IL-21和IFN基因多态性与慢性乙型肝炎疗效血清学应答的关系
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摘要
目的探讨白细胞介素-21(IL-21)及其受体(IL-21R)和干扰素(IFN)基因多态性与乙型肝炎患者抗病毒治疗血清学应答的关系。方法 200例慢性HBV感染且抗病毒治疗3年患者(HBeAg血清学转换组50例,对照组150例),检测常规、生化和病毒学指标。MassArray技术检测200个样本IL-21及其受体和IFN相关15个位点单核苷酸基因多态性(SNP),并分析SNP与HBeAg血清学转换及HBsAg下降幅度间的关系。结果 15个位点中共7个HBeAg血清学转换阳性关联位点,分别是IL-21 rs12505138(A> G)、rs17005929(T> C)、rs6840978(C> T),IL-21R rs8057551(A> G)、rs8061992(C> A)、rs3093301(T> C)和IFNA rs1831391(A> C),以上7个位点在HBeAg血清学转换组中相应等位基因频率均显著高于对照组(均P <0.05)。其中IL-21 rs12505138、rs17005929和IFNA rs1831391为新发现的位点。126例继续原抗病毒药物治疗并完成48周随访患者数据提示携带IFNA17 rs1831391 CC基因型与HBsAg下降幅度独立相关(P=0.027,95%CI:-0.122~-0.008)。结论本研究发现7个HBeAg血清学转换阳性关联位点,包括3个新发现的位点,有助于预测乙型肝炎治疗中患者HBeAg血清学转换。
Objective To investigate the association of IL-21,IL-21R and IFN gene polymorphism with serological response in Hepatitis B patients with antiviral therapy.Methods 200 chronic HBV infection patients with three-year nucleoside analogue(NA)therapy were enrolled(HBeAg seroconversion group,50 cases;control group,150 cases).All patients were received blood cell count,biochemical indicators,virological index measurements.IL-21,IL-21R and IFN related SNPs gene polymorphism were detected using MassArray.Results A total of 7 HBeAg seroconversion associated SNPs were found,including IL-21 rs12505138(A>G),rs17005929(T>C),rs6840978(C>T),IL-21R rs8057551(A>G),rs8061992(C>A),rs3093301(T>C)and IFNA rs1831391(A>C).The frequency of IL-21 rs12505138 A allele and AA genotype,rs17005929 T allele and TT genotype,rs6840978 C allele,IL-21R rs8057551 A allele and AA genotype,rs8061992 C allele and CC genotype,rs3093301T allele,IFNA rs1831391 A allele and AA genotype in HBeAg seroconversion group was significantly higher than those in control group.Among them,IL-21 rs12505138,rs17005929 and IFNA rs1831391 had not been reported before.126 patients were completed 48 weeks of follow-up,and data showed the independent correlation between carrying IFNA rs1831391 CC genotype and HBsAg decline(β=-0.200,95%CI:-0.122~-0.008,P=0.027).Conclusion 7 HBeAg seroconversion which are positive associated SNPs,including 3 newly identified SNPs,may help predict HBeAg seroconversion in Hepatitis B patients with NA therapy.
Objective To investigate the association of IL-21,IL-21R and IFN gene polymorphism with serological response in Hepatitis B patients with antiviral therapy.Methods 200 chronic HBV infection patients with three-year nucleoside analogue(NA)therapy were enrolled(HBeAg seroconversion group,50 cases;control group,150 cases).All patients were received blood cell count,biochemical indicators,virological index measurements.IL-21,IL-21R and IFN related SNPs gene polymorphism were detected using MassArray.Results A total of 7 HBeAg seroconversion associated SNPs were found,including IL-21 rs12505138(A>G),rs17005929(T>C),rs6840978(C>T),IL-21R rs8057551(A>G),rs8061992(C>A),rs3093301(T>C)and IFNA rs1831391(A>C).The frequency of IL-21 rs12505138 A allele and AA genotype,rs17005929 T allele and TT genotype,rs6840978 C allele,IL-21R rs8057551 A allele and AA genotype,rs8061992 C allele and CC genotype,rs3093301T allele,IFNA rs1831391 A allele and AA genotype in HBeAg seroconversion group was significantly higher than those in control group.Among them,IL-21 rs12505138,rs17005929 and IFNA rs1831391 had not been reported before.126 patients were completed 48 weeks of follow-up,and data showed the independent correlation between carrying IFNA rs1831391 CC genotype and HBsAg decline(β=-0.200,95%CI:-0.122~-0.008,P=0.027).Conclusion 7 HBeAg seroconversion which are positive associated SNPs,including 3 newly identified SNPs,may help predict HBeAg seroconversion in Hepatitis B patients with NA therapy.
