hCNT1及MRP4基因多态性对慢性乙型肝炎核苷类似物抗病毒治疗应答的影响

目的 探讨人核苷转运蛋白1(hCNT1/SLC28A1)及多药耐药蛋白4（MRP4/ABCC4）基因多态性与治疗乙型肝炎核苷类似物药物恩替卡韦(ETV)及替比夫定(LdT)治疗慢性乙型肝炎的病毒学应答关系。 方法 136例慢性乙型肝炎患者分别采用ETV和LdT治疗（各68例），根据治疗后病毒学应答反应分为完全病毒应答（CVR）和原发部分应答（PPR）组，对两组患者的临床及病毒学检测结果进行分析，并采用多重单碱基延伸分型技术（Multiplex SNaPshot）检测两组初治患者hCNT1/SLC28A1基因4个位点（rs2242046, rs2242047, rs2290272, rs8187758），以及MRP4/ABCC4基因4个位点（rs2274407, rs3765534, rs11568658, rs11568668）的基因型及等位基因频率,比较两组患者的基因多态性。 结果 136例慢性乙型肝炎患者ETV和LdT治疗后PPR患者77例（56.6%），CVR患者59例（43.4%），两组基线乙型肝炎病毒（HBV）DNA载量、HBV基因分型及乙肝表面E抗原（HBeAg）阳性对抗病毒应答疗效差异均无统计学意义(P=0.148，P=0.622，P=0.071)。hCNT1/SLC28A1基因的rs2290272位点、MRP4/ABCC4基因的rs11568658位点基因型分布差异有统计学意义（P=0.043，P=0.049），其中rs2290272位点的等位基因频率差异有统计学意义(P=0.045)。单倍型分析发现，hCNT1/SLC28A1基因C/A/T/C组合及MRP4/ABCC4基因C/C/G/G组合中，CVR组高于PPR组（P=0.024，P=0.005）。 结论 hCNT1/SLC28A1基因的rs2290272 C/T和MRP4/ABCC4基因的rs11568658 G/G等位基因型会降低抗病毒疗效的应答。同时，单倍型C/A/T/C及C/C/G/G会提高核苷类似物ETV及TdL对乙肝病毒疗效的应答。

Effect of Human Concentration Nucleoside Transporters 1 and Multi-drug Resistance Protein 4 Gene Polymorphism on Response of Chronic Hepatitis B to Nucleoside Analogues Treatment

Objective To investigate the effect of human concentration nucleoside transporters 1(hCNT1/SLC28A1) and multi-drug resistance protein 4(MRP4/ABCC4) gene polymorphism on the response of chronic hepatitis B patients to nucleoside analogues treatment. Methods There were 136 patients of chronic hepatitis B treated with entecavir (68) or telbivudine (68). The allele and gene frequency distributing of the four loci of hCNT1/SLC28A1 and MRP4/ABCC4 as well as the polymorphisms were detected in all patients by multiplex snapshot single base extension method. Based on the treatment response, the patients were divided into primary partial response (PPR) group and complete viral response (CVR) group, hCNT1/SLC28A1 and MRP4/ABCC4 gene polymorphism between these two groups were analyzed. Results The rates of PPR and CVR were 56.6% (77/136) and 43.4% (59/136) respectively. There was no statistical difference in baseline HBV DNA value, hepatitis B virus genotype and HBeAg status between PPR and CVR groups (P=0.148, P=0.622,P=0.071) .The distribution of allelotype rs2290272 C/T and rs11568658 G/G in PPR group were higher than those in CVR [CM(155mm]group (P=0.043, P=0.049). Haplotype of C/A/T/C and C/C/G/G in CVR group were higher than those in PPR group (P=0.024,P=0.005). Conclusion The single nucleotide polymorphisms (SNPs) of two candidate genes, including rs2290272 C/T of hCNT1/SLC28A1 and rs11568658 G/G of MRP4/ABCC4, may weak the response of chronic hepatitis B to nucleoside analogues treatment, as well as haplotype of C/A/T/C and C/C/G/G may enhance the response.