分型。通过序列特异性引物聚合酶链反应（SSP-PCR）进行杀伤细胞免疫球蛋白样受体（KIR）的基因分型。HLA-C中的一个SNP（rs2308557）与HBeAg阳性CHB患者的联合反应显著相关（P = 0.003）。该SNP与控制KIR结合的HLA-C组C1或C2分类相关。在联合反应的HBeAg阳性患者中，观察到KIR2DL1与其配体HLA-C2的组合明显多于无反应者（13/14比11/27，P = 0.001）。具有KIR2DL1/C2基因型的患者基线丙氨酸氨基转移酶（ALT）水平（136对50 U/L，P = 0.002）显著高于无此组合的患者。此外，KIR2DL1-C2预测反应独立于基线时的乙肝病毒（HBV）基因型和ALT。HLA-C和KIR基因型与接受基于干扰素疗法的HBeAg阳性CHB患者的反应密切相关。与其他已知的反应标志物相结合，HLA-C/KIR基因型能够更准确地选择可能对基于干扰素的疗法有反应的患者。