引文
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[9]GISH R G,LOK A S,CHANG T T,et al.Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B[J].Gastroenterology,2007,133(5):1437-1444.
[10]MARCELLIN P H E,BUTI M,GANE E,et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B[J].N Engl J Med,2008,359(23):2442-2455.
[11]GHANY M G.Current treatment guidelines of chronic hepatitis B:The role of nucleos(t)ide analogues and peginterferon[J].Best Pract Res Clin Gastroenterol,2017,31(3):299-309.
[12]姚佳燕,晁康,李敏睿,等.白细胞介素-21在慢性乙型肝炎病毒感染自然史不同阶段的表达分析[J].实用医学杂志,2015,31(7):1061-1064.
[13]LI N,ZHU Q,LI Z,et al.IL21 and IL21R polymorphisms and their interactive effects on serum IL-21 and IgE levels in patients with chronic hepatitis B virus infection[J].Hum Immunol,2013,74(5):567-573.
[14]FESTEN E A M,GIYETTE P,SCOTT R,et al.Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis[J].Gut,2009,58(6):799-804.
[15]GUO Y,ZHANG L,YANG T,et al.IL21R and PTH may underlie variation of femoral neck bone mineral density as revealed by a genome-wide association study[J].J Bone Miner Res,2010,25(5):1042-1048.
[2]GALMOZZI E,FACCHETTI F,GROSSI G,et al.IFNL4rs368234815 and rs117648444 variants predict off-treatment HBsAg seroclearance in IFN-treated HBeAg-negative chronic hepatitis B patients[J].Liver Int,2018,38(3):417-423.
[3]LIU X,SHEN Z,ZHANG H,et al.Interleukin-21 is associated with early antiviral response in patients with hepatitis B e antigen-positive chronic hepatitis B and nonalcoholic fatty liver disease[J].J Interferon Cytokine Res,2016,36(6):367-373.
[4]YAO J Y,CHAO K,LI M R,et al.Interleukin-21 gene polymorphisms and chronic hepatitis B infection in a Chinese population[J].World J Gastroenterol,2015,21(14):4232-4239.
[5]GAO Q J,XIE J X,WANG L M,et al.Interaction effects among IFN-γ+874,IL-2-330,IL-10-1082,IL-10-592 and IL-4-589 polymorphisms on the clinical progression of subjects infected with hepatitis B virus and/or hepatitis C virus:a retrospective nested case-control study[J].BMJ Open,2017,7(8):e013279.
[6]中华医学会肝病学分会.中华医学会感染病学分会.慢性乙型肝炎防治指南(2015更新版)[J].中华肝脏病杂志,2015,23(12):888-905.
[7]WANG F S,FAN J G,ZHANG Z,et al.The global burden of liver disease:the major impact of China[J].Hepatology,2014,60(6):2099-2108.
[8]RAZAVI-SHEARER D,GAMKRELIDZE I,NGUYEN M H,et al.Global prevalence,treatment,and prevention of hepatitis B virus infection in 2016:a modelling study[J].Lancet Gastroenterol Hepatol,2018,3(6):383-403.
[9]GISH R G,LOK A S,CHANG T T,et al.Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B[J].Gastroenterology,2007,133(5):1437-1444.
[10]MARCELLIN P H E,BUTI M,GANE E,et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B[J].N Engl J Med,2008,359(23):2442-2455.
[11]GHANY M G.Current treatment guidelines of chronic hepatitis B:The role of nucleos(t)ide analogues and peginterferon[J].Best Pract Res Clin Gastroenterol,2017,31(3):299-309.
[12]姚佳燕,晁康,李敏睿,等.白细胞介素-21在慢性乙型肝炎病毒感染自然史不同阶段的表达分析[J].实用医学杂志,2015,31(7):1061-1064.
[13]LI N,ZHU Q,LI Z,et al.IL21 and IL21R polymorphisms and their interactive effects on serum IL-21 and IgE levels in patients with chronic hepatitis B virus infection[J].Hum Immunol,2013,74(5):567-573.
[14]FESTEN E A M,GIYETTE P,SCOTT R,et al.Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis[J].Gut,2009,58(6):799-804.
[15]GUO Y,ZHANG L,YANG T,et al.IL21R and PTH may underlie variation of femoral neck bone mineral density as revealed by a genome-wide association study[J].J Bone Miner Res,2010,25(5):1042-1048.