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目的探讨IL28B基因多态性与HBeAg阳性慢性乙型肝炎患者聚乙二醇化干扰素α(PEG-IFN)治疗应答的关系。方法采集212例接受PEG-IFN治疗48周的HBeAg阳性慢性乙型肝炎患者外周血,提取基因组DNA,应用时间飞行质谱技术(MassARRAY)检测IL28B基因的3个SNP位点rs12980275、rs12979860、rs8099917的多态性。应答定义为:PEG-IFN治疗48周,患者HBV DNA<200 IU/mL、HBeAg血清学转换及ALT复常。结果应答患者为74例,无应答者138例,应答率为34.9%。HBV基因分型以C型为主(C型117例,B型95例)。rs12980275基因型AA和N-AA(AG/GG)的比例分别为77.8%和22.2%;rs12979860基因型CC和N-CC(CT/TT)的比例分别为78.3%和21.7%;rs8099917基因型TT和N-TT(TG/GG)的比例分别为79.2%和20.8%。这3个SNP位点干扰素治疗应答组和非应答组中等位基因的频率和基因型的分布差异均有统计学意义(P<0.05)。在多因素分析中,校正了性别、年龄、HBV基因型、基线HBV DNA水平及基线ALT水平后,发现IL28B野生纯合基因型(AA、CC和TT型)是PEGIFN高应答率的独立预测因素。其中rs12980275基因型AA、N-AA的有效率分别为38.8%、21.3%(OR 2.70,95%CI1.21~6.01;P=0.015);rs12979860基因型CC、N-CC的有效率分别为38.6%、21.7%(OR 2.56,95%CI 1.15~5.67;P=0.021);rs8099917基因型TT、N-TT的有效率分别为38.7%、20.5%(OR 2.80,95%CI 1.23~6.39;P=0.015)。此外,还发现了一个由rs12980275和rs12979860组成的单体域,其中单体型A-C与干扰素高应答率显著相关(OR2.53,95%CI 1.20~5.34;P=0.015)。结论IL28B基因多态性与HBeAg阳性慢性乙型肝炎患者对PEG-IFN治疗的应答密切相关,IL28B野生纯合基因型(AA、CC和TT型)是PEG-IFN高应答率的独立预测因素。
Objective To investigate the relationship between IL28B gene polymorphism and peginterferon alfa (PEG-IFN) in HBeAg-positive chronic hepatitis B patients. Methods Genomic DNA was extracted from 212 patients with HBeAg-positive chronic hepatitis B treated with PEG-IFN for 48 weeks. Mass spectrometry (MassARRAY) was used to detect the polymorphisms of rs12980275, rs12979860 and rs8099917 in three SNPs of IL28B gene State. The response was defined as: 48 weeks of PEG-IFN treatment, with HBV DNA <200 IU / mL, HBeAg seroconversion and ALT normalization. Results There were 74 responders and 138 nonresponders, with a response rate of 34.9%. HBV genotypes are predominantly C (117 in type C and 95 in type B). The ratios of genotypes AA and N-AA (AG / GG) of rs12980275 were 77.8% and 22.2% respectively; the proportions of rs12979860 genotype CC and N-CC CT / TT were 78.3% and 21.7% And N-TT (TG / GG) were 79.2% and 20.8%, respectively. There were significant differences in allele frequency and genotype distribution between interferon treated and non-responder groups at the three SNP sites (P <0.05). In a multivariate analysis, gender-age, HBV genotype, baseline HBV DNA levels, and baseline ALT levels were corrected for IL28B wild homozygous genotypes (AA, CC, and TT) as independent predictors of high rates of PEGIFN . The effective rates of genotypes AA and N-AA of rs12980275 were 38.8% and 21.3% respectively (OR 2.70 and 95% CI 1.21 to 6.01; P = 0.015). The effective rates of rs12979860 genotype CC and N-CC were 38.6% (OR 2.56, 95% CI 1.15-5.67; P = 0.021). The effective rates of rs8099917 genotype TT and N-TT were 38.7% and 20.5% (OR 2.80 and 95% CI 1.23-6.39, P = 0.015). In addition, a single domain consisting of rs12980275 and rs12979860 was also found, in which haplotype A-C was significantly associated with high response rates to interferon (OR 2.53, 95% CI 1.20-5.34; P = 0.015). Conclusion The IL28B gene polymorphism is closely related to the response of patients with HBeAg-positive chronic hepatitis B to PEG-IFN treatment. The genotypes of IL28B homozygotes (AA, CC and TT) are independent predictors of high response rate of PEG-IFN.