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应答的关系

Relationship between IL28B gene polymorphisms and peginterferon alpha treatment response in patients with HBeAg-positive chronic hepatitis B

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rsl2980275、rsl2979860、rs8099917的多态性。应答定义为：PEG-IFN治疗48周，患者HBVDNA〈200Iu／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）。rsl2980275基因型AA和N—AA（AG／GG）的比例分别为77．8％和22．2％；rsl2979860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〈O．05）。在多因素分析中，校正了性别、年龄、HBV基因型、基线HBVDNA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PEG-IFN高应答率的独立预测因素。其中rsl2980275基因型AA、N—AA的有效率分别为38．8％、21．3％（OR2．70，95％CI1．21～6．01；P=0．015）；rsl2979860基因型CC、N—CC的有效率分别为38．6％、21．7％（OR2．56，95％CI1．15～5．67；P=0．021）；rs8099917基因型TT、N—TT的有效率分别为38．7％、20．5Voo（OR2．80，95％C11．23～6．39；P=0．015）。此外，还发现了一个由rsl2980275和rsl2979860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％CI1．20～5．34；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 whether IL28B polymorphisms could affect the peginterferon alpha （PEG- IFN） treatment response in patients with HBeAg positive chronic hepatitis B （CHB）. Methods A total of 212 HBeAg- positive GHB patients with PEG-IFN monotherapy were recruited in the study. We collected peripheral blood from patients and extracted their genomic DNA. Polymorphisn of IL28B gene SNPs, rs12980275, rs12979860 and rs8099917 were detected by using the Sequenom MassArray system. Response was defined as HBV DNA level 〈 200 IU/mL, HBeAg seroconversion and normal aminotransferase （ALT） levels after 48-week PEG-IFN treatment. Results 212 patients were infected with hepatitis B virus （HBV） genotype B （44.8%） and C （55.2%） with a total response rate of 34.9%. The proportions of IL28B genotypes were 77. 8% and 22. 2% for AA/N-AA （AG or GG） at rs12980275; 78.3% and 21.7% for CC/N-CC （CT or TT） at rs12979860; and 79.2% and 20. 8% for TT/N-TT （TG/GG） at rs8099917 respectively. For the three SNPs, there were significant differences between the response （R） and non- response （NR） groups both in allele frequencies and genotype distributions （P ~ 0. 05）. IL28B wild homozygous genotypes （AA, CC and TT） were independently associated with high rates of R. IL28B genotype was independently associated with R for AA versus N-AA （OR 2.70, 95 % CI l. 21-6.01 ; P = 0, 015） at rs12980275 after the adjustment of gender, age, HBV genotype, baseline levels of HBV DNA and ALT. There were similar results for rs12979860 CC versus N-CC （OR 2.56, 95% CI 1.15-5.67; P = 0. 021） and rs8099917 TT versus N-TT （OR 2.80, 95% CL 1.23- 6.39; P = 0. 015） respectively. Furthermore, one block formed by rs12980275 and rs12979860 was identified in this study. In multivariate analyses, the most common haplotype A-C was independently associated with high rates of R （OR 2.53, 95% CI 1. 20-5. 34; P = 0. 015）. Conclusion IL28B gene polymorphism was associated with the PEG-IFN treatment response to HBeAg positive CHB patients. IL28B wild homozygous genotypes （AA, TT and CC） were independently associated with high rates of R.